REVISION NOTES

FOR THE MRCOG

PART 1
The Library
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Revision Notes for the
MRCOG Part 1
This book is due for return on or before the last date shown below

20 pec 2014

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4B,
4
3

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4
3
Revision Notes for the
MRCOG Part 1
y

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:

Arisudhan Anantharachagan
Specialist Registrar in Obstetrics and Gynaecology
London Deanery
London

Ippokratis Sarris
Specialist Registrar in Obstetrics and Gynaecology
London Deanery
London
and
Honorary Research Fellow
Nuffield Department of Obstetrics and Gynaecology
University of Oxford
Oxford

Austin Ugwumadu
e

Consultant Obstetrician and Gynaecologist

St George's Healthcare NHS Trust
and
Honorary Senior Lecturer
St George’s University of London
London

Foreword by
Sabaratnam Arulkumaran
Professor and Head of Obstetrics and Gynaecology
St George’s University of London
St George’s Healthcare NHS Trust
London

OXFORD
UNIVERSITY PRESS
OXFORD
UNIVERSITY PRESS

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Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct.
Readers must therefore always check the product information and clinical procedures with the most up to date published
product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety
regulations. The authors and publishers do not accept responsibility or legal liability for any errors in the text or for the
misuse or misapplication of material in this work.
Foreword

The MRCOG part 1 has long been a challenging exam for doctors because a large number of basic
science topics need to be read and understood. This book consists of 13 chapters covering the basic
sciences needed. The applied knowledge required to practice obstetrics and gynaecology is interwoven
with the basics. Practice of obstetrics and gynaecology requires a sound knowledge of pathology,
immunology, microbiology, pharmacology, intrapartum screening, medical physics and its applications,
and research methodologies, and these subjects are comprehensively covered.
The chapters are well laid down with clear subdivisions explaining the essential topics in that
particular field. The chapter on genetics starts with molecular biology, moves on to cellular division
and replication, and finishes with chromosomal and genetic disorders. This complex subject is
explained using tables and figures to help candidates to understand it without difficulty.
Knowledge of embryology is essential to understand congenital malformations. Embryo-genesis,
and the formation of the placenta, foetal membranes, body cavities, and diaphragm are explained. The
development of every system in the body is related to applied clinical knowledge. The chapter on
anatomy deals with the relevant anatomy, i.e. the surface anatomy of trunk, abdomen, and pelvis,
followed by that of the gastrointestinal, urinary, and genital tract. Vascular, lymphatic, and neural
distribution for surgery is well-explained. Neuro-anatomy related to endocrine aspects and the rel-
evant areas of the fetal skull is also explained. The chapter on physiology deals with acid base balance
followed by the physiology of the various organs. Physiology of foetal and placental tissues and
changes in pregnancy are discussed.
Hormones influence the biochemistry of an individual. The chapter on biochemistry deals with the
structure of cells and the issues related to the metabolism of carbohydrates, fats, and proteins.
Endocrinology is intrinsically linked to the field of obstetrics and gynaecology and it has been dealt
with in detail, from sex hormones to hormones from the hypothalamus, pituitary, thyroid, and adrenal
glands. The others that play a role, such as the renin-angiotension system, pancreatic hormones, and
placental hormones in pregnancy, labour, puerperium, and lactation, are also dealt with in detail.
Inflammation, cellular adaption, cellular injury, wound healing, neoplasia, and issues relating to the
body in general, such as coagulation, sepsis, and shock are dealt with in the chapter on pathology
followed by specific issues related to the genital tract and disorders of pregnancy. Infection has a
major role to play in gynaecological diseases.
Microbiology has been dealt with in four sections: bacteria, fungi, protozoa, and viruses. Therapeutics
related to pregnancy and gynaecology are dealt with, including specific medication of analgesics,
antibiotics, anti-fungals, anti-virals, and anti-malarial drugs. Specific drugs used in pregnancy such as
uterotonics, anti-hypertensives, anti-epileptics, and anticoagulants are dealt with in detail. Contraceptives
are unique to our field and are explained in detail.
Intrapartum care is an area of major dissatisfaction and medical litigation. A basic understanding
of labour and intrapartum surveillance of the foetus is explained. It is important to understand the
basic physics related to ultrasound, ionizing radiation, and non-ionizing radiation, for the clinician's
practice and to provide explanations for patients if they have concerns about the use of this technology
a vi Foreword <

during pregnancy. Today’s research is the clinical practice of tomorrow. The clinician should
understand research methodology and the medical statistics used to interpret the results. This is
lifelong learning for good practice and is discussed in the final chapter.
It is credit to the authors of this book that they have condensed this vast area of knowledge into
what is necessary, leaving out non-essential reading. |would recommend this book to those preparing
for the MRCOG part 1 and for practicing clinicians as it presents the knowledge that forms the basis
of our clinical practice.
Sir Sabaratnam Arulkumaran
Professor & Head of Obstetrics & Gynaecology
St George’s University of London
18.4.11
Preface

Never regard study as a duty, but as the enviable opportunity to learn ... for your own
personal joy and to the profit of the community to which your later work belongs.
Albert Einstein, theoretical physicist (1879 -1955)

Learn, revise, practise; the triad of exam preparation. There are no shortcuts to knowledge and the
principles for success in any exam are the same. Royal College membership examinations are no
exception.
Most textbooks tend, by nature and out of necessity, to be verbose. Put simply, for one to under-
stand a topic it needs to be explained. For revision purposes, however, it is necessary only for the key
knowledge points to be present. This is where notes come in handy. Notes serve as a map of infor-
mation that needs to be remembered. The effectiveness and quality of note-taking methods are
highly variable. Inevitably some facts will not be identified during revision. This leads to lost points in
the exam and can make the difference between passing and failing. This book offers a backbone for
revision; ‘the perfect notes that one would make if they had all the necessary information and time
available to do so’. With the curriculum at its core (found at www.rcog.org.uk) it will provide you
with a guide to your revision. It is a high yield revision book that includes the knowledge and facts
needed to pass the MRCOG part 1 exam and brings together the required fundamentals of all the
basic sciences, Nevertheless, we would encourage you to annotate and draw in the margins of the
book, thus personalizing your ‘revision notes’ to suit your own needs and learning style. Effectively,
we would like you to turn it in to your very own ‘perfect’ aide memoire.
The book aims to be ‘user friendly’, making the task of finding and revising information easy. There
are sections covering each of the basic sciences required. Information is concise with facts presented
in visually easy to remember formats, such as boxes, flow diagrams, figures, and lists. Every piece of
information in the book can essentially be viewed as the equivalent of the answer to a potential exam
question. The dimensions of the book have been chosen specifically to allow it to be carried easily,
helping with revision even in the most unlikely places (such as a quiet on-call, in between patients in
theatre, on the train, or even the sofa!). Knowledge of the basic scientific principles that underpin
clinical conditions is a prerequisite to attaining true understanding of our specialty. To demonstrate
the relevance and applicability of the basic science knowledge, interspersed throughout the text are
cross-references to clinical practice that can be found in the next book of the series, Training in
Obstetrics and Gynaecology. Although not necessary for the MRCOG part 1 exam, this aims to encour-
age readers to retain the knowledge they have strived to acquire. This holistic approach will help
with the next stage: application of basic science to pathological processes, both in everyday clinical
practice and for the more pragmatic goal of passing the MRCOG part 2 exam in the future.
Our vision was to produce the book that we wished we had when we were revising for the
MRCOG part 1 exam. The team of authors has been especially assembled for the complementary
strengths and expertise that each brings. Arisudhanhas extensive experience as a candidate
passing college membership exams (he holds MRCOG, MRCS and MRCGP qualifications, all of which
require thorough basic science knowledge and a good exam technique). Ippokratis is the lead editor
of the successful and award-winning Oxford University Press title Training in Obstetrics and Gynaecology
and as such brings his experience in presenting information in a fresh and easy to assimilate manner.
Austin has a keen interest and breadth of knowledge with regards to basic sciences relevant to
obstetrics and gynaecology, and ran a popular and successful MRCOG part 1 course for some time.
Along with co-authoring this work, he is also the editor of the upcoming larger Oxford University
Press book Basic Science in Obstetrics and Gynaecology.
All of the authors love the specialty and we find particular interest in understanding and solving
problems from basic principles. We hope we can pass on some of that enthusiasm through these
pages. Although we aspired to deliver a faultless book, we appreciate that perfection is unattainable
and subjective. Any mistakes found lie with us. We encourage and would greatly appreciate readers
to write to us with any suggestions, corrections, and feedback for the future.

How to use this book

The book has a simple layout, with numbered and bulleted points, figures, boxes, and tables.
Interspersed throughout the book you will find in the margin of the pages two types of cross-

reference. The first one, denoted by the symbol and followed by a chapter number, is a cross-
reference to a chapter within this book. To avoid repetition, you are being directed to a chapter with
information relevant to the section next to which the cross-referencing symbol lies. The second type
To in

of cross-reference, denoted by the symbol on and followed by a chapter number, links the basic
science information found in this book to clinical practice that can be found in the next book of the
series, Training in Obstetrics and Gynaecology. Although this is not necessary information for the
MRCOG part 1 exam, you might find it a useful link between basic sciences and clinical practice for
your future career. Finally, this book contains a large amount of information and, as is inevitable in
medicine, abbreviations. A complete list of these can be found at the front of the book, which will
help refresh your memory if needed. We hope that you enjoy the book, and good luck with the
exam!

Acknowledgements

We would like to thank Fiona Goodgame and Christopher Reid for believing in our vision and com-
missioning the book, Katy Loftus, Sian Jenkins, and Lotika Singha for tirelessly helping with the prepa-
ration and production of the manuscript, the reviewers for helping improve the final content, the
countless corridor consultations with our colleagues and students, and finally our families and friends
for their selfless encouragement and support.

Arisudhan, Ippokratis, Austin

Contents

List of abbreviations xi

Ss Genetics 1
Embryology 15
Anatomy 51
Physiology 111
Biochemistry 177
Endocrinology 199
Pathology 227
Immunology 269
oo
NN
WwW
kh
uu
co
on Microbiology 283
= So Pharmacology 303
—_ —_ Intrapartum science 341
=N Medical physics and clinical applications 349
13 Research tools 369

Index 383
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List of abbreviations

1,25(OH),D, calcitriol/1,25- APTT activated partial thromboplastin

dihydroxycholecalciferol time
17B-HSD 17B-hydroxysteroid absolute risk
dehydrogenase acute respiratory distress
1°
primary syndrome
2,3-DPG 2,3-diphosphoglycerate antiretroviral therapy
25(OH)D, 25-hydroxycholecalciferol atrial septal defect
yh
secondary anterior superior iliac spine
oh
tertiary adenosine-5’-triphosphate
5-HT 5-hydroxytryptamine receptors alveolar ventilation
receptors atrioventricular
B-hCG B subunit of human chorionic atrioventricular node
gonadotropin
nr wavelength bis die (two times a day)
pm micrometre Bcl-2-associated death promoter
ug microgram arterial blood hydrostatic
yGy microgray pressure
pmol micromole Bacillus Calmette Guérin
AA amino acid B-cell lymphoma 2
Ab antibody blood hydrostatic pressure
ACE angiotensin converting enzyme bone mineral density
ACEi angiotensin converting enzyme body mass index
inhibitor blood oncotic pressure
Acetyl CoA acetyl coenzyme A blood pressure
Ach acetylcholine biparietal diameter
ACTH adrenocorticotropic hormone benign prostatic hypertrophy
ADEK vitamins A, D, E, and K beats per minute
ADH antidiuretic hormone becquerel
ADMA asymmetrical dimethylarginine breast cancer
ADP adenosine diphosphate bacterial vaginosis
AF atrial fibrillation venous blood hydrostatic
AFI amniotic fluid index pressure
AFP a.-fetoprotein
Ag antigen carbon atom
AIDS acquired immune deficiency coulomb
syndrome speed of sound
ALP alkaline phosphatase carbohydrate antigen
ANA antinuclear antibody calcium ion
ANOVA analysis of variance congenital adrenal hyperplasia
ANP atrial natriuretic peptide complete androgen insensitivity
ANS autonomic nervous system syndrome
APS antiphospholipid syndrome cyclic adenosine monophosphate
od xii List of abbreviations

compensatory anti-inflammatory DPG 2,3-diphosphoglycerate

response DPP dipeptidyl peptidase-4
category DPPC dipalmitoylphosphatidylcholine
corticosteroid binding globulin DSV dead space volume
cholecystokinin DVT deep vein thrombosis
carcinoembryonic antigen
cystic fibrosis exempli gratia
cystic fibrosis transmembrane oestrone
conductance regulator oestradiol
cervical glandular intraepithelial oestriol
neoplasia Epstein-Barr virus
cyclic guanosine monophosphate extracellular fluid
confidence interval electrocardiogram/
curie electrocardiography
cervical intraepithelial neoplasia ethylenediaminetetraacetic acid
chloride ion end-diastolic volume
centimeter of water ejection fraction
Cytomegalovirus epidermal growth factor
central nervous system extremely high frequency
carbon monoxide extractable nuclear antigens
cardiac output endothelial nitric oxide synthase
carbon dioxide erythropoietin
combined oral contraceptive pill endoplasmic reticulum
catechol-O-methyl transferase expiratory reserve volume
cyclo-oxygenase 1 erythrocyte sedimentation rate
cyclo-oxygenase 2 end-systolic volume
continuous positive airway
pressure frequency
corticotrophin-releasing hormone fragment antigen binding
crown-rump length flavin adenine dinucleotide
C-reactive protein reduced flavin adenine
cholesterol side chain cleavage dinucleotide
cerebrospinal fluid fragment crystallizable region
computed tomography Food and Drug Administration
cardiotocography fibrin degradation products
computed tomography forced expiratory volume in 1s
pulmonary angiogram free fatty acids
coefficient of variation fresh frozen plasma
central venous pressure fibroblast growth factor
Chest X-ray fetal growth restriction
’ . .

feedback inhibitor of lactation

diacylglycerol Fédération Internationale de
dichorionic diamniotic Gynécologie et d’Obstétrique
distal convoluted tubule FN false negative
dichlorodiphenyltrichloroethane FNR false negative rate
N, N-diethyl-meta-toluamide FP false positive
dual energy X-ray absorptiometry FPR false positive rate
dehydroepiandrosterone FRC functional residual capacity
dehydroepiandrosterone sulphate FSH follicle stimulating hormone
dihydrotestosterone FTA-ABS fluorescent treponemal antibody-
diabetes insipidus absorption
disseminated intravascular FVC forced vital capacity
coagulation
diiodotyrosine gram
decilitre glucose 6-phosphate
deoxyribonucleic acid dehydrogenase deficiency
 Listofabbreviations xiii oe

GABA y-aminobutyric acid lodide ion

GBS group B streptococcus id est
GDP guanosine diphosphate intramuscular
GFR glomerular filtration rate international units
GH growth hormone intravenous
GHRH growth-hormone-releasing iodine
hormone inspiratory capacity
giga hertz interferon
gastric inhibitory peptide immunoglobulin
gastrointestinal tract insulin-like growth factor
granulocyte-macrophage colony- immunohistochemistry
stimulating factor interstitial hydrostatic pressure
gonadotrophin-releasing interleukin
hormone inflammatory nitric oxide
guanosine-5’-triphosphate synthase
gray interstitial oncotic pressure
intrapleural pressure
hour(s) inositol triphosphate
hydrogen ion lonising Radiation Regulations
water inspiratory reserve volume
hydrogen peroxide intrinsic sympathomimetic activity
highly active antiretroviral idiopathic thrombocytopenic
therapy purpura
haemoglobin intrauterine contraceptive device
hepatitis B core antigen intrauterine system
hepatitis B e-antigen inferior vena cava
hepatitis B surface antigen in vitro fertilization
human chorionic gonadotropin intravenous urogram
hydrochloric acid
bicarbonate ion potassium ion
carbonic acid kilocalorie
high density lipoprotein kilodalton
hydroxysteroid dehydrogenase kilogram
haemolysis, elevated liver kilohertz
enzymes, low platelets potassium hydroxide
hepatitis virus kilopascal
human epidermal growth factor
receptor 2 ength
human immunodeficiency virus itre
human leucocyte antigen umbar vertebral level
3-hydroxy-3-methyl-glutaryl- ight amplification by stimulated
coenzyme A emission of radiation
hereditary non-polyposis actate dehydrogenase
colorectal cancer ow-density lipoprotein
human placental lactogen uteinizing hormone
hydrogen phosphate anion arge loop excision of the
human papillomavirus transformation zone
heart rate ow molecular weight heparin
hormone replacement therapy ogarithm with base 10
hydroxysteroid dehydrogenase ipopolysaccharide
heat-shock protein ikelihood ratio
human T-cell lymphotrophic lysergic acid diethylamide
virus
HUS haemolytic uraemic syndrome square metre
Hyper-PTH hyperparathyroidism membrane attack complex
Hz hertz monoamine oxidase
ae xiv _ List of abbreviations

MAO! monoamine oxidase inhibitor NNRTI non-nucleoside reverse

MAP mean arterial pressure transcriptase inhibitor
MCA middle cerebral artery NNT Number needed to treat
MCDA monochorionic diamniotic NO Nitric oxide
MCMA monochorionic monoamniotic NOS Nitric oxide synthase
MEN multiple endocrine neoplasia NPV Negative predictive value
mEq milliequivalent NRTI Nucleoside reverse transcriptase
milligram inhibitor
magnesium ion NSAID Non-steroidal anti-inflammatory
milligray drug
major histocompatibility complex Neural tube defect
megahertz Nucleotide reverse transcriptase
minute(s) inhibitor
Mullerian inhibiting substance
monoiodotyrosine oxygen
millilitre omni die (once a day)
milli-international unit odds ratio
millimole osmole
cubic millimetre
millimetres of mercury mathematical constant pi
multiple organ dysfunction pressure
syndrome plasminogen activator
mole plasminogen activator inhibitor
multiple organ system failure partial androgen insensitivity
milliosmole syndrome
magnetic resonance imaging prostatic acid phosphatase
messenger ribonucleic acid peripheral benzodiazepine
meticillin-resistant Staphylococcus receptor
aureus partial pressure of carbon dioxide
metres per second polycystic ovary syndrome
multiple sclerosis polymerase chain reaction
melanocyte stimulating hormone proximal convoluted tubule
milliSievert patent ductus arteriosus
millivolt platelet-derived growth factor
minute ventilation physiological dead space
pulmonary embolism
number of observations in a peak expiratory flow rate
sample pre-eclampsia
nitrogen molecule prostaglandin
sodium ion prostaglandin D
nicotinamide adenine prostaglandin dehydrogenase
dinucleotide prostaglandin E,
reduced nicotinamide adenine prostaglandin F,
dinucleotide prostacyclin
neodymium-doped yttrium negative logarithm (base 10) of
aluminium garnet hydrogen jon concentration
necrotizing enterocolitis protease inhibitor
net filtration pressure pelvic inflammatory disease
nanogram pulsatility index
ammonia negative logarithm (base 10) of
ammonium ion an equilibrium constant K
National Institute for Health and peripheral nervous system
Clinical Excellence partial pressure of oxygen
natural killer phosphate ion
nanometers pro-opiomelanocortin
NMDA N-methyl-b-aspartic acid progesterone-only pill
 List of abbreviations xv a

PPAR peroxisome proliferator-activated SPRM selective progesterone receptor

receptors modulator
PPH postpartum haemorrhage SROM spontaneous rupture of
PPI proton pump inhibitor membranes
PPV positive predictive value SRY sex determining region Y
PSA prostate-specific antigen SSRIs selective serotonin reuptake
PT partial thromboplastin time inhibitors
PTH parathyroid hormone STAN ST analysis
PTHrP parathyroid hormone-related STAR steroidogenesis acute regulatory
peptide START short-term antiretroviral therapy
PTT partial thromboplastin time STEAR selective tissue oestrogenic
PTU propylthiouracil activity regulator
paraventricular nucleus sievert
pulmonary vascular resistance stroke volume
superior vena cava
quartile systemic vascular resistance
quater die sumendus (four times
a day) tissue-type plasminogen activator
tension
radius tesla
resistance thoracic vertebral level
red blood cell ter die sumendum (three times
respiratory distress syndrome a day)
roentgen equivalent man triiodothyronine
resistance index tetraiodothyronine/thyroxine
ribonucleic acid triacylglycerol/triglyceride
receiver operator characteristic tuberculosis
renal plasma flow thyroid-binding globulin
rapid plasma reagin tricarboxylic acid cycle
relative risk tidal volume
respiratory rate transforming growth factor
ribosomal ribonucleic acid T-cell helper 1
reverse triiodothyronine T-cell helper 2
residual volume total iron-binding capacity
total lung volume
second(s) true negative
sacral vertebral level tumour necrosis factor
standard deviation true negative rate
subarachnoid haemorrhage true positive
sinoatrial node Treponema pallidum
Standard deviation haemagglutination assay
standard error of the mean Treponema pallidum particle
selective oestrogen receptor agglutination assay
modulator true positive rate
sex hormone-binding tartrate reabsorption alkaline
globulin phosphatase
Systéme international d’unités thyrotrophin-releasing
(International system of units) hormone
syndrome of inappropriate transfer ribonucleic acid
antidiuretic hormone transient receptor potential
hypersecretion cation channel, subfamily v,
systemic inflammatory response member 6
syndrome tuberous sclerosis complex
systemic lupus erythematosus thyroid-stimulating hormone
somatic nervous system thrombotic thrombocytopenic
superoxidase dismutase purpura
a0 xvi _ List of abbreviations ;

TTTS twin-to-twin transfusion VIN vulval intraepithelial neoplasia

syndrome VIP vasoactive intestinal peptide
TV tidal volume VMA vanillylmandelic acid
vsD ventricular septal defect
UA umbilical artery vWF von Willebrand factor
UHF ultrahigh frequency varicella zoster immune globulin
ULGLs uterine large granulolymphocytes varicella zoster virus
UO urine output
UTI urinary tract infection watts
UV ultraviolet weber
white blood cell
V/Q scan ventilation/perfusion scan mean
vc vital capacity
Vd volume of distribution observation
VDRL Venereal Disease Research mean
Laboratory (test)
VEGF vascular endothelial growth YST yolk sac tumour
factor
CHAPTER 1

Genetics

CONTENTS
Molecular biology 1
Cellular division and replication 4
Chromosomal abnormalities 6
Genetic disorders 10

Molecular biology

1. Nucleotides
@ Made up of
i. A sugar molecule
ii. A nitrogenous base
iii. A phosphate group
® Sugar molecule
i. Composed of 5 carbon atoms in a circular structure forming a pentose ring
= Deoxyribose in DNA
= Ribose in RNA
ii. Base is attached to carbon-1
iii. Phosphate is attached to carbon-5
@ Nitrogenous base: there are 2 types (Box 1.1)
i. Purines
ii. Pyrimidines
@ Base pairs
i. Cand G (3 hydrogen bonds)
ii, A and T/U (2 hydrogen bonds)

Box 1.1 Types of nitrogenous base

a ee
® Guanine -G ® Cytosine -C
® Adenine -A ® Thymine —T (only in DNA)
® Uracil —U (only in RNA)

2. Nucleic acids
® Long polymers of nucleotides
® Two types — DNA and RNA
Doe 2S apter 1 Genetics

DNA
i. Double-stranded helix held together by hydrogen bond
ii. Strands associate into pairs and run in opposite directions (anti-parallel)
iii, The sugar is deoxyribose and the pyrimidine is thymine
iv. DNA bond = phosphodiesterase (5’ — 3’)
v. Replication involves
= Unwinding of double-stranded DNA by DNA helicase, resulting in the formation of
2 DNA strands
™ Copying of DNA by DNA polymerase, using one strand as a template
= Winding back of the DNA strands by DNA ligase, when temperature drops (annealing)
RNA
i, 3 types
& mRNA = involved in transcription
= rRNA (ribosomal)
B tRNA (transfer) = involved in translation
ii. The sugar is ribose and the pyrimidine is uracil

3. Codons
Is genetic code
Is made of RNA
Consists of 3 sequential nucleotides
Is degenerate (i.e. more than 1 codon can specify the same amino acid but no codon
specifies more than 1 amino acid)
Total possible number of codons is 64 (because DNA contains 4 nucleotides)

4. Genes
Are a stretch of nucleotides that code for a polypeptide
Determine the amino acid sequence and therefore the function of a protein
Represent an inherited unit of information
Are made up of 2 regions
i, Exons (coding area)
= They code for the protein that the gene encodes
® The exon sequence is highly conserved between individuals
ii, Introns (non-coding areas)
= Length outweighs that of exons
= Not well conserved between individuals
= Spliced out during processing to mRNA ,

5. Chromosomes
Contained in nuclei
They are linear strands of DNA that contain genes, regulatory elements, and nucleotide
sequences
Are ‘H’ shaped consisting of 2 identical parts called chromatids held together by a
centromere (Fig. 1.1)
There are 22 homologous autosomal pairs and 1 pair of sex chromosomes
Size
i. Largest = chromosome 1
ii. Smallest = chromosome 22
Detected at metaphase
i. Identified by Giemsa staining
ii, Colchicine inhibits spindle formation
iii. EDTA inhibits deoxyribonuclease
 Molecular biology 3

® Structure
i, Arms
& Short =p
= Long=q
ii, Centromeres = the region where the two identical sister chromatids come in contact
® Based on the position of the centromere, the following types of chromosomes have been
described
i. Metacentric (i.e. the 2 arms of the chromosome are equal in length)
ii, Submetacentric
iii, Acrocentric
iv. Telocentric (do not exist in humans)
v. Holocentric (do not exist in humans)
® Can be classified into 7 groups (Box 1.2)

<q Centromere

Chromatid —__»

Figure 1.1 Structure of a chromosome

Box 1.2 Human chromosome groups

® Large ; © Large © Medium ® Medium

@ Metacentric © Submetacentric ® Submetacentrics ® Acrocentric

® Short ® Short ® Very short

® Submetacentric ® Metacentric ® Acrocentric

6. Protein synthesis
@ DNA is transcribed to mRNA (messenger RNA)
i. By RNA polymerase
ii. DNA strand is read in the 3’ > 5’ direction, mRNA is transcribed in the 5’ — 3’ direction
® mRNA is translated to amino acids
®@ Requires ribosomes

7. Polymerase chain reaction

® PCR amplifies selected areas in a DNA strand
®@ Does not work on RNA (would need to be converted to DNA first by the reverse
transcriptase enzyme)
@ Needs 3 components
i. 2 primers
 4 Chapter 1 Genetics

ii, 4 deoxynucleotides
iii, Taq polymerase
@ Logarithmic amplification

8. Blotting
® Northern = RNA
® Southern = DNA
® Western = Protein
i. Requires protein antibodies

9. Proteomics
Is the qualitative and quantitative comparison of proteins under different conditions to
further unravel biological processes
Involves separation using 2-dimensional gel electrophoresis (Box 1.3)

Box 1.3 Dimensions of gel electrophoresis

® Based on isoelectric point ® Based on size

© Voltage is applied along pH gradient © Voltage is applied perpendicular to the original

Cellular division and replication

1. Cell cycle
Is a series of events in a cell that lead to its division and replication
Has four phases (Fig. 1.2)
Interphase
i. Is part of cell cycle consisting of 3 phases (G1, G2, and S)
ii, Is nota phase in mitosis
Chromosome replication occurs only during S phase
i, Diploid = cells with pairs of homologous chromosomes
ii, Haploid = contains one member of each homologous pair of chromosomes
Proliferation genes
i, c-Myc
ii, c-Jun
Inhibiting gene
i, pgs

"S64 (se Gap)

M (Mitosis) $ (Synthesis)

G2 (2nd Gap)

Figure 1.2 Cell cycle phases

 Cellular division and replication 5

2. Stem cells
e Characterized by
i. Capacity for self-renewal over a prolonged period of time
ii, Potency
Potency is the capacity to differentiate into specialized cell types (Fig. 1.3)
Totipotent cells can differentiate into extra-embryonic and embryonic cell types

Pluripotent ~

Figure 1.3 Stem cell lineage

3. Mitosis
Is the process of cell division that results in the production of 2 identical daughter cells from
a single parent cell
Involves
i. Nuclear division
ii, Cytokinesis
Occurs exclusively in eukaryotic cells
Consists of 4 stages (Fig. 1.4)

Anaphase oe Telophase

Figure 1.4 Stages of mitosis

@ Prophase
i. Chromatins condense
ii, Centrosomes present close to nucleus
iii. A centrosome consists of a pair of centrioles
®@ Metaphase
i. Nuclei disappear
ii. Nuclear membrane disintegrate
iii. Centrioles migrate to both poles
iv. Mitotic spindles form
v. Chromosomes align at metaphase plate
e@ Anaphase
i. Kinetochore microtubules shorten separating the chromatids
ii. Kinetochore is the point on the chromosome where the mitotic spindles attach
@ Telophase
i. Chromosomes decondense
ii, Reformation of nuclear membranes
iii, Mitosis spindles disappear
iv. Is followed by cytokinesis

4. Meiosis
® sa type of cell division in which
i. Germ cells are produced
ii. 4 haploid daughter cells are produced from a single diploid parent cell
 6 Chapter 1 Genetics tyes

@ Involves
i. Reduction in genetic material
ii, 2 successive nuclear divisions
® Consist of2 stages (each stage has 4 phases)
i, Meiosis 1— separates homologous chromosomes producing 2 haploid cells
ii. Meiosis 2 —is similar to mitosis
® Meiosis 1 is a reductional division consisting of 4 phases (Fig. 1.5)

Metaphase 1 Anaphase 1 Telophase 1

Figure 1.5 Stages of meiosis 1

® Prophase1 involves (Fig. 1.6)

i. Pairing of homologous chromosomes (paired homologous chromosomes are called
bivalent)
ii. Crossing over of chromatids occur at chiasmata
iii. Migration of centrosome to both poles of the cell
iv. 3 phases
@ Metaphase 1— Homologous chromosome pairs align at metaphase plate
@ Anaphase 1 — Kinetochore microtubules shorten, separating the homologous chromosomes

Synchronous
Zygotene Pachytene
process (migration
‘(Pairing of (Chromosomal
Diplotene Diakinesis of centrosomes to
homologous cross-over occurs
opposite poles of
chrosomes occurs) in this stage)
the cell)

Figure 1.6 Stages of prophase 1

5. Genetic transfer is based on mendelian inheritance

® Derived by Gregor Mendel
t
@ Mendel’s Law has 2 principles
i, Law of segregation — states that each gamete receives only 1 allele for each gene
ii, Law of independent assortment — states that alleles of different genes assort
independently of one another during gametogenesis
® 4 models of inheritance
i. Autosomal dominant
ii. Autosomal recessive
ili, X-linked dominant
iv. X-linked recessive
v. Mitochondrial

Chromosomal abnormalities

Classification of chromosomal abnormalities

1. There are 2 types of chromosomal abnormalities
 Chromosomal abnormalities 7 oe

® Aneuploidy = change in number of chromosomes

i. Down's syndrome (trisomy 21)
ii, Edwards’ syndrome (trisomy 18)
iii, Patau’s syndrome (trisomy 13)
iv. Turner’s syndrome (monosomy X)
® Structural
i. Translocation
ii. Inversion
iii. Deletion (forms ring chromosomes)
iv. Duplication
v. Insertion

2. Mosaics is the presence of 2 or more genetically different cell lines derived from a single zygote

Examples of aneuploidies
1. Trisomies — general facts
@ Due to
i. Non-disjunction at meiosis 1 (>70%)
ii. Non-disjunction at meiosis 2
ili. Mosaicism (<5%)
® Increases with maternal age
The greater the number of extra chromosomes the greater the probability of learning
disabilities if the individual survives

2. Down’s syndrome
®@ Trisomy 21
®@ Prevalence is 1: 700 live births (the incidence is higher at conception; 80% undergo
spontaneous pregnancy loss)
® Dueto
i. Primary trisomy 21 (accounts for 95% of non-dysjunction at meiosis in maternal (85%) &
paternal (15%) cell line)
ii. Robertsonian translocation of chromosomes 14 : 21 (3%)
iii. Mosaicism (1%)
® Features
i. Raised nuchal translucency
ii. Dysmorphic features (small ears, upslanting palpebral fissures, flat facial profile,
brachycephaly)
iii. Hypotonia
iv. Cardiac abnormalities — arteriovenous (AV) canal defect
v. Gastrointestinal tract (GIT) abnormalities
®& Duodenal atresia
= |mperforate anus
® Hirschsprung’s disease
vi. Conductive hearing loss
® Increased risk of
i. Alzheimer’s disease
ii, Acute myeloid leukaemia/acute lymphoblastic leukaemia
Tin iii. Hypothyroidism
Syn ® Maternal age risk for Down’s syndrome
Chpt 6.12 i. 25 years old = 1: 1500
ii, 30 years old = 1; 900
iii. 35 years old = 1; 350
iv. 40 years old = 1; 100
 8 Chapter 1 Genetics

v. 45 years old = 1: 30
iii, 50 years old = 1: 11
iv. Cut-off for invasive screening = 1: 250

3. Edwards’ syndrome
@ Trisomy 18
@ Prevalence is 1 ; 3000 live births with a male to female ratio of 1:2
@ Features
i. Increased nuchal translucency
ii. Musculoskeletal defects
= Limb defects
B Rockerbottom feet (convex bottom of foot with projecting heel)
= Overlapping fingers
ili. Facial defects
= Micrognathia
# Cleft lip
= Cleft palate
iv. Cardiac defects
= Ventricular septal defect (VSD)
= Atrial septal defect (ASD)
@ Patent ductus arteriosus (PDA)
v. Abdominal defects
= Exomphalos
= Inguinal hernia
= Diaphragmatic hernia
B® Renal malformations
vi. Intrauterine growth restriction
® Mortality rates
i. By 1 month = 30%
ii. By 2 months = 50%
iii. By 1 year = 90%

4, Patau’s syndrome
® Trisomy 13
@ Prevalence is 1 : 5000 live births
® Incidence increases with maternal age
@ Features '
i, Midline defects
= Hypotelorism (abnormally decreased distance between the eyes)
Holoprosencephaly (failure of the prosencephalon to develop into 2 hemispheres)
Cleft lip
Cleft palate
Scalp defects
ii. Post axial polydactyly
iii. Congenital heart defects
iv. Renal abnormalities
v. Omphalocele
vi. Intrauterine fetal growth restriction
© Mortality rates is almost 100% by 1 month of age

5. Sex chromosome aneuploidies

® Incidence in
i, Males = 1: 400
ii, Females = 1: 600
 Chromosomal abnormalities 9

® Includes
i. Klinefelter’s syndrome (47, XXY)
ii, Turner’s syndrome (45, X0)
6. Lyon’s hypothesis
®@ Barr body
i. Is inactivated X chromosome
ii, Present if >2 X chromosomes in a cell
& ® Inactivation of 1X chromosome occurs in females at 15-16 days gestation
: 7. Turner’s syndrome
Chpt 2.7 ® Monosomy 45, XO
® Prevalence = 1: 2500 female live births
® Features
i, Raised nuchal translucency
ii. Cystic hygroma
iii, Lymphoedema
iv. Neck webbing
vy. Short stature
vi. Wide carrying angle of arm
vii, Shield shaped chest with widely spaced nipples
viii. Coarctation of aorta
ix. Gonadaldysgenesis
x. Renal anomalies including horseshoe kidney
® Intellectually normal
® Risk of gonadoblastoma
8. Klinefelter’s syndrome
@ 47, XXY
®@ Incidence = 1: 1000 live births
® Features
i. Tall
ii. Small testes with hypogonadotrophic hypogonadism
iii. Infertility

Examples of structural chromosome abnormalities

1. Translocation
® |s the exchange of 2 segments of chromosome between non-homologous chromosomes
@ 2 types
i. Balanced (an even exchange of material with no excess or loss of genetic material)
ii, Unbalanced (unequal exchange of genetic material resulting in extra or missing genes)
®@ Robertsonian translocation results from fusion of the long arms of 2 acrocentric
chromosomes
2. Deletion (Box 1.4)
Box 1.4 Examples of syndromes due to structural chromosomal abnormalities caused by deletion

: : Angelman Prader-Willi
Velocardiofacial (DiGeorge) 15qi 1-13 15q11-13

aan Maternal deletion Paternal deletion

@ Immune deficiency ® Happy disposition @ Obese
® Parathyroid dysfunction causing ® Macroglossia © Hypogonadism
hypocalcaemia © Ataxia ® Hypotonia
@ Autism ® Seizures
® Congenital heart disease ® Learning difficulties
® Cleft lip + palate
a 10 Chapter 1 Genetics

aaa enn ems Daan alee

a

Genetic disorders

Types of genetic disorders

ile Genetic disorders consist of 3 types
@ Autosomal
i. Autosomal dominant
ii. Autosomal recessive
@ Sex linked
® Mitochondrial

Autosomal dominant
@ Males and females affected equally
Inheritance = 1:2
New mutations are common
Has features of variable expressivity and reduced penetrance
Include
i. Myotonic dystrophy
ii, Huntington’s chorea
iii, Achondroplasia
iv. Neurofibromatosis types 1 and 2
v. Tuberous sclerosis—
vi. Familial polyposis coli
vii. Marfan’s syndrome
viii. Osteogenesis imperfecta
ix. Polycystic kidney disease
x. Porphyria
xi. von Willebrand’s disease
NOORAA'S
Autosomal recessive
® Both parents must be carriers
® Inheritance = 1:4
® tis not possible to trace autosomal recessive conditions via the family tree
® Includes
i. Cystic fibrosis (CF)
ii, Sickle cell disease
iii, Thalassaemia nine assoy > 13 | e
) phenylala
iv. Phenylketonuria
v. Glycogen storage disorders
vi. Congenital adrenal hyperplasia
vii, Wilson’s disease

X-linked recessive
® Inheritance = 1: 2 sons of carrier females
® Daughters of all affected males are carriers
® No male to male transmission
© Shows a knight’s move pattern of transmission (i.e. any male grandchildren of affected male
would be at risk)
® Includes
i, Duchenne muscular dystrophy
ii, Fragile X syndrome
iii, Red-green colour blindness
iv. Glucose 6-phosphate dehydrogenase (G6PD) deficiency
 Genetic disorders 11

v. Christmas disease (factor XI deficiency)

vi. Haemophilia A & B (factor VIII & IX deficiency)
vii. Neurogenic diabetes insipidus
viii. Lesch-Nyhan syndrome
ix, Wiskott—Aldrich syndrome
x. Agammaglobulinaemia

5. X-linked dominant
® Inheritance = 1: 2 offspring of affected females
® Often manifest very severely in males, frequently leading to spontaneous loss or neonatal
death of affected male pregnancies
@ Includes
i. Incontinentia pigmenti
ii, Rett syndrome
iii. Vitamin D resistance rickets

6. Mitochondrial
® Mitochondrial DNA is inherited through the maternal line because sperm do not contribute
to the zygote beyond their nuclear DNA
® A mitochondrially inherited condition can affect both sexes but is only passed on by affected
mothers
@ Includes
i. Leber’s hereditary optic neuropathy
ii. Leigh’s syndrome

Examples of genetic disorders

ra j \ feytt
rite fe ‘ Ver \eee
1. Tuberous sclerosis ~ (| '

® lsarare multisystem genetic disease that causes tumours to grow in the brain and other
vital organs
® Js caused by mutation of either
i. TSC1 gene (encodes for protein hamartin) — located on chromosome9
ii, TSC2 gene (encodes for the protein tuberin) — located on chromosome 16
Hamartin and tuberin are suppressors of tumour growth '
Features
i, Learning difficulties
ii. Epilepsy
iii. Cardiac rhabdomyomas
iv. Renal angiomyolipomas
v. Skin manifestations
® Angiofibromas (rash manifesting in ‘butterfly’ distribution over nose, nasolabial folds,
and cheeks)
= Hypomelanotic macules (‘ash-leaf spots)
= Shagreen patches (discoloured leathery patches of skin)
= Ungual fibromas
vi. Brain abnormalities
= Subependymal nodules
=" Cortical tubers

2. Cystic fibrosis aulosom A recess

@ |sa disease of exocrine secretion
®@ Increased chloride in sweat
@ Prevalence is 1: 2000
@ Carrier rate in Caucasians = 1: 23
 12 Chapter 1 Genetics

Is caused by a mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) gene
CFTR gene
i. Is located on chromosome 7
ii. Produces a chloride ion protein, which is responsible for anion transport
iii, There are over 1400 mutations that can affect the CFTR gene
iv. Most common mutation of CFTR gene is AF508 occurring in 70% of cases
Chloride ion channel regulates the movement of chloride ions from inside to outside of the
cell except in the sweat ducts, where it facilitates chloride movement from sweat to
cytoplasm
@ Hallmark of CF is viscid (excessive) mucus production, which blocks the ducts of mucus-
secreting organs leading to
i. Recurrent chest infections
ii, Poor alveolar gas exchange
iii. Infertility
iv. Pancreatitis
v. Cirrhosis
vi. Intestinal obstruction
vii. Malabsorption (require supplementation with the fat soluble ADEK vitamins)
viii. Osteoporosis
ix. Diabetes
® Infertility is due to
i. Congenital absence of vas deferens in males
ii. Thickened cervical mucus in females
Toin

G3. Sickle cell disease (HbS)

pt 7.22 ® ls caused by a point mutation in the B-globin chain of haemoglobin
wm al @ Isduetoa single base change (adenine (GAG) is substituted with thymine (GTG)) causing
fe glutamic acid to be replaced by valine
i. Glutamic acid is hydrophilic
ii, Valine is hydrophobic
@ Prevalence in London = 1: 500
® Two types
i. Homozygous = HbSS
ii. Heterozygous = HbAS
® Causes loss of red blood cell due to loss of (RBC) elasticity and sickling
Disruption of RBC membrane causes short life span of RBC (10-20 days)
® Anaemia is caused by haemolysis of RBC by spleen (rate of haemolysis > rate of RBC
production)
® Complications (Box 1.5)
®@ Types of sickle crisis
i, Vaso-occlusive crisis
ii. Acute chest syndrome (fever, chest pain, difficulty breathing, and pulmonary infiltrates
on chest radiograph (CXR))
iii. Aplastic crisis (triggered by parvovirus B19)
iv. Splenic sequestration crisis
v. Haemolytic crisis (common in patients with coexisting G6PD deficiency)
© Blood film shows sickling of RBCs and may show features of hyposplenism (codocytes and
Howell-Jolly bodies)
© Treatment
i. Cyanate (irreversibly inhibits sickling of RBCs)
ii. Hydroxyurea (reactivates fetal haemoglobin production)
iii, Analgesics
 Genetic disorders 13

iv. Penicillin
v. Vaccinate for encapsulated organisms (Haemophilus influenza, Streptococcus pneumoniae,
and Neisseria meningitides)
vi. Blood transfusion and exchange transfusion
vii. Bone marrow transplant

Box 1.5 Complications of sickle cell disease

=® Hyposplenism
oo
@ Stroke e Avascular necrosis of
| ® Jaundice
® Autosplenectomy ® Pulmonary head of femur ® Cholelithiasis
hypertension ® Chronic renal failure

=® Osteomyelitis
oa
@ Fetal growth
® Overwhelming post- restriction (FGR)
splenectomy infection © Pre-eclampsia
© Miscarriage

4. Thalassaemia
®@ Results in reduced rate of synthesis of 1 of the globin chains that make haemoglobin (Hb)
Chpt 7.21 ® Types
i. O-— production of « chain affected
ii, B — production of B chain affected
iii. 6 — production of 6 chain affected
iv. E thalassaemia (similar to B thalassaemia)
v. S thalassaemia (similar to sickle cell anaemia)
vi. C thalassaemia
@ Prevalent in
i. Mediterranean
ii, Arab
iii. Maldives — has the highest incidence of thalassaemia in the world
® Haematological consequences (anaemia) in thalassaemia is due to
i. Hypochromia (i.e. low intracellular haemoglobin)
ii, Excess of unimpaired chain — leads to cell membrane damage and reduced RBC survival
time
@ RBC morphological abnormalities on blood film include
i. Anisocytosis
ii, Poikilocytosis
iii. Microcytosis
iv. Hypochromia
v. Target cells
vi. Basophilic stippling
vii. Fragmented RBCs

5. a-thalassaemia
® Severity depends on the number of a-globin gene affected (there are 4)
i. Silent carrier (1 gene affected)
ii, Trait (2 genes affected) — associated with mild hypochromic anaemia
iii, Haemoglobin H disease (3 genes affected) — leads to moderate anaemia with
splenomegaly
a 14. Chapter 1 Genetics

iv. Bart's hydrops (4 genes affected) — causes in utero death

® Clinical features include
i. Tissue hypoxia
ii. Hydrops fetalis
® In fetus
i. Initial survival is due to haemoglobin Portland
ii. Fetal distress is noted after 12 weeks when haemoglobin Portland is replaced by
haemoglobin Barts
® Haemoglobin H and Barts have an extreme high affinity for oxygen and thus inhibit delivery
of oxygen to tissues

6. f-thalassaemia
® Prevalence in
i, UK=1: 10000
ii. South Asia = 3: 100
iii. Cyprus = 1:7
®@ Has 3 classifications
i. Major = genetically homozygous for B-thalassaemia gene
ii. Minor/trait = genetically heterozygous
iii. Intermedia = genetically heterozygous
® Clinical features include
i. Fatigue
ii, Anaemia
iii. Jaundice
iv. Shortness of breath
v. Skeletal deformities due to increased erythropoiesis
vi. Hepatosplenomegaly due to extramedullary haematopoiesis
vii. Haemochromatosis due to excess iron absorption from the gut
viii. Delayed physical and sexual development due to haemochromatosis
@ Infants born with B-thalassaemia will usually presents with symptoms from 6 months of age
when fetal haemoglobin is replaced by adult haemoglobin
© Treatment for B-thalassaemia major
i, Regular blood transfusion
ii. Folic acid supplementation
iii. Vitamin D and calcium supplementation
iv. Chelation therapy (desferrioxamine) to remove excess iron from the body following
repeat transfusions ;
v. Splenectomy
vi. Bone marrow transplant
vii. Cord blood transfusion
 CHAPTER 2
————————EE

Embryology

CONTENTS Gastrointestinal system 33

Embryogenesis 15 Urinary system 37
Placenta and fetal membranes 19 Reproductive system 38
Body cavities and diaphragm 24 Nervous system 43
Musculoskeletal system 26 Face and neck development 46
Respiratory system 28 Eye development 49
Cardiovascular system 29 Ear development 50

Embryogenesis

1. Definitions
e@ Zygote is a fertilized ovum
® Embryo = 2-8 weeks following fertilization
@ Fetus = 9 weeks to term

2. Chronology post fertilization

@ Fertilization
i. Occurs at the ampulla of the fallopian tube
ii, Occurs 12 hours post ovulation
@ Second meiotic division is complete following fertilization
Chpt 1 ® First mitotic division is complete at 30 hours post fertilization

3. Chronology in the 1st week of life (Fig. 2.1)

@ Day 2 —zygote (2 cell) stage
@ Day 3
i. Morula (16 cell) stage
ii, Reaches uterine cornu
@ Day 4 » embi yoplasr who
i. Blastocyst stage propo as ne anno p last
ii, Enters uterine cavity gh Aes
@ Day 6-—implantation begins

4. Blastocyst
® |s composed of
i. An inner cell mass (known as embryoblast) — which later forms the embryonic tissues
ii, An outer layer of cells (known as trophoblast) — which later forms the extra-embryonic
tissues, e.g. placenta
 16 Chapter 2 Embryology cae

© Comprises 70-100 cells

® Has a fluid-filled cavity known as blastocoele
@ Prior to gastrulation the trophoblast differentiates into 2 cell lineages
i. An outer syncytium (also known as syncytiotrophoblast)
ii, An inner layer of cytotrophoblast

*Zygote (2 cell) *Morula (16 cell) *Blastocyst stage *|mplantation

stage stage Enters uterine begins
*Reaches uterine cavity
cormua

Figure 2.1 Chronology of fetal development in the 1st week of life

* Decidual *Lacunar stage * Lacunae «lmplantation is

reactions occurs * Exocoelomic formation complete
* Bilaminar disc membrane forms + Extra-embryonic «Primary chorionic
forms mesoderm villi form
* Amniotic cavity appears * Chorionic cavity
forms | * Extra-embryonic appears
coelom forms ¢ Uteroplacental
circulation begins
i

Figure 2.2 Chronology of fetal development in the 2nd week of life

5. 2nd week of development (Fig. 2.2)

© Day 8
i. Decidual reaction occurs
ii. Implantation initiates decidualization of the endometrial stroma
iii. Formation of embryonic bilaminar disc
iv. Amniotic cavity develops within the epiblast
® Bilaminar disc is derived from the inner cell mass (embryoblast) and is composed of
i, Epiblast (i.e. the dorsal germinal layer)
ii. Hypoblast (i.e. the ventral germinal layer)
® Day9
i, Lacunar stage begins '
ii, Hypoblast forms the exocoelomic (Heuser’s) membrane that lines the yolk sac
@ Day 12
i. Formation of lacunae in syncytiotrophoblast, which communicate with endometrial
sinusoids
ii, Extra-embryonic mesoderm (derived from yolk sac cells) forms
iii. Extra-embryonic coelom forms
= Also known as chorionic cavity
= Formed by lacunae which appear within the extra-embryonic mesoderm (between
the exocoelomic membrane and cytotrophoblast) that merge
@ Day 13
i. Implantation complete
ii, Cytotrophoblast forms primary chorionic villi
iii. Yolk sac is called the secondary yolk sac due to the presence of the chorionic cavity
iv. Syncytiotrophoblast secretes hCG
y. Uteroplacental circulation begins
 Embryogenesis 17

® Connecting stalk
i. Connects embryo to cytotrophoblast
ii. Derived from extra-embryonic mesoderm
iii, Is the forerunner of the umbilical cord

6. 3rd week of development (Fig. 2.3)

® Day 15
i. Primitive streak appears at the caudal end
= ot
ii, Primitive node appears at the cephalic end of the streak (cra
iii. Ectodermal cells migrate towards the streak and then detach from it, spreading out
laterally and beneath it to form the intra-embryonic mesoderm
® Intra-embryonic mesoderm lies between the ectoderm and endoderm, except in two
locations where the ectoderm meets the endoderm
i. Prochordal plate (buccopharyngeal membrane)
ii. Cloacal plate
@ Buccopharyngeal membrane breaks down at 4th week
® Cloacal membrane breaks down at 7th week
®@ Notochord formation
i. Cells from primitive node migrate cranially towards prochordal plate
ii. This forms the notochordal plate which becomes the future notochord
®@ Day 16
i. Allantois (allantoenteric diverticulum) appears
ii, Allantois is the diverticulum that forms from the posterior wall of the yolk sac and
extends into the connecting stalk
@ Neurulation
i. Process of formation of brain and spinal cord
ii. Neural plate is formed at day 18
@ Primitive heart tube forms at day 20
® First heart beat is noted at day 21

* Primitive streak * Neurulation “| © First pair of

and node forms occurs (neural / somites form
* Gastrulation plate forms) coelom forms Primitive heart
starts tube forms
*Intra-
embryonic
mesoderm
forms
* Notochord
forms

Figure 2.3 Chronology of fetal development in the 3rd week of life

7. Gastrulation
@ ls the formation of the 3 germ layers
® Occurs in the 3rd week of development
®@ Ectoderm gives rise to intra-embryonic mesoderm
© Components derived from the ectoderm, mesoderm, and endoderm are listed in Box 2.1

8. Embryo folding
® Occurs in 2 planes
i. Longitudinal (due to enlargement of cranial end)
ii. Transverse (due to enlargement of somites)
® Occurs from day 21-24
 18 Chapter 2 Embryology

Box 2.1 Components derived from the ectoderm, mesoderm, and endoderm

TI
i
® Epidermis ® Muscles e GIT
® Nervous system ® Skeletal system © Respiratory tract
® Connective tissues ® Endocrine glands
© Auditory system
© Urinary system

9. Fetal development from week 4 to 7 (Fig. 2.4)

Week 4 Week 5
Day 22-28 Day 29-35

* Septum primum + Lens pit and optic + Lungs begin to form + Fetal heart tone
appears cups form + Lymphatic system audible
+ Branchial arches + Nasal pits form begin to form * Nipples form
form * Leg buds form * Gonadal ridges * Hair follicles begin to
+ Neural tube closes * Rudimentary blood begin to be form
+ Otic pits appear moves through perceptible * Spontaneous limb
* Pulmonary primitive vessels movements can be
primordium appears connecting to the detected by
* Hepatic plate appears yolk sac ultrasound
* Cystic diverticulum
forms
+ Dorsal pancreatic bud
forms
* Spleen forms
+ Urorectal septum
appears
* Ureteric bud forms

Figure 2.4 Chronology of fetal development from week 4 to 7

10. Fetal development from week 7 to 20 (Fig. 2.5)

Week 8-10 Week 11-14 Week 21

* Eyelids close *Lanugo * Eyebrow and *Alveoli form
and will not develops eyelashes
reopen until *Fetal skin is appear
the 28th week transparent * Nails appear
* Tooth buds *Meconium * Quickening
appear forms in the occurs
*RBCs are intestinal
produced in tract
the liver

Figure 2.5 Chronology of fetal development from week 7 to 20

11. Fetal development from week 25 to 37 (Fig. 2.6)

Mesoderm
1, Mesoderm has 3 parts (Box 2.2)

2. Somites
® Are rounded elevations of paraxial mesoderm which appear on either side of the neural
tube under the surface ectoderm on the dorsal aspect of the embryo from base of skull to
tail region
® First pair appears at day 20
@ Develop at a rate of 3 pairs/day
 Placenta and fetal membranes 19

® Maximum number is 42—44 pairs

® Consist of
i. Dermomyotomes (form connective tissue and muscles)
ii, Sclerotomes (form bones)

3. Lateral plate mesoderm

® Is continuous with extra-embryonic mesoderm
®@ Gives rise to
i. Somatic mesoderm (lines the amnion)
i, Splanchnic mesoderm (lines the yolk sac)

4. Intra-embryonic coelom
® |s formed on day 19
® |s formed from merging of the clefts within the lateral plate
® ls continuous with extra-embryonic coelom
@ ls the forerunner of the serous cavities

*Fetal length *Fetal "| «Fetal length *Fetal length

— 38cm weight — 2kg — 40-48 cm — 48-53cm
*Fetal ¢Rhythmic Fetal
weight — breathing | weight
— 2.5
1.2kg movement | —3kg
occurs

gro
SRE

Figure 2.6 Chronology of fetal development from week 25 to 37

Box 2.2 Parts of the mesoderm

- Paraxial mesoderm (fm _ Intermediate mesoderm [M_Lateral plate mesoderm —__

© Is segmental © Forms the urogenital system ® Forms the somatic and
® Forms somites splanchnic mesoderm

Placenta and fetal membranes

General facts
1. Embryonic nutrient requirements
® During fertilization and initial blastocyte formation nutrients are obtained by diffusion via the
zona pellucida from the accumulated fluid in the blastocoele
@ From day 12 to term the embryo obtains nutrients from the maternal blood via the
uteroplacental circulation

2. The endometrial stromal cells become large and accumulate glycogen in response to
® Circulating progesterones
® Blastocyst

3. Decidual reaction
@ Are cellular changes at the site of implantation, which include
i, Syncytiotrophoblast-induced erosion of endometrium
ii, Congestion and dilation of maternal vessels
 20 Chapter 2 Embryology

iii. Endometrial tissue oedema

iv. Endometrial cell shape becoming polyhedral
v. Increase in endometrial cell glycogen and lipid deposition
vi. Increase in endometrial vascularization
Occurs at day 12 of embryonic life

4. In pregnancy the decidua (endometrium)

Is identifiable as 3 discrete layers
i. Basalis (ie. where implantation takes place and the basal plate is formed)
ii. Capsularis (overlies the chorion)
iii, Parietalis (covering the rest of the endometrial cavity except the implantation site)
Capsularis and parietalis comes into contact with each other and obliterate the uterine
cavity at 4 months of gestation

5. Histology of early pregnancy is characterized by the presence of

Chorionic villi
Decidua
Trophoblast
Fetal membranes
Fetal somatic tissue

Presence of decidua on its own in a histological sample is not enough to confirm a diagnosis
of pregnancy

7. Arias-Stella are changes in the endometrial glands due to the effects of progesterone

Placenta
le The placenta has both maternal and fetal components
Maternal parts are derived from decidua basalis
Fetal parts consist of the villi of the chorion frondosum

The placenta is structurally composed of 2 units

Chorionic plate
Basal plate (the region of the placenta on the maternal side)

Chorionic plate is of fetal origin and is composed of

Amnion
Extra-embryonic mesenchyme
Cytotrophoblast :
Syncytiotrophoblast

The basal plate of the placenta is made up of

Fetal-derived parts from
i, Cytotrophoblast
ii, Syncytiotrophoblast
Maternal-derived part (from decidua basalis)

Vili
Are chorionic projections suspended in the intervillous space
Purpose is to maximize the area of interchange with the maternal blood
Each contains a capillary plexus supplied by branches of the umbilical vessels
Interchange occurs with maternal blood brought to the intervillous space by branches of the
uterine vessels

Development of chorionic villi

Day 9 is the lacunar stage
 Placenta and fetal membranes 21

® Day 12 — formation of primary chorionic villi

i. Clefts appear in the syncytiotrophoblast called lacunae, which communicate with
maternal endometrial sinusoids
ii. Cytotrophoblast forms primary chorionic villi
® Day 15 — formation of secondary chorionic villi
i, Extra-embryonic mesoderm invades the core of primary chorionic villi converting them
into secondary chorionic villi
ii. Secondary villi line the entire chorion
@ Day 21
i. Tertiary chorionic villi form
ii, Tertiary chorionic villi are villi containing blood vessels
@ Day 28
i. Free villi form
ii, Cytotrophoblast in the tertiary villi disappears
® Chorion leafisformed from the chorionic villi located on the anembryonic pole. These
become compressed against the decidua capsularis and become avascular
® Chorion frondosum is located at the embryonic pole

. Tertiary villi of chorion frondosum

®@ Grow towards the basal plate and attach to the decidual tissue via the cytotrophoblast shell
® Also known as anchoring villi

. Anchoring villi give rise to side branches called intermediate villi, which in turn produce
terminal villi

Terminal villi
® Develop as sprouts of syncytiotrophoblast
® Take over function from intermediate villi in third trimester of pregnancy

1 oO. Placental villi maturation includes

® Capillary enlargement
®@ Thinning of syncytiotrophoblast
® Cytotrophoblast disappearance

1 —_. Intervillous space

@ |s blood-filled space between anchoring villi
@ Also known as trophoblastic lacunae

2s Development of the cytotrophoblast layer

® Formed by cytotrophoblast of anchoring villus, which expands into the basal plate until a
further layer outside the syncytiotrophoblast arises
Penetrates into the decidua and myometrium
Colonizes the wall of spiral arteries, leading to destruction of the smooth muscle layer and
changes in the elasticity of the spiral arteries
@ This migration is under strict temporal spatial control
@ Insufficient penetration leads to pre-eclampsia
® Excessive penetration leads to chorion carcinoma

13. Placental septa

@ Also known as inter-cotyledon septa
Arise from decidua at 4 months of fetal life
Divide placenta into 15-20 lobes
Do not reach the chorionic plate
Do not limit circulation of maternal blood from one cotyledon to the next
 22 Chapter 2 Embryology

14, Placental membrane

® |s the partition between fetal and maternal circulation
® Composed of fetal tissue that is initially 4 layers thick; the layers are
i. Fetal capillary endothelium
ii Connective tissue of the villi
iii, Cytotrophoblast
iv. Syncytiotrophoblast
® From 4 months of fetal life, the placental membrane becomes thinner due to villous
maturation

15. Umbilical cord

e@ Dimensions at term
i. Length = 50-60cm
ii. Diameter = 1.5-2cm
® Contains
i, 2 umbilical arteries
ii 1 umbilical vein
iii. Wharton’s jelly
@ 1: 100 newborns have only 1 umbilical artery and 20% of them will have a coexisting vessel
or heart abnormality
® Usually inserts in the placenta near the centre, but other insertions include
i. Eccentric — cord insertion is off-centre and up to 2cm away from the edge
ii. Marginal — cord inserts from within 2cm and up to the edge of the placenta
iii. Velamentous — cord inserts into the membranes and then travels within the membranes
to the placenta; the exposed vessels are not protected by Wharton’s jelly

16, Wharton’s jelly

® |s made up of mucopolysaccharides
@ Derived from extra-embryonic mesoderm
® Protects umbilical blood vessels
© Contains
i, Fibroblasts
ii, Macrophages

17. Fibrinoid deposits accumulate in the placenta

® Begins from 4 months of fetal life
® Occurs in 3 regions of the placenta
i, Subchorial Langhan’s layer within the chorion plate
ii, Rohr’s layer beneath the stem villi within the basal plate
iii. Nitabutch’s layer in the deciduas basalis within the basal plate (this is the layer where
placenta detaches at birth)
® Can take up a maximum of 30% of placental volume without affecting its function

Fetal membranes
1. Fetal membranes
® |saterm applied to structures derived from the blastocyst that do not contribute to the
embryo
® Are made up of 4components (Box 2.3)

2. Amnion
® Amniotic cavity is formed by day 7 of embryonic life
® Has 5 layers
i, Cuboidal epithelium
 Placenta and fetal membranes 23

ii. Basement membrane

iii. Compact layer
iv. Fibroblast layer
v. Spongy layer (remnant of extra-embryonic coelom)
® Does not contain blood vessels, lymphatics, or nerves

Box 2.3 Components of the fetal membranes

® Inner side is formed ® Double-layered ® Becomes incorporated ® Isa diverticulum of

from ectoderm membrane into the GIT the yolk sac
® Outer side is formed ® Formed by © Becomes attached to
from mesoderm trophoblast and extra- the urinary bladder
embryonic mesoderm

3. Chorion is composed of 4 layers

Cellular layer
@ Reticular layer
® Basement membrane
® Trophoblast

4. Sharing of placenta and fetal membranes in twins depends on the stage at which a single
zygote divides (Box 2.4)
®@ 2 types of twins
i. Monozygotic
ii, Dizygotic (constitute 70% of twin pregnancies)
® Monozygotic twins can be
i. DCDA: separation occurs at morula stage; by day 3
ii, MCDA: separation occurs at days 4-8 (accounts for 70% of monozygotic twins)
ii. MCMA: separation occurs after amnion is formed; between days 9 and 12 (accounts for
1% of monozygotic twins)
iv. Conjoint: separation occurs after day 12 (incidence is about 1 : 100000 pregnancies)
@ All dizygotic twins are dichorionic
3% of monochorionic twins have 2 placental masses
® Chorionicity is better determined by ultrasonography before 14 weeks gestation
i. A (lambda) sign indicates dichorionic diamniotic (DCDA)
ii. ‘T’ sign indicates monochorionic diamniotic (MCDA)

Box 2.4 Stage of zygote division and resultant type of twining

Splitting of inner cell:

Splitti t la sta mass within a single Spies sites Soares : ;
nails Meee dnsieen, in oe ; 3 of bilaminar disc — ~ Splitting after day12
(day 3) blastocyte 2 :
(day 9-12) : Z ;
(day 4-8)
® 2 amnions ® 2amnions ®@ 1 amnion ® 1 amnion
® 2 chorions © 1 chorion ® 1 chorion ® 1 chorion
® 2 placentae ® 1 placenta ® 1 placenta ® 1 placenta
© Embryos share body
parts
 24 Chapter 2 Embryology

Placental disorders
lp Molar pregnancy
® |s characterized by the presence of hydatidiform mole
@ Prevalence in the UK is 1 : 714 live births
® Categorized into 2 groups
i. Complete moles
ii, Partial moles
®@ Complete moles
i. Characterized by diffuse swelling of villous tissue and diffuse trophoblastic hyperplasia in
the absence of embryonic or fetal tissue
ii. Occurs when an empty egg is fertilized by one or two normal spermatozoa (dispemic
fertilisation is < 20%)
iii. Are diploid
iv. Genotype is 46, XX or 46, XY
v. All nuclear genes are paternal
@ Partial moles
i, Characterized by focal swelling of villous tissue and focal trophoblastic hyperplasia in the
presence of embryonic tissue
ii, Occur when a normal haploid egg is fertilized by two (or three) spermatozoa
iii. Are triploid (ie. contains 3 sets of chromosomes)
iv. Genotype is, in decreasing order of frequency: 69, XXY or 69, XXX or 69, XYY
®@ Prognosis
i. 80% of hydatidiform moles are benign
ii. 15% will develop into invasive moles (persistent trophoblastic disease)
iii, 2-3% may develop into choriocarcinoma

Placenta accreta
® Occurs when the placenta is morbidly adherent to the myometrium
® Due to deficient deciduas basalis

. Placenta increta is the term applied when the placenta invades the myometrium but has not
breached the uterine serosa

Placenta percreta is the term applied when the placenta breaches the serosa of the uterus

Succenturiate lobe is defined as one or more accessory lobes of the placenta that are
T. in
attached to the bulk of the placenta by blood vessels running through the fetal membranes
Obs
Gyn Twin-to-twin transfusion syndrome (TTTS)
hpt 8.30 @ |s due to abnormal connecting blood vessels (arterioarterial or venovenous anastomoses) in
the twins’ placenta resulting in an imbalanced flow of blood from one twin to another
@ Risk of TTTS
i. In monochorionic twins = 15%
ii, More common in MCDA than MCMA twins
© Treatment is fetoscopic laser ablation of interconnecting blood vessels
Severity is graded with the Quintero classification system (stages 1-5) (Box 2.5)

Body cavities and diaphragm

ile The embryo takes a 3-dimensional shape during the 4th week of development via folding
resulting in
® Formation of GIT
® Conversion of intra-embryonic coelom into a closed cavity
 Body cavities and diaphragm 25

Box 2.5 Quintero classification system of TTTS

oe — Stages
® Discrepancy in ® Bladder of donor ® Critically abnormal ® Fetal hydrops present
amniotic fluid volume twin is not visible by fetal Doppler studies
ultasonography

® Demise of one or
both twins

2. The body cavities

@ Include
i. Peritoneal
ii. Pericardial
iii, Pleural
®@ Arise from coelomic cavity
® Are lined by 2 serous layers (the somatic and splanchnic mesoderm) (Box 2.6)

Box 2.6 Serous layers of body cavities

anchnicmesoderm
® |s in contact with the ectoderm © Adheres to the endoderm
® Gives rise to parietal layer of serous membrane ® Forms the visceral layer of the serous membrane

3. Septum transversum
®@ ls asheet of mesoderm
@ Appears on day 22
@ |s rostral to (in front of) the developing heart
® |s cranial to pericardial cavity before folding
® Forms the central tendon of the diaphragm

4. Intra-embryonic coelom before folding

®@ Appears as a ‘U’-shaped cavity
® The bend of the ‘U’ lies anteriorly and represents the pericardial cavity
@ Each arm of the ‘U’ represents the
i. Pericardioperitoneal canal
ii. Peritoneal cavity
@ nthe umbilical region the peritoneal cavity opens into the chorionic cavity allowing
herniation of midgut into the umbilical cord

5. After folding
® Asaresult of the head folding, the heart swings ventral to foregut
@ Septum transversum is wedged between heart and yolk sac
® Pericardial cavity opens into the pericardioperitoneal canal, which opens into the peritoneal
cavity
® At this stage the septum transversum is an incomplete partition between the thorax and
abdomen
6. Division of intra-embryonic coelom forms 4 cavities
@ 2 pleural
® 1 peritoneal
® 1 pericardial
 26 Chapter 2 Embryology

7. Diaphragm is formed by 5 components

Septum transversum
The body wall
i. From somatic mesoderm
ii. The peripheral part of the diaphragm attaches to the ribs — hence receiving its sensory
innervation from the lower 6 intercostal nerves
Mesentery of the oesophagus (forms the muscular crura of the diaphragm)
Pleuroperitoneal membrane
Cervical somites
i. During the 4th week the septum transversum lies in the cervical region opposite the 3rd,
4th, and 5th cervical somites
ii. Myoblasts from each somite contribute to the diaphragmatic musculature
iii. Hence diaphragmatic innervation is via nerves C3—C5
iv. C3-C5 fuse to form the phrenic nerve

Musculoskeletal system

ile Mesenchyme
® Gives rise to musculoskeletal system
@ |s derived from
i. Mesodermal cells of somites
ii. Somatopleuric layer of lateral plate mesoderm
iii. Neural crest cells (head region)
®@ Has ability to
i. Migrate
ii. Differentiate into many different cell types

2. Bone formation
Occurs via condensation of mesenchymal cells
Consists of 2 types of ossification (Box 2.7)
Axial skeleton is derived from the paraxial mesoderm which organizes as somites

Box 2.7 Types of ossification

i ea Membranous ossification Endochondral ossification

® Does not involve cartilage ® Occurs by replacement of hyaline cartilage
Is responsible for development of flat bones ® |s responsible for development of long bones
(e.g. skull, clavicle)

Vertebral column
Development goes through 3 stages
ii Mesenchymal condensation around notochord (Fig. 2.7)
ii. Cartilaginous transformation
ili. Ossification, which starts at 6th week of fetal life and ends at the 25th year of adult life
Vertebral arch
i. Gives rise to the costal and transverse processes
ii. Fuses to form the spinous process
Formation of vertebral body depends on notochord
Formation of vertebral arch depends on sclerotome interaction with the surface ectoderm
 Musculoskeletal system 27

® Intervertebral disc has an

i, Outer annulus fibrosus (derived from sclerotomes)
ii. Inner nucleus pulposus (derived from notochord)
@ The vertebra is intersegmental in origin due to its formation from 2 sclerotomes
@ The spinal nerves are segmental

Centrum pinous process a

(vertebral body) Vertebral arch Fe asa
formation by formation
scleretomes

Figure 2.7 Stages of mesenchymal condensation around notochord

4. Sternum
@ Develops from a pair of cartilaginous bars that form in the ventral body wall
@ These bars fuse in the midline in a craniocaudal sequence

5. Ribs
@ Arise from costal process of vertebra
®@ Grow laterally towards the sternum

6. Skull
® |s composed of
i. Neurocranium (which surrounds the brain)
ii, Viscerocranium (which surrounds the mouth, pharynx, and larynx)
® The bones of the cranial base develop
i, From occipital sclerotomes
ii. By endochondral ossification
@ The skull cap develops
i. From mesenchyme of neural crest
ii. By intramembranous ossification

7. Fontanelles
® Are unossified mesenchyme
® There are 6 fontanelles
i. Anterior
ii. Posterior
iii, 2 anterior lateral
iv. 2 posterior lateral
® Most fontanelles disappear during the 1st year of life
e® Anterior fontanelle ossifies at 18 months of life

8. Appendicular skeleton
@ In the limbs, bones form initially in the most distal part
® Ossification is via endochondral ossification except for the clavicle
® Ossification centres first appear at 8 weeks of development
@ Shaft of limb bones are ossified at 12 weeks of development. However:
i. Carpal bones remain cartilaginous until after birth
ii. Ossification of tarsal bones begin at 16th week of development
iii. Smaller tarsal bones do not ossify until 3 years after birth
® At birth
i. The shaft (diaphysis) of long bones are completely ossified
 28 Chapter 2 Embryology

ii, Epiphyses are still cartilaginous

ii, Secondary ossification centres occur in epiphyses few years after birth

9. Muscles
® Skeletal muscles develop from myoblasts derived from somites
®@ Head musculature is derived from
i, Pharyngeal arches
ii. Neural crest mesenchyme
® Each myotome divides into
i. Ventral hypomere, which forms muscles of anterior and lateral wall (e.g. rectus
abdominis, internal/external oblique, and transversus abdominis)
ii. Dorsal epimere, which forms muscles of posterior wall (e.g. erector spinae)
® Dorsal limb muscle mass gives rise to extensor groups
e Ventral limb muscle mass gives rise to flexor groups

Respiratory system

1. The epithelial component of the respiratory system develops from the ventral wall of
the endodermal lining of the foregut as a diverticulum that grows into the surrounding
splanchnopleuric mesoderm.

2. Splanchnopleuric mesoderm gives rise to the following components of lower respiratory

tract
® Visceral pleura
© Cartilage
® Smooth muscle
® Blood vessels

3. The respiratory diverticulum

® Separates from the foregut by development of bilateral longitudinal ridges called the
tracheo-oesophageal folds
The tracheo-oesophageal folds fuse together to form the tracheo-oesophageal septum
® Gives rise to
i. Trachea (tracheal bifurcation lies at thoracic vertebral level 4 at birth)
ii, Lung buds

4. The larynx '

® |s lined by epithelium from endoderm
® Laryngeal cartilage and muscles arise from pharyngeal arches

5. Lung buds
® Divide many times to form the bronchial tree
® This division is known as branching morphogenesis
i, Right lung bud divides into 3 secondary lung buds
ii, Left lung bud divides into 2 secondary lung buds
iii. Bronchial tree division is not complete until after birth
® Full lung maturation is reached at 6-7 years of age
New alveoli continue to be formed up to 10 years of age
6. Lung epithelium
® Is initially cuboidal and thins with ageing
© Respiration is not possible until this epithelium thins sufficiently to form squamous
epithelium
 Cardiovascular system 29

® This begins at 26 weeks of fetal life

® Consists of2 types of epithelial cells
i. Type 1 (line the alveoli)
ii. Type 2
™ Produce surfactant
m Appear at about 24 weeks of fetal life
7, Pleura is composed of 2 layers
® Somatic layer formed by somatopleuric mesoderm
@ Visceral layer formed by splanchnopleuric mesoderm

Cardiovascular system

1. One of the first systems to develop

2. In early embryo nutrients are derived from

®@ Trophoblastic digestion of uterine mucosa
© Diffusion from the contents of the yolk sac

3. Initial components of cardiovascular system appear as angiogenic cell clusters in the extra-
embryonic mesoderm lining the yolk sac

4. The primitive heart begins beating at day 21

The heart
1. Heart formation
@ Angiogenic cell clusters merge in a rostral to prochordal plate direction to form the
cardiogenic area
® Cardiogenic cells form paired heart tubes
® The dorsal aortae develop on either side of the midline and connect with the heart tubes
@ Heart tubes fuse due to the longitudinal and lateral folding of the embryo
®@ The tube is suspended in the pericardial cavity by dorsal mesocardium
® The dorsal mesocardium breaks down leaving the heart attached merely at the margins of
the pericardium
® The heart tube elongates in the pericardial cavity
@ At day 23 the elongation is more than the volume available in the pericardial cavity
@ Hence the tube bends, forming the cardiac loop
® Bends occur at
i. Bulboventricular groove
ii. Atrioventricular groove

2. Heart tube consists of

e@ A single atrium
@ A single ventricle
@ An atrioventricular canal

3. Atrioventricular valves
® Form in the region of the atrioventricular canal
® Formed by the endocardial cushions

4. Bulbus cordis
® Lies between primitive ventricle and the atrial outflow
® Proximal third becomes the right ventricle
@ Becomes the conus cordis (eventually becomes the truncus arteriosus)
 30 Chapter2 Embryology

5. Atrial septum
Septation begins at about 4 weeks
Septum primum
i. Develops in the roof of the common atrium
ii. Grows towards the endocardial cushions
Ostium primum
i. Is the opening between the septum primum and endocardial cushions
ii, Closes with further growth
Ostium secundum
i. Occurs as ostium primum closes
ii. It is a small hole in the septum primum
Septum secundum
i. Forms to the right of septum primum
ii, Grows over septum primum
iii. Does not completely divide the atria, leaving an opening, the foramen ovale

6. Foramen ovale
Functional closure occurs after birth due to change in pressure between the two atria (i.e.
increased left-sided heart pressure and decreased right-sided pressure caused by air
breathing and start of pulmonary circulation)
Becomes fossa ovalis after birth

7. Ventricular septum is composed of 2 components (muscular and membranous parts)

(Box 2.8)

Box 2.8 Components of the ventricular septum

® Develops from floor of ventricle and grows towards ® Formed by endocardial cushions and
endocardial cushions aorticopulmonary septum
® This component does not reach the endocardial ® Accommodates the atrioventricular conducting
cushions, leaving a gap bundle

8. Truncus arteriosus gives rise to

Ascending aorta
Pulmonary trunk
Aortic sac ,
9. Aorticopulmonary septum
Forms at week 5
Forms from the left and right truncoconal swellings that occur within the conus cordis and
truncus arteriosus
Develops as a spiralling structure

Venous drainage of the heart

1. Sinus venosum
Empties into the common atrium via a single opening
Consists of
i, Left horn (becomes the coronary sinus)
ii, Right horn
Right horn of sinus venosum
i, Becomes the dominant horn
 Cardiovascular system 31

ii, Becomes the proximal part of

= Inferior vena cava (IVC)
™ Superior vena cava (SVC)
® Drains the following vein pairs
i. Common cardinal veins
ii. Vitelline veins
iii. Umbilical veins

2. Sinus venarum
® Consists of the
i. Right horn of sinus venosum
ii. Wenae cavae
® Lies on the posterior atrial wall

3. Right auricle is the primitive atrium

4. Cristae terminalis
® Accrest that separates the trabeculated right auricle from the smooth sinus venarum
® Corresponds to the sulcus terminalis (is a groove on the exterior of the heart)
® Pectinate muscles project from this crest to the auricle
® Lower part forms the IVC valve in fetal heart
i. This disappears after birth
ii. Functions to direct blood to foramen ovale

Arterial system
1. Arterial system includes
®@ Aortic arches
® Paired dorsal aortae (will eventually unite to form the descending aorta)

2. Aortic arches
® Aortic sac gives off vessels to the pharyngeal arches (that begin to develop from week 4)
@ An artery develops within each pharyngeal arch, each of which meet the aortic sac
® 5 or 6 pair of aortic arches are formed (Box 2.9)
®@ Aortic arch joins the dorsal aorta on each side
®@ The aortic sac divides to form the right and left dorsal aorta

Box 2.9 Aortic arches and their resultant arteries

ist aortic arch pair 2nd aortic-arch pair 3rd aortic arch pair _ 4th aortic arch pair
® Maxillary artery © Disappears © Common carotid ® RIGHT — Proximal
© External carotid part of right subclavian
® Proximal part of artery
internal carotid © LEFT — Arch of aorta

5th aortic arch pair. 6th aortic arch pair

® Disappears © RIGHT — Distal part of
right subclavian artery
@ LEFT PROXIMAL —
Pulmonary artery
® LEFT DISTAL —
Ductus arteriosus
 32 Chapter 2 Embryology

3: Ductus arteriosus
® Becomes ligamentum arteriosum after birth
® Closure is stimulated by bradykinin

Distal part of internal carotid is formed by dorsal aorta

Left subclavian arises from 7th intersegmental artery, which is a branch of the dorsal aorta

Right dorsal aorta disappears between the 7th intersegmental artery and the start of the
fused dorsal aorta

Path of recurrent laryngeal nerve is different on both sides due to the different arrangement
of the 6th aortic arch pair
@ Left — the nerve hooks under ductus arteriosus
® Right — the nerve hooks under right subclavian artery

Vitelline artery
®@ Supplies the yolk sac
® Exists as a pair
® Fuses to form
i Coeliac artery
ii. Superior mesenteric artery
ili. Inferior mesenteric artery

Umbilical arteries
® Supply deoxygenated blood from the fetus to the placenta
@ Arise from common iliac artery
@ After birth
i. The distal portion of the artery obliterates to form the medial umbilical ligaments
ii. The proximal portions persist as the internal iliac and vesicular arteries

Venous system
ik At week 5 of embryonic life there are 3 major sets of veins
@ Umbilical
@ Vitelline
® Cardinal (drains head and body)

Umbilical veins
® Initially there are 2 umbilical veins
® Both proximal portions disappear
© The right distal portions disappear
© Left distal umbilical vein
i, Connects with ductus venosus to bypass the liver
ii. After birth becomes ligamentum teres and lies in the falciform ligament

Ductus venosus
® Connects to IVC
@ After birth becomes ligamentum venosum

Vitelline veins forms

® Sinus venosus
® Hepatic vessels

Longitudinal venous channels

® Form by week 5 of embryonic life
® Are paired
 Gastrointestinal system 33 a:

® Include
i. Azygos veins
ii. Supracardinal veins
iii, Subcardinal veins
© Become progressively asymmetrical, resulting in right-sided dominance by week 7, leading to
i, Formation of the IVC, which includes the supracardinal and subcardinal veins
ii. The left azygos vein, becoming the hemiazygos vein
iii. A resultant left to right shunt

Gastrointestinal system

General facts
1. The endoderm forms the
@ Foregut
@ Midgut
i. Is in continuity with the remaining yolk sac
ii, Vitello-intestinal duct connects the yolk sac and the midgut
® Hindgut
Liver
Pancreas

Splanchnopleuric lateral plate mesoderm contributes to

®@ Connective tissue
@ Smooth muscle
@ Serosal layer of gut tube

Dorsal mesentery
®@ Suspends the gut tube in the body of the embryo
®@ Formed by serosal membrane
e Attaches to the posterior wall of the embryo
® Extends from lower oesophagus to cloaca
e@ With further growth the dorsal mesentery is lost for some parts of the gut tube
i. Duodenum
ii, Ascending colon
iii, Descending colon

. Dorsal mesogastrium
@ ls the dorsal mesentery of the stomach
@ Becomes the greater omentum

Ventral mesentery
® Forms at the caudal part of foregut
@ |s derived from the septum transversum
@ Covers the
i. Stomach
ii, Terminal oesophagus
iii. Initial portion of duodenum
@ The liver develops within the ventral mesentery and divides it into 2 parts
i. Falciform ligament (connects liver to ventral wall of embryo)
ii, Lesser omentum (lies between stomach and liver)
® Mesenteries are double layered, allowing structures (such as nerves and blood vessels) to lie
within them
 34 Chapter 2 Embryology

6. A structure is intraperitoneal when it is completely invested in splanchnopleuric mesoderm

all around

7. A structure is retroperitoneal when it is not suspended by dorsal mesentery

Foregut
1. Foregut consists of
@ Oesophagus
Stomach
Duodenum
Pancreas
Liver

2. The foregut is divided into the

® Cranial portion
i. Forms the pharynx
ii. Associated with pharyngeal arches
® Caudal portion

3. Oesophagus
@ ls the part of the caudal foregut
® Lies in the posterior mediastinum
®@ Gives rise to the respiratory diverticulum
© Lengthens due to the growth of thoracic organs

4, Stomach
® Undergoes a clockwise 90° rotation (i.e. rotates to the right)
@ This pulls the dorsal mesentery over to the left side
® Consequently a small gap is formed between the stomach and the dorsal wall, called the
lesser sac

5. Spleen develops in the dorsal mesogastrium

6. Gastrosplenic ligament is the portion of the dorsal mesogastrium that lies between the
stomach and the spleen

7. Lienorenal ligament is the portion of the dorsal mesogastrium that lies between the spleen
and the dorsal wall of the embryo

8. Pancreas '
® Lies in the dorsal wall of the embryo
® Develops from endodermal lining of the duodenum
® At4 weeks of embryonic development 2 pancreatic buds arise
i. Dorsal
m Lies within the dorsal mesentery
@ |s the larger of the 2 buds
® ts duct is the main pancreatic duct
ii, Ventral (lies within the ventral mesentery)
® As the duodenum rotates right
i, The ventral bud moves dorsally to lie superior to the dorsal bud
ii, Entrapping the superior mesenteric blood vessel between the dorsal and ventral buds
iii. Both the buds fuse
® Both pancreatic ducts fuse
i, Entering the medial wall of the duodenum
 Gastrointestinal system 3 ae

ii, To form the major duodenal papilla

® Tail of pancreas lies within the double layer of the lienorenal ligament

9. Lesser sac
@ Is limited in its extend by the greater omentum (as the double layer of the greater omentum
fuse laterally)
® Communicates with the greater sac via the aditus

10. Duodenum
@ Arises from
i. Foregut
ii, Midgut
@ The bile duct lies in the junction between foregut and midgut
@ Lumen of duodenum
i. Initially is hollow
ii, At 2 months offetal development it is solid
Lies in the posterior abdominal wall
Gives rise to the pancreas which lies within the mesoduodenum
Is ‘C’ shaped
Has a dual arterial supply

1 = . Mesoduodenum is lost with further development

® Consequently the duodenum is covered with peritoneum only on its anterior surface,
known as the parietal peritoneum
@ The posterior leaf of the mesoduodenum regresses
i. Thus the posterior surface of duodenum is attached to the dorsal wall of embryo
ii, This seals off the lower extent of the aditus to the lesser sac

se Liver
® Hepatic diverticulum
i. Arises on the ventral wall of duodenum and just above the ventral pancreatic duct
ii. Pushes into the septum transversum
® Gall bladder
i. Arises from a ventral outpouching of the hepatic diverticulum
ii, Its duct initially is solid (failure to recanalize the duct results in extrahepatic biliary
atresia)
® The peritoneum covers all of the liver except the bare area (this is the area in contact with
the diaphragm)
® Kupffer cells
i. Are bone marrow derived
ii. Line liver sinusoids
@ At 10 weeks of embryonic life liver produces blood cells

Midgut
i Starts at the midpoint of the duodenum

Ds, Terminates approximately 2/3 of the way along the transverse colon

3. Its artery is the superior mesenteric artery

The midgut rapidly elongates but as the peritoneal cavity is small it

® Herniates out of the abdominal cavity into the umbilical cord
@ Herniation occurs at 6 weeks and returns at 10 weeks. This is a physiological umbilical
hernia
 36 Chapter 2 Embryology

® As the gut enters the umbilical cord it rotates 90° anticlockwise

® Onreturn to the abdomen it rotates a further 180° anticlockwise resulting in the caecum
moving from its subhepatic position to the right iliac fossa
®@ The rotation is about the axis of the vitello-intestinal duct
@ Abnormal herniation of midgut is of 2 types (Box 2.10)

Box 2.10 Types of abnormal midgut herniation

Indirect herniation ® Direct herniation via abdominal wall

Herniates via the umbilicus ®@ Lies in the amniotic sac and hence is not covered by
Covered with a layer of amnion amnion ;
Associated with other structural and chromosomal ® Not associated with chromosomal abnormalities
abnormalities (e.g. Trisomy 18 — Edwards’ syndrome)

The midgut forms

The second half of the duodenum
@ |leum
® Jejunum
® Ascending colon
® Proximal 2/3 of the transverse colon

The mesentery of the following organs are reabsorbed

® Duodenum
® Ascending colon
®@ Descending colon

The transverse mesocolon

© |s the dorsal mesentery of the transverse colon
@ It fuses with the anterior 2 layers of the greater omentum, thus appearing that the
transverse colon is attached to the posterior surface of the greater omentum

Meckel’s diverticulum
® |saremnant of the vitello-intestinal duct
® Rules of 2
i, 2 inches (5cm) long
ii. 2ft (61cm) from ileocaecal valve
ili, 2% of population has it
® Contains
i. Gastric mucosa
ii. Pancreatic mucosa
@ Inflammation of it is often mistaken for appendicitis

Hindgut
i Forms the
® Distal 1/3 of the transverse colon
® Descending colon
® Rectum
®@ Upper half of anal canal

2. Forms epithelial layer of

@ Urinary bladder
® Urethra
 Urinary system 37

3. Initially opens into the primitive cloaca, which communicates with the allantois

4. Urorectal septum
® A band of mesenchymal tissue
® Divides the primitive cloaca into
i. Urogenital sinus anteriorly
ii, Rectum posteriorly
® Becomes the perineal body when it reaches the cloacal membrane
® Perineal body divides the perineum into
i. Urogenital triangle
ii. Anal triangle
®@ Cloacal membrane breaks down at 7 weeks of embryonic development
5. Allantois
@ Non-functional
® Connects primitive cloaca to umbilicus
® Becomes the urachus, which eventually becomes the median umbilical ligament
® In some species the allantois contributes to the formation of the placenta

6. Anal canal
@ Mucosa of anal canal derived from
i. Upper half —endoderm
ii. Lower half —ectoderm (proctodeum)
@ Pectinate line
i. Demarcates the two embryological parts of the anal canal
ii. Located at base of anal columns
iii. Marks a change in
= Blood supply
= Nerve supply
® Epithelial lining
@ Anal canal lumen
i. Occluded at 7 weeks by the ectoderm
ii. At 9 weeks this is recanalized

Urinary system

1. Origins of the urinary system

@ Bulk of the urogenital system is derived from intermediate intra-embryonic mesoderm
(forms the nephrogenic cord that underlies the urogenital ridge)
®@ Develops in the trunk
® Craniocaudal development (Box 2.11)

Box 2.11 Development of the urinary system

® Non-functional ® Produces urine ® Produces urine

® Temporary ® Becomes the definitive human
kidney

2. The initial structures that develop in the urogenital system have excretory functions
 38 Chapter 2 Embryology

3. Two components are necessary for development of an excretory system

® Capillary bed
® Tubules (glomeruli)

4. Mesonephros
® Develops in the lower thoracic and lumbar region
® Cavities appear in the mesonephros
i Which become the tubules (Bowman’s capsules)
ii. Join laterally to form the mesonephric duct
@ Mesonephric duct
i, Drains into the urogenital sinus
ti, Forms the bladder trigone
. In males — produces ductus deferens and efferent ductules of testes
iv. In females — produces Gardner’s ducts

5. Metanephros
® Consists of
i. Ureteric bud
ii. Metanephric blastema
@ Ureteric bud
i. Outgrowth of mesonephric duct and eventually grows into the metanephric duct
ii. Forms the
® Definitive ureter
= Renal pelvis
2 Calyces
= Collecting ducts
® Metanephric blastema
i, Condensation of nephrogenic cord tissue around ureteric bud
ii. Forms the nephrons (formation continues until 32 weeks of intrauterine life)
@ Functional from 10 weeks (urine produced passes into the amniotic fluid as the cloacal
membrane disappears at week 7)

6. Bladder arises from the urogenital sinus after the cloaca has been divided

Gyn Reproductive system

1. Indifferent gonad
® Develops from intermediate mesoderm
® Situated on the gonadal ridge (which is the medial portion of the urogenital ridge)
® Primordial germ cell migration
i, Starts at week 6 of embryonic life
ii, Originates from the wall of the yolk sac
iii, Cells migrate to the genital ridge
iv. Path is via dorsal mesentery of the hindgut
vy. Induced formation of primitive sex cord
® Primitive sex cord is derived from mesonephros and overlying coelomic epithelium
2. Testis
© The default is for the gonad to develop into an ovary
® Sex determining region of Y chromosome (known as the SRY gene)
i, Produces testis-determining factor
ii, Promotes testicular development
ili, Induces differentiation of gonad mesenchymal cells into interstitial Leydig cells
 Reproductive system 39

® Primitive sex cords

i, Penetrate the medulla and form the testicular cords, which anastomose to form the rete
testis
ii. Differentiate into Sertoli cells
ili, Become seminiferous tubules (which are solid cylinders until after puberty, when they
are canalized)
© Rete testis is continuous with mesonephric duct
® Leydig cells produce testosterone from week 8
@ Sertoli cells produce anti-Mullerian hormone from week 8

. Ovary
®@ Absence of testis-determining factor causes
i, Sex cords in the medulla to degenerate
ii. Formation of vascular medullary stroma
@ Surface epithelium gives rise to second-generation cortical cords
@ At4 months of fetal life primordial germ cells invest in the secondary cords

. The development of a female internal genitalia occurs in the absence of testosterone and
anti-Mullerian hormone

. Initially 2 pairs of genital ducts arise

@ Mesonephric (also known as Wolffian or Leydig’s ducts)
@ Paramesonephric (also known as Mullerian ducts)

. Mesonephric duct
@ Loses its urinary function once the metanephros supersedes the mesonephros
@ Persists in males and regresses in females
@ Forms
i. Ductus deferens
ii. Epididymis
iii. Seminal vesicles
iv. Prostatic utricle
v. Trigone
® Opens into the urogenital sinus
@ Differentiation is due to testosterone being produced from week 8 of embryonic life

. Paramesonephric duct
@ Persists in females and regresses in males
Regression is due to anti-Mullerian hormone
Lies lateral to mesonephric duct
Is a longitudinal invagination of the coelomic epithelium overlying the urogenital ridge
The cranial end of the duct
i. Opens into the peritoneal cavity
ii. Becomes the fimbriae of the uterine tubes
® Caudal ends of the duct
i. Fuse in the midline bringing together the 2 peritoneal folds forming the broad ligament
ii. Form the uterovaginal canal

. Uterovaginal canal
® Forms the
i, Uterus
ii, Upper half of vagina
® Fuses with the sinovaginal bulb (swelling on the urogenital sinus)

. Sinovaginal bulb
® Gives rise to the lower half of the vagina
 40 Chapter 2 Embryology

Right gonadal ridge

Paramesonephric duct
beginning to form
Germ cells Mesonephric duct
Yolk stalk

Paramesonephric duct

(b)
Regressing mesonephric ducts

Left mesonephric duct

Developing ba
ovaries jh

if Para-
\} —~—— mesonephric
\e {| ducts
\ \ \\

\
\
}

Ik Uterorectal pouch
(c) Right ovary (of Douglas)
Broad and Rectum / : '
suspensory Uterovaginal F sets hes
ligaments primordium | fy erus an

Fused paramesonephric
canals Sinovaginal bulb
(forming uterus) } beginning to 1 Hymen
hollow out TOK Urogenital
_
sinus

(d) Uterovesical pouchparamesonephric duct

making oviduct

Figure 2.8 Development of the internal genitalia

Reproduced from the Oxford Textbook of Functional Anatomy, Vol. 2, by Patricia MacKinnon and John Morris © Oxford
University Press 2005.

® Forms the vaginal plate

® Initially is solid and is later canalized

10. Urogenital sinus

® Forms
i. Bartholin’s glands
 Reproductive system 41 Ce

ii, Skene’s gland (paraurethral/ lesser vestibular) — is analogous to the male prostate
® Has 3 portions
i, Vesico-ureteric (gives rise to bladder)
ii, Pelvic (gives rise to prostate)
iii. Phallic

11. Testicular descent

®@ Mediated through guidance of the gubernaculums
® |s towards the labioscrotal swelling
® Gubernaculum in females becomes
i. Ovarian ligament
ii, Round ligament
®@ Processus vaginalis
i. An outpouching of peritoneum from the coelomic cavity protruding into the labioscrotal
swelling, into the space created by the gubernaculum
ii, Precedes the testis into the scrotum
iii. Forms the inguinal canal as it pushes through the 3 layers of abdominal wall
iv. Becomes the tunica vaginalis
@ Has 2 phases
i. Independent phase (testis reaches deep inguinal ring at 7 months of fetal life)
ii, Hormone dependent (from 7—9 months of fetal life)
® Factors determining testicular descent
i. Elongation of fetal trunk
ii. Increase in intra-abdominal pressure
iii, Regression of gubernaculum

12. External genitalia (Fig. 2.9)

® Are undifferentiated until 9 weeks of fetal life
@ The default development is towards a female phenotype
@ Dihydrotestosterone (DHT) stimulates external genitalia virilization in the male embryo
@ At5 weeks a cloacal fold forms
i. On either side of the cloacal membrane
ii, Fuses anteriorly to give rise to the genital tubercle
iii. Forms the
® Labia minora
= Penile urethra (at the end of 3months of development the cloacal folds fuse
anteriorly)
© Lateral to the cloacal fold are the genital swellings
i. In the female they form the labia majora
ii, In the male they fuse to form the scrotum
® Genital tubercle elongates under hormonal influence to form
i. Clitoris in female
ii, Penis in male

Reproductive development disorders

1. Ambiguous genitalia at birth
@ Incidence is 1 ; 4000
@ Aetiology is either virilization of a genetically female infant or under-masculinization of a
genetically male infant (Box 2.12)
® Severity of the ambiguity is classified according to the Prader stages 1-5 (Box 2.13)

2. Partial or complete androgen insensitivity

® X-linked inheritance disorder in 2/3 of cases
42 Chapter 2 Embryology

Genital tubercle

Urethral folds
Urogenital slit
Labioscrotal swelling

Urogenital slit
Figure | used
by Sherfey. Urethral folds
Labioscrotal
swelling

Anus

49.0mm 45.0mm

Glans penis
Clitoris
Urethral Meatus

Labia
minora
Scrotum
Vaginal
orifice
Labia
; Raphe
majora

Anus

Figure 2.9 Development of the external genitalia

Reproduced from the Oxford Textbook of Functional Anatomy, Vol. 2, by Patricia MacKinnon and John Morris © Oxford
University Press 2005.

Box 2.12 Aetiology of ambiguous genitalia at birth

46, XY under-masculinization 46, XX virilization oo ang ttle baal

sexual development
® Partial androgen insensitivity © Congenital adrenal hyperplasia © True hermaphroditism
(PAIS) ® Placental aromatase deficiency
® Complete androgen insensitivity ® In-utero exposure to maternal
(CAIS) androgens
® 5a-reductase deficiency (unable
to convert testosterone to
DHT)
® Gonadal dysgenesis (e.g. Swyer’s
syndrome)
 Nervous system 43

Box 2.13 Prader stages

® lsolated clitoromegaly ® Clitoromegaly ® Clitoromegaly

® The rest of the genital © Partially fused labia © Completely fused labia
area and internal ® The vagina and ® The vagina and urethra
organs resemble those urethra open into a share a single opening
of a typical girl funnel-shaped area (the urogenital sinus)

® Micropenis ® lsolated crypto-

® The labia are orchidism
completely joined like © The external genitalia
a scrotum look like a typical
® The vagina and boy’s
urethra share a single ®@ The vagina and
opening near the base urethra share a single
of the phallus opening at the tip of
the phallus

@ Characterized by
i. Normal testicular production of androgens
ii, Abnormal androgen receptors
@ Leads to incomplete virilization of external genitalia
® The testes are usually positioned in the inguinal canal bilaterally

3. Mayer—Rokitansky—Kuster—Hauser syndrome is a congenital malformation of the female

internal genitalia due to Mullerian duct failure that leads to an absent or rudimentary uterus
but with normal ovarian function

Nervous system

1. Forms mainly from ectoderm

2. Formation starts at 3 weeks of intrauterine life

3. Neurulation is formation of
® Neural plate (day 18)
® Neural fold (day 20)
® Neural tube (day 22)

4. Neural plate
® |s an ectodermal thickening
® Widest at cranial end

5. Neural folds
© Are lateral to the neural plates on each side
® Form the neural groove
@ Ultimately fuse to form the neural tube
® Give rise to neural crest

6. Neural crest
@ Lies beneath surface ectoderm
@ Migrates laterally
® Gives rise to a wide range of structures (see Box 2.14)
 44 Chapter 2 Embryology 7

7. Neural tube
® Cranially forms the brain
® Caudally forms the spinal cord
© An opening at each end of the tube, called the neuropore
i. Anterior neuropore closes at day 24
ii. Posterior neuropore closes at day 26
Lined with neuroepithelium
Neural tube lumen becomes the ventricular system

Box 2.14 Neural crest derivatives

@ Arachnoid and pia

aa
© Dorsal root ganglia © Melanocytes
ce
e Adrenal medulla
matter ® Cranial nerve ganglia ®@ Odontoblasts ® Dermis of face
® Glial cells © Paravertebral © Ccells (thyroid © Skull cap bones
® Schwann cells sympathetic ganglia parafollicular cells) —
@ Parasympathetic also derived from the
ganglia in GIT 5th pharyngeal pouch

8. Nerve cells arise from

® Neuroepithelium (neuro-ectoderm), giving rise to
i. Neuroblasts
ii. Glioblasts
= Astrocytes
® Oligodendrocytes
iii, Ependyma
@ Bone marrow (mesoderm), giving rise to microglial cells

9. There are 4 types of neural tube defect (NTD)

® Spina bifida occulta (unfused vertebral arch)
@ Spina bifida cystica (2 subtypes)
i, Neural tube and its coverings protrude through the vertebral arch
ii. Meningocoele
® Neural tube lies in its normal position
= Cyst formed by protruding subarachnoid membrane and space
iii, Meningomyelocoele — neural tube lies ectopically in the cystic space
iv. Associated with hydrocephalus
®@ Rachischisis
i. No neural tube
ii. Neural tissue is fused with skin

Spinal cord
1. Consists of 3 zones
© Neuroepithelial (ventricular) layer
® Mantle zone — becomes the grey matter
@ Marginal zone
i, Contains axons entering and leaving the mantle zone
ii. After myelination this area looks white

2. Has 2 plates divided by the sulcus limitans

@ Alar
i. Dorsal plate
 Nervous system 45

ii, Sensory region

@ Basal
i. Ventral plate
ii, Motor region
3. Extends the entire length of the vertebral column until the 3rd month of intrauterine life after
which it ends at lumbar vertebral level 2 (L2) due to overgrowth of the vertebral column

Brain
1. 3 dilatations occur at the cranial end of the neural tube
® Prosencephalon (forebrain)
@ Mesencephalon (midbrain)
@ Rhombencephalon (hindbrain)

2. Due to limited space the tube bends at 2 places

® Cervical — lies between rhombencephalon and spinal cord
® Cephalic — lies in mesencephalon

3. The 3 primary vesicles develop into 5 secondary vesicles

®@ Prosencephalon develops in to
i. Telencephalon
= Bilateral portions
®™ Become the cerebral hemispheres
ii. Diencephalon — becomes thalamus and hypothalamus
Mesencephalon
®@ Rhombencephalon develops into
i. Metencephalon — becomes pons and cerebellum
ii, Myelencephalon — becomes medulla

4. Ventricular system
The neural tube lumen becomes the ventricular system
4th ventricle lies in the rhombencephalon
3rd ventricle lies in the diencephalons
Lateral ventricles lie in the telencephalon
Cerebral aqueduct connects the 3rd and 4th ventricles
Intraventricular foramen connects the lateral and 3rd ventricles

5. Meninges
@ Dural sac ends at sacral vertebral level 2 (S2)
® Spinal cord meninges arise from the paraxial mesoderm
®@ Cephalic meninges arise from
i. Neural crest
ii, Mesoderm
® Choroid plexus
m@ Dura

6. Pituitary gland develops from 2 sources

@ Downgrowth from the floor of the diencephalons forming the posterior pituitary
(neurohypophysis)
@ Upgrowth from the stomodaeum (ectodermal portion of oral cavity)
i. Known as Rathke’s pouch
ii. Appears at 3rd week of intrauterine life
iii. Loses its connection with oral cavity at the 8th week of intrauterine life
iv. Forms the anterior pituitary (adenohypophysis)
 46 Chapter 2 Embryology
ee ee ee ee ee eee

Face and neck development

1. The face and neck are derived from a series of branchial arches that lie on either side of the
stomodaeum

2. Pharyngeal arches (Table 2.1)

® Develop in the 4th week of embryonic life
e Arise from neural crests
® Five pairs of arches (1, 2, 3, 4, and 6)
®@ 5th pharyngeal arch
i. ls rudimentary
ii. Disappears
@ Each arch consists of
i. A core of mesenchyme, which differentiates into
® Cartilage
& Muscle
@ Aortic arch artery
ii, An inner endoderm (gives rise to pharyngeal pouches)
iii, An outer ectoderm (gives rise to pharyngeal clefts)
® Each pharyngeal arch is supplied by a cranial nerve

Table 2.1 Pharyngeal arches

Arch Nerve Muscles Bones and cartilages

1st Trigeminal Of mastication Malleus

1. Mylohyoid Incus
2. Anterior belly of digastric Sphenoid
3. Tensor veli palatine
4. Tensor tympani

2nd Facial Of facial expression Stapes

1. Buccinator Styloid process
2. Stapedius Lesser horn of hyoid
3. Stylohyoid bone
4. Posterior belly of digastric
3rd Glossopharyngeal Stylopharyngeus Greater horn (lower
part) of hyoid bone
4th Vagus Pharyngeal Thyroid cartilage
Cricothyroid Cricoid cartilage
6th Vagus Muscles of Arytenoid cartilages
1. Larynx
2. Oesophagus

3. Pharyngeal clefts
® Only the first pair contributes (forms the external acoustic meatus)
@ 2nd pharyngeal arch enlarges and grows as a flap covering the remaining clefts and forms the
platysma muscle
® Remnants of lower cleft may form a cervical sinus

4. Pharyngeal pouches (Box 2.15)

© Derived from endoderm of the foregut growing laterally as pockets on each side of the
pharynx
 Face and neck development «a

@ 3rd and 4th pharyngeal pouches have dorsal and ventral portions
® Tympanic membrane is formed by
i. Ectoderm of 1st pharyngeal arch
ii. Intermediate layer
iii. Endoderm layer of 1st pharyngeal pouch

Box 2.15 Pharyngeal pouches and their derivatives

® Tubotympanic recess © Palantine tonsil © DORSAL- Inferior ® DORSAL — Superior

© Middle ear parathyroid glands parathyroid glands
® Auditory tube @ VENTRAL — Thymus @ VENTRAL -
@ Tubal tonsil gland Ultimobranchial body

© Ultimobranchial body
(fuses with lateral lobe
of thyroid gland)
® Parafollicular cells
(produce calcitonin)

5. Thyroid gland
® Grows from the thyroid diverticulum
i. Divides into the left and right thyroid lobes
@ Thyroglossal duct
i. Connects the foramen caecum to the thyroid gland
ii. Detaches from the pharyngeal floor
iii. Gives rise to the pyramidal lobe of the thyroid

Tongue
1. Develops from
@ Epithelium of the floor of the pharynx
® Muscles invade the tongue in 2nd month from occipital myotomes bringing hypoglossal
nerve innervation with it

2. Anterior 2/3 of the tongue is formed by 3 swellings from the 1st pharyngeal arch
® 2 lateral lingual swellings
® Tuberculum impar

3. Posterior 1/3 of the tongue is formed by the hypobranchial eminence derived from
® 3rd pharyngeal arch
® 4th pharyngeal arch

4. Sulcus terminalis
@ V shaped groove
® Represents line of fusion between 1st and 3rd pharyngeal arches

5. Foramen caecum
® |samidline depression in the sulcus terminalis
@ Appears as an invagination of the endoderm at the floor of the pharynx between the 1st and
2nd pharyngeal pouches
@ Marks the origin of the thyroid diverticulum
 48 Chapter 2 Embryology

6. Nerve innervation
Anterior 2/3
i, Lingual branch of mandibular nerve (trigeminal nerve)
ii, Chorda tympani nerve (facial nerve)
Posterior 1/3
i. Vagus
ii, Glossopharyngeal
Vallate papillae (lies anterior to sulcus terminalis)
i. Glossopharyngeal nerve (due to forward migration of posterior 1/3 of the tongue
mucosa across the sulcus terminalis)

Face
1. Develops from neural crest as 5 swellings
© Frontonasal prominence forms
i. Forehead
ii, Nose
iii, Philtrum
iv. Primary palate
Paired maxillary prominences form
i. Cheek
ii, Maxéilla
iii. Zygoma
iv. Lateral portions of upper lip
v. Secondary palate
Paired mandibular prominences form
i. Cheek
ii. Lower lip
iii. Mandible

2. Events that shape the facial appearance

® Nasal placodes
i. Appear on frontonasal prominence
ii, Medial nasal processes fuse to form intermaxillary segment
Maxillary prominences
i, Fuse with the lateral and medial nasal processes to form the upper lip
Nasolacrimal groove ,
i. Separates the lateral nasal process from the maxillary prominence
ii, Ectoderm floor forms the nasolacrimal duct
ili, Upper end forms the nasolacrimal sac
Mandibular prominences
i, Fuse laterally with the maxillary prominences to form the mouth and cheek
ii, Fuse in the midline to form the lower jaw

3. Nasal cavity
® Nasal placodes invaginate to form the nasal pit
® Nasal pit
i. Becomes the nasal sac
ii. Also known as anterior nares
Nasal sac
i. Grows upwards
ii, Separated from oral cavity by oronasal membrane
ili. Oronasal membrane breaks down at 7th week of intrauterine life
 Eye development 49

Posterior nares open into the pharynx

Nasal septum
i. Develops at the 9th week of intrauterine life
ii, Develops from the medial nasal processes
iii, Grows towards the palate
Maxillary sinus
i. Grows from lateral nasal cavity
ii, Grows into maxillary bones
The remainder of the paranasal sinuses develop after birth

4. Palate develops from fusion of

Primary palate (derived from the intermaxillary segment)
Secondary palate (formed by a pair of palatine process from the maxillary prominence)

Eye development

1. Placodes
Are thickened areas of ectoderm in the head region of the embryo
Form as a result of interaction between the neural tube and the overlying ectoderm
Become columnar
Invaginate
Migrate deep to the surface ectoderm

2. Optic vesicles
Are the earliest indication of the eye
Develop at 4th week of intrauterine life
Are an outgrowth from the lateral wall of the forebrain
Induce development of the lens placode
Become the optic cup

3. Optic stalk is the connection between the optic vesicle and the forebrain

4. Lens vesicle
Formed by lens placode
Detaches from surface ectoderm
Sinks into optic vesicle

5. Hyaloid artery
Branch of ophthalmic artery
Supplies
i. Lens (the branch of which eventually regresses)
ii. Retina
Runs along the choroidal fissure

6. Retina
Formed by 2 layers of the optic cup
j. Outer layer forms the pigmented layer
ii. Inner layer forms the rods and cones
At the rim of the optic cup the retina gives rise to
i. Ciliary body
ii. Iris
cS 50 Chapter 2 Embryology

7. The mesenchyme around the optic cup condenses to form

Inner choroids
Outer sclera

8. Cornea
Anterior part of the sclera
Transparent

9. Eyelids
Develop as folds of ectoderm
Grow over the cornea
Both the eyelids fuse initially (they separate at 5-7 months of intrauterine life)
The inner layer of the eyelid (ectoderm) becomes the conjunctiva

Ear development

. The ear develops from 3 different regions

@ External ear — 1st pharyngeal cleft
® Middle ear — 1st pharyngeal pouch
® Inner ear — otic placode

. Otic placode
® Close to hindbrain
® First part of ear to develop at 22 days of embryonic life
® Invaginates as the otic vesicle

. Otic vesicle
® Forms
i. Dorsal vestibular portion
ii. Ventral cochlear portion
® Gives rise to the endolymphatic sac
e Vestibular portion has 2 parts
i. Larger — utricle
ii, Smaller — saccule
® Utricle gives rise to 3 semicircular ducts
@ Structures within the otic vesicle form the membranous labyrinth
‘
 CHAPTER 3

Anatomy

Se SS EE ee eee ee ee ee ee ee ee eee.

CONTENTS Female genital tract 82

Trunk surface anatomy 51 Vascular tree — arteries 89
Abdomen 52 Vascular tree — veins 93
Pelvis 60 Lymphatic system 94
Gastrointestinal tract 66 Neuroanatomy 95
Accessory gastrointestinal and other organs 73 Endocrine anatomy 104
Urinary system 75 Fetal skull 109
Male genital tract 79

Trunk surface anatomy

1. Vertebral levels
@ 72 - Suprasternal notch
@ 1T5-Angle of Louis
® 719 - Xiphoid
®@ 11-Transpyloric plane of Addison
i. Halfway between suprasternal notch and pubis
ii, One hand width below xiphoid
iii. Crosses
@ Pancreatic neck
™ Duodenojejunal flexure
™ Fundus of gall bladder
= Tip of 9th costal cartilage
® Renal hilum
iv. Termination of spinal cord
@ 13 -Subcostal plane (line that joins the inferior margins of 10th rib)
® L4-lliac crest plane
i, Bifurcation of aorta
®@ §2- Posterior superior iliac spines
i. Termination of dural sheath

Position of umbilicus is variable, but is usually at vertebral level L3-L5

Costal margin is the medial margins formed by the false ribs (7-10)

Linea semilunaris is the lateral border of the rectus abdominis

Se

5. McBurney’s point is 2/3 of the way laterally along the line from the umbilicus to the anterior
superior iliac spine on the right side
 52 Chapter 3 Anatomy

6. Palmer’s point is 2/3 of the way laterally along the line from the umbilicus to the point of
intersection between the midclavicular line and the costal margins of the 9th rib

Arcuate line of Douglas is

® Where inferior epigastric vessels enter the rectus sheath
@ Point of termination of posterior rectus sheath
® Halfway between the umbilicus and the pubis

. Linea alba
® |sa fusion of abdominal muscle aponeuroses
® Stretches from xiphoid to pubic symphysis

Organs palpable in a normal adult

® Liver — lower border
® Right kidney — lower pole
® Caecum
®@ Sigmoid
e Aorta

10. Paracentesis is done at

® Midline (linea alba)
@ Lateral to McBurney’s point (to avoid inferior epigastric vessels)

Abdomen

Abdominal wall
ile Abdominal fasciae
® Trunk has only superficial fascia composed of
i, Fatty layer of Camper
ii, Deep fibrous layer of Scarpa
® Scarpa’s fascia
i, Blends in with deep fascia of upper thigh
ii, In the perineum it continues as Colles’ fascia

1h, Abdominal wall muscles (Table 3.1)

® Anterior wall muscles
i. Rectus abdominis
® Lateral wall muscles
i. External oblique
ii, Internal oblique
iii. Transversus abdominis
® Posterior wall muscles
i. Diaphragm
ii, Quadrates lumborum
iii. Psoas major
iv. lliacus

3, Rectus sheath aponeurosis

® Is made up of
i. Anterior leaf
ii, Posterior leaf
Posterior leaf is present only from below the costal margins to the arcuate line
® Composition (Table 3.2)
 Abdomen 53

Table 3.1 Abdominal wall muscles

SN
eee

Muscle Origin Insertion Innervation/notes

Anterior Rectus 5-7th costal Pubic crest Tendinous insertions

abdominal abdominis cartilages 1. 3 between xiphoid and
wall umbilicus
2. 1 below umbilicus
. Only on anterior rectus
a . Superior epigastric
WwW

vessels pierce the

rectus at this sites
External Outer surface of the 1. Xiphoid Innervated by anterior
oblique lower 8 ribs 2. Linea alba primary rami of T7-T12
3. Pubic crest
4. Pubic tubercle
5. Anterior half of
iliac crest

Internal 1, Lumbar fasciae 1. Lower 6 costal Innervated by anterior

oblique 2. Anterior 2/3 of cartilages primary rami of T7-112
Iliac crest 2. Linea alba
3. Lateral 2/3 of 3. Pubic crest
Inguinal ligament

Transversus 1. Lower 6 costal 1. Linea alba Innervated by anterior

abdominis cartilages 2. Pubic crest primary rami of T7-T12
2. Lumbar fascia
3. Anterior 2/3 of
Iliac crest
4. Lateral 1/3 of
Inguinal ligament

Posterior Psoas major Transverse process Lesser trochanter —__Innervated by anterior

abdominal of lumbar vertebrae of femur primary rami of L1 and L2
ll
“9 Acts as hip flexor

Psoas Bodies of T12 and L1___Iliopectineal Lies on psoas major

ee eee Absent in 40% of people

lliacus Upper 2/3 of inner Lateral side of Innervation is via the

aspect of lliac crest psoas major femoral nerve
tendon
Acts as hip flexor

Table 3.2 Rectus sheath composition

Above the costal Costal margins to arcuate Below the arcuate line of
margins line of Douglas Douglas

Anterior leave External oblique External oblique External oblique

Internal oblique Internal oblique
Transversus abdominis

Posterior None Internal oblique None

leave Transversus abdominis
 oF Chapter 3 Anatomy

Ligaments, canals, and fossae

1. Inguinal ligament
Also known as ligament of Poupart
Runs from anterior superior iliac spine (ASIS) to pubic tubercle
Aponeurosis formed by external oblique

2. Inguinal canal
3.8.cm long
Lies parallel and above inguinal ligament
Runs from internal to external ring
Internal ring
i. Lies on the transversalis fascia
ii. Midpoint of inguinal ligament
iii, Medially demarcated by inferior epigastric vessels
iv. 1.26cm above femoral artery
External ring
i. V-shaped
ii, Defect in external oblique aponeurosis
iii, Lies above and medial to pubic tubercle
Canal relations (Fig. 3.1)

OVE = Internal oblique;

ransversus abdominis.

ANTERIOR — Skin;
POSTERIOR —
Inguinal fascia; external
Conjoint tendon;
canal oblique aponeurosis;
transversalis fascia
internal oblique

BELOW — Inguinal ligament

Figure 3.1 Inguinal canal relations

3, Conjoint tendon
Fusion of
i, Internal oblique
ii, Transversus abdominis
Inserts into
i. Pectineal line
ii, Pubic crest

4. Spermatic cord comprises of

3 fascial layers
i, External spermatic (formed by external oblique aponeurosis)
ii, Cremasteric (formed by internal oblique)
iii. Internal spermatic (formed by transversalis fascia)
 Abdomen 55

® 3 arteries
i. Testicular (branch of aorta)
ii, Vas (branch of inferior vesicle)
iii. Cremasteric (branch of inferior epigastric)
3 nerves
i. Ilioinguinal (on top of cord)
ii, Cremasteric (branch of genitofemoral nerve)
ili. Sympathetic
3 other structures
i. Vas deferens
ii, Pampiniform plexus of veins
iii. Lymphatics

5. Femoral triangle
® Content
i. Femoral nerve
ii, Femoral artery
iii, Femoral vein
iv. Deep inguinal nodes
® Boundaries (Fig. 3.2)

SUPERIOR
— Inguinal
ligament
Femoral
triangle

MEDIAL - FLOOR - Iliacus; psoas

Adductor tenson; pectineus; adductor
longus longus

Figure 3.2 Femoral triangle boundaries

6, Femoral sheath (Fig. 3.3)

@ |s derived from extraperitoneal intra-abdominal fascia
i. Anterior = Transversalis fascia
ii. Posterior = lliacus fascia
Contains the
i. Femoral canal
ii, Femoral artery
iii, Femoral vein
® Does not contain the femoral nerve
 56 Chapter 3 Anatomy

Femoral sheath

Figure 3.3 Femoral sheath content (from lateral to medial)

7. Femoral ring
®@ Entrance to femoral canal
© Is oval
® Larger in females
@ Diameter = 1.25cm
® Contains
mat
ii. Lymph node (Cloquet’s)
® Boundaries (Fig. 3.4)

TERIOR— Inguinal
ligament

LATERAL — MEDIAL —
Femoral
Femoral : Lacunar
; ring ;
vein ligament

POSTERIOR -— Pectineus; pectineal

fascia; Astley Cooper ligament

Figure 3.4 Femoral ring boundaries

8. Lacunar ligament
® Also known as Gimbernat’s ligament
® Is part of aponeurosis of external oblique that is reflected backwards and lateralwards and is
attached to the pectineal line of pubis
Larger in males
Posterior margin is attached to pectineal ligament
Anterior margin is attached to inguinal ligament
9. Adductor canal
® Also known as
i. Subsartorial
ii. Hunter's
 Abdomen 57

@ Aponeurotic tunnel in the middle third of the thigh

Extends from apex of femoral triangle to the adductor hiatus
®@ Boundaries
i. Anterior and lateral = vastus medialis
ii, Posteriorly = adductor longus and magnus
@ Lying on the aponeurosis is the sartorius muscle
® The canal contains
i. Femoral vessels
ii. Saphenous nerve

10. Hasselbach’s triangle

®@ lsaspace bounded by
i, Laterally — inferior epigastric artery
ii. Medially — rectus abdominus
iii. Inferiorly — inguinal ligament
@ Also known as the inguinal triangle
@ Site of direct inguinal hernia

Peritoneal cavity
1. Peritoneal cavity is
®@ Formed by primitive coelomic cavity of the embryo
@ Serous lined
® Closed in the male
® Consist of the (Fig. 3.5)
i. Greater sac
ii. Lesser sac

Lesser omentum
Falciform ligament of liver

Gastrolienal Hepatic artery

ligament bile duct, and
portal vein

Epiploic
foramen
Inferior
vena cava

Phrenicolienal ligament
Aorta

Figure 3.5 Relations of the lesser (marked in dark grey) and greater (marked in purple) sac
Reproduced from Gray's Anatomy, 20 US ed., http://www.bartleby.com/107/246.html, with permission from Bartleby.com,
Inc.

2. Lesser sac
@ |s the cavity formed by the lesser and greater omentum
 58 Chapter 3 Anatomy hee

® Also known as omental bursa

Projects downwards between the layers of greater omentum (usually obliterated)
Boundaries
i. Left = spleen
ii. Right = epiploic foramen
iii, Superior = liver
iv. Anterior = stomach
v. Posterior = pancreas

3. Epiploic foramen
Is also known as foramen of Winslow
Is the entrance to the lesser sac
Borders (Fig. 3.6)

ANTERIOR —
POSTERIOR —
Epiploic Free border
Inferior vena
foramen of lesser
cava
omentum

INFERIOR —
Ist part of
duodenum;
hepatic
artery

Figure 3.6 Borders of epiploic foramen

4. Lesser omentum
Also known as gastrohepatic omentum
Is a double layer of peritoneum extending from liver to lesser curvature of the stomach
Is divided into 4 ligaments
i, Hepatogastric
ii. Hepatoduodenal
iii, Hepatopkrenic
iv. Hepato-oesophageal
Free border of lesser omentum contains portal vein, common bile duct, and hepatic artery
enclosed in Glisson’s capsule (Fig. 3.7)

5. Greater omentum
Also known as gastrocolic omentum
It is a large fold of peritoneum that extends from the stomach to the posterior abdominal
wall after encasing the transverse colon
 Abdomen

Is continuous with
i, Duodenum on the right
ii. Gastrolienal ligament on the left
iii. Blood supply = right and left gastroepiploic vessels
Is divided into 4 ligaments
i. Gastrocolic
ii. Gastrosplenic
iii. Gastrophrenic
iv. Splenorenal

6. Ligaments within the peritoneal cavity

Umbilical ligaments
i, Median (also known as urachus, an embryological remnant of the allantois)
ii, Medial (an embryological remnant of the umbilical artery)
iii. Lateral (overlies the inferior epigastric artery)
Falciform ligament (runs from umbilicus to liver)
Ligamentum teres
i. Remnants of umbilical vein
ii, Passes between quadrate and left liver lobes
iii, Attaches to the free border of falciform ligament

7. Intraperitoneal fossae — there are 4

The lesser sac
Intersigmoid
Paraduodenal (between duodenojejunal junction and inferior mesenteric vessels)
Retrocaecal

8. Subphrenic spaces — there are 5

Subphrenic
i. Right and left
ii. Divided by falciform ligament
Right subhepatic (Morison’s)
Left subhepatic (lesser sac)
Right extraperitoneal (between bare area of liver and diaphragm)

RIGHT -
Common
bile duct

Free border of lesser omentum

Figure 3.7 Content of the free border of the lesser omentum

 60 Chapter 3 Anatomy

Pelvis

Bones and ligaments

1. Pelvis is made up of
Innominate bones
Sacrum
Coccyx

2. Innominate bones consist of 3 bones

Ilium
Ischium
Pubis

3. lliopectineal eminence
Is the point of fusion between the pubis and ilium
Lateral to it, 2 muscles pass in a groove
i. Iliacus
ii. Psoas major

4. Obturator foramen is bounded by the pubis and ischium

5. Acetabulum is the fusion point of all 3 innominate bones

6. Sacrum
Is made up of 5 fused vertebrae
ls triangular
Sacral promontory represents the anterior border of the upper part of
sacrum
Consists anteriorly of
i. Central mass
ii, 2x row of 4 anterior sacral foramina
iii, 2 * lateral mass
iv. 2 X ala (superior aspect of lateral mass)
Consists posteriorly of
i. Sacral canal
ii, 2 * row of 4 posterior sacral foramina
iii, Sacral hiatus (transmits the 5th sacral nerve)
iv. Sacral cornua
v. Superior articular facet
Dural sheath terminates at S2, beyond which the sacral canal contains
i, Fatty tissue of extradural space
ii, Cauda equina
iii, Filum terminale

7, Coccyx is made up of 3-5 fused vertebrae

8. Pelvic joints
Symphysis pubis is not a synovial joint
Sacroiliac joint is a synovial joint

9. Pelvic brim is bounded by

Pectineal line
Arcuate line
 Pelvis 61

® Sacral promontory
© Upper margins of symphysis pubis

10. Linea terminalis consists of

@ Arcuate line
@ Pectineal line
® Pubic crest

11. Pelvic outlet

® Js bounded by
i, Pubic arch (ischiopubic rami)
ii, 2X sciatic notch
ili, Coccyx
®@ Diamond in shape

12. Dimple just above the buttocks defines

CO) Sp)
® Sacroiliac joint
@ Termination of dural sheath
© Posterior superior iliac spines

13. Sacrospinous ligament runs from the ischial spine to the sacrum/coccyx

14. Sacrotuberous ligament runs from sacrum to ischial tuberosity

15. Boundaries of greater sciatic foramen (Fig. 3.8)

ANTEROLATERAL — Greater POSTEROMEDIAL

Greater sciatic sciatic ~ Sacrotuberous
notch foramen ligament

INFERIOR — Sacrospinous
ligament

Figure 3.8 Boundaries of the greater sciatic foramen

16. Boundaries of lesser sciatic foramen (Fig. 3.9)

 62 Chapter 3 Anatomy

ANTERIOR - Ischial
tuberosity

SUPERIOR — Lesser LATERAL —-

Sacrospinous sciatic Lesser sciatic
ligament foramen notch

POSTERIOR — Sacrotuberous
ligament

Figure 3.9 Boundaries of the lesser sciatic foramen

17. Female versus male pelvis (Table 3.3)

Table 3.3 Female versus male pelvis

Male Female

Acetabulum Large Small

Obturator foramen Round Oval
Ischial tuberosity Inturned Everted

Pelvic inlet Heart shaped Oval

Pelvic canal Long ’ Short
Pelvic outlet Small Large
Inferior pubic rami angle Acute Wide (90°)
Ischial tuberosity angle - Admits 4 knuckles
Sacrum Long and narrow Short and wide

18. Pelvis measurements (Table 3.4)

@ Plane of inlet = 60° to the horizontal
Diagonal conjugate = 12.7cm (promontory of sacrum to lower border of pubic symphysis)
Anteroposterior outlet is from midpoint of pubic symphysis to apex of coccyx
Transverse outlet is the distance between the ischial tuberosities
Oblique outlet is from midpoint of sacrotuberous ligament to junction of opposite ischial
and pubic rami
 Pelvis 63

Table 3.4 Pelvic measurements in centimetres

SS ee ee ee

Transverse Oblique Anteroposterior

Inlet 27 11.5 10
lliopectineal eminence — Sacral promontory — symphysis
opposite sacroiliac joint pubis
Mid Wiles LS eS)
Lower sacroiliac joint — $3 — Midpoint of pubic symphysis
midpoint of obturator
membrane

Outlet 10 HS a7
Distance between Pubis to sacrococcygeal joint
ischial tuberosities

Pelvic muscles (Table 3.5)

Table 3.5 Pelvic muscles

Muscle Origin Insertion Notes

Piriformis af, Anterior part of sacrum Greater trochanter 1. Exits pelvis via greater
2. Greater sciatic foramen of femur sciatic foramen
. Anterior surface of 2. Is pierced by the common
sacrotuberous ligament peroneal nerve

Obturator ile Medial surface of obturator Greater trochanter Exits pelvis via lesser sciatic
internus membrane of femur foramen
. Ischium
. Pubis

Obturator fo Obturator membrane Greater trochanter

externus 2 Obturator foramen of femur

Fasciae
1. Pelvic fascia
@ |s the term applied to the connective tissue of the covering of the pelvis
@ Includes the fascial coverings of
i. Levator ani
ii. Obturator internus

2. Endopelvic fascia
@ |s the extraperitoneal tissue of the
i. Uterus (parametrium)
ii, Vagina
iii. Bladder
iv. Rectum
® Gives rise to 3 sets of ligaments
i. Cardinal ligaments
ii, Uterosacral ligaments
ii, Pubocervical ligaments (extend from cardinal ligaments to pubis)
 64 Chapter 3 Anatomy

® These 3 ligaments
i. Support the cervix and vaginal vault
ii, Are lengthened in pelvic floor prolapse

3. Cardinal ligaments
@ Also known as
i. Transverse ligaments
ii. Mackenrodt’s ligaments
® Pass laterally from the cervix and upper vagina
® Attach to pelvic side walls along the line of insertion of the levator ani
® Pierced by ureters

4, Uterosacral ligaments
® Originate
i. From posterolateral aspect of cervix
ii, At the level of isthmus
e@ Attached to
i. Periosteum of sacroiliac joints
ii, Lateral part of S3
® Encircle the pouch of Douglas

5. Round ligament
® Together with the ovarian ligament is equivalent to the male gubernaculum
®@ Blood supply is via uterine artery

Pelvic floor
1. The pelvic floor is made up of 2 components
e@ Pelvic diaphragm (Table 3.6)
i. Levator ani
ii, Coccygeus muscle
® Superficial muscles of the perineum forming
i, Anterior (urogenital) triangle
ii, Posterior (anal) triangle

Table 3.6 Pelvic diaphragm

?
Pelvic floor
muscle Origin Insertion Notes

Levator ani 1, Posterior aspect of pubic bone 1. Perineal body Forms

2. Fascia of side wall of pelvis 2. Anal sphincter 1. Levator prostate
(covering obturator internus) 3. Coccyx 2. Sphincter vaginae
3. Ischial spine 4. Median fibrous 3. Puborectalis
raphe 4. Pubococcygeus
5. lliococcygeus
Coccygeus 1. Sacrospinous ligament Coccyx
2. Ischial spine
a
ee ee eee

2. Anterior (urogenital) triangle is bound by

® Line across ischial tuberosities
® \schiopubic inferior rami
 Pelvis 65

. Perineal membrane
@ Is attached to the urogenital triangle
® Is pierced by
i. Urethra
ii. Vagina
® Forms 2 spaces
i. Deep perineal pouch
ii. Superficial perineal pouch

. Deep perineal pouch

® Is bound by perineal membrane and levator ani fascia
® Contains
i. External urethral sphincter
ii, Deep transverse perineal muscle
iii. Bulbourethral glands (Cowper's)

. Superficial perineal pouch

®@ Boundaries
i. Superiorly = perineal membrane
ii. Inferiorly = perineal fascia (Colles’ fascia)
® Contains
i. Superficial perineal muscles
ii. Bulbospongiosus
iii. Ischiocavernosus
iv. Bartholin’s glands (greater vestibular glands)
v. Crura ofclitoris

. Perineal body
@ ls a fibromuscular node
® Lies in the midline at the junction of the anterior and posterior perineum
® |s the point of attachment for
i. External anal sphincter
ii. Bulbospongiosus
iii. Transverse perineal muscles
iv. Levator ani

. Posterior (anal) triangle

® ls the space between the ischial tuberosities and coccyx
® Contains
i. Ischiorectal fossa
ii, Levator ani
iii. Anus

. Ischiorectal fossa
® Contains
i, Lobulated fat
ii. Anus
iii. External anal sphincter
iv. Alcock’s canal
@ Fossae on either side communicate with each other behind the anus
@ Boundaries (Fig. 3.10)

. External anal sphincter attaches to

® Perineal body
66 Chapter 3 Anatomy

® Coccyx
@ Puborectalis

MEDIAL = External
LATERAL — anal sphincter;
Obturator fascia levator ani fascia

Ischio-
rectal
fossa

FLOOR —-
SUPERIOR —
Subcutaneous
Levator ani
fat; skin

POSTERIOR —
Sacrotuberous
ligament; gluteus
maximus

Figure 3.10 Boundaries of ischiorectal fossa

Gastrointestinal tract

Stomach
1. Is Jshaped

2. Consists of
® Fundus
® Body
® Pyloric antrum

3. Body secretes
®@ Pepsin
®@ HCl (oxyntic cells)

4, Pyloric antrum secretes

® Alkaline juices
® Gastrin

5. Incisura angularis marks the junction between the body and pyloric antrum

6. Vein of Mayo marks the junction between the pylorus and duodenum

7. Sphincters
® Cardia
® Pylorus
. . : i -as = te Gas sintestinal tract S67
j

_ 8. Borders (Fig. 3.11)

| = ERIOR
— Left costal margi
ae _ diaphragm; left tobe of liver

POSTERIOR — Lesser sac;

SUPERIOR — Left ; pancreas; transverse
dome of
_ mesocolon; spleen; splenic
diaphragm ~ artery; left kidney; left
= suprarenal gland

Figure 3.11 Relationship of stomach to other abdominal organs

9. Blood supply is via branches of the coeliac axis (Fig. 3.12)

® Left gastric artery
® Splenic artery
® Hepatic artery

Left gastric artery

Short gastric artery

Splenic artery

Left gastroepiploic
5 ue artery
'- Coeliac axis

Right gastric artery.

Hepatic artery Cystic artery

Right gastro-
: Sale epiploic artery
Gastroduodenal
arter f
¥ Superior
pancreatoduodenal
artery

Figure 3.12 Arterial branches of the coeliac axis

 68 Chapter 3 Anatomy

10. Lymphatics
® Area 1 (superior 2/3 of stomach) drains directly to aortic nodes
@ Area 2 (right 2/3 of inferior 1/3 of stomach) drains via subpyloric node to aortic nodes
© Area 3 (left 1/3 of inferior 1/3 of stomach) drains via suprapancreatic node to aortic nodes
11. Nerve supply
e Vagus nerve
@ Posterior nerve of Latarjet

Duodenum
‘le C shaped

2. Contains Brunner’s glands

3. 25.5cm long

4, Covered by peritoneum for 2.5cm then becomes retroperitoneal

5. Divided into 4 parts

6. 1st part
® 5cm long
® Relations (Fig. 3.13)

; ANTERIOR - Liver; gall bladder

1st part of
duodenum

POSTERIOR - IVC; portal veins;

common bile duct; gastroduodenal
artery

Figure 3.13 1st part of duodenum and its spatial relations

a . 2nd part
® 75cm long
® Curves around head of pancreas
® Contains
i, Major duodenal papilla (also known as ampulla of Vater) — which is the opening of the
major pancreatic duct (also known as duct of Wirsung) and the common bile duct
ii, Minor duodenal papilla — which is the opening of the accessory pancreatic duct (also
known as duct of Santorini)
iii. Sphincter of Oddi
® Relations (Fig. 3.14)
 Gastrointestinal tract

8. 3rd part
® 10cm long
@ Runs transversely towards the left
® Relations (Fig. 3.15)

9. 4th part is 2.5cm long

ANTERIOR — Transverse colon

2nd part of
‘ duodenum

POSTERIOR = Right kidney; ureter

Figure 3.14 2nd part of duodenum and its spatial relations

ANTERIOR - Superior mesenteric

vessel; mesenteric root

3rd part of
duodenum

POSTERIOR — IVC; aorta; L3

Figure 3.15 3rd part of the duodenum and its spatial relations

10. Duodenojejunal junction is identified by

® Ligament of Treitz (a peritoneal fold from the right crus of the diaphragm containing some
smooth and skeletal muscle fibres)
 70 Chapter 3 Anatomy

@ Inferior mesenteric vessels descend from behind the pancreas immediately to the left of the
junction

11. Blood supply

® Superior pancreatoduodenal artery
@ Inferior pancreatoduodenal artery (branch of superior mesenteric artery)

Small intestines
1. Measure 3-10m long

2. Small intestine mesentery

® Js 15cm long
® Starts at duodenojejunal junction (L2)
® Ends at right sacroiliac joint

3. Have valvulae conniventes

4, Jejunum versus ileum

® Jejunum has a thicker wall
@ jejunum has a larger diameter
® jejunum lies in the umbilical region
© |leum has a thicker and more fat laden mesentery
® Mesenteric vessels form 1-2 arcades at the jejunum while at the ileum they form
3-5 arcades

Large intestine
1, Comprises 7 portions
Caecum (along with the appendix)
Ascending colon (20cm long)
Transverse colon (45.5 cm long)
Descending colon (25.4cm long)
Sigmoid (12.7-76 cm long)
Rectum (12.7 cm long)
Anal canal (3.8 cm long)

2. Has appendices epiploicae (fat-filled peritoneal tags) except for

® Appendix
® Caecum
® Rectum

3. Has taenia coli (3 flattened bands running from base of appendix to retrosigmoid junction)
except for
® Appendix
® Rectum

4. Has sacculations

5. Peritoneal coverings (Box 3.1)

6. Mucosa has
® Goblet cells
® No villi

7. Nerve plexus
® Meissner’s (in submucosa layer)
® Auerbach’s (between muscular layers)
 Gastrointestinal tract

Box 3.1 Peritoneal coverings of the large intestine

© Transverse colon © Ascending colon ® Caecum

© Sigmoid ® Descending colon © Appendix

Rectum
1. Has no peritoneal covering in its
®@ Upper 1/3 posteriorly
®@ Middle 1/3 posteriorly and laterally
®@ Entire lower 1/3

Commences at $3

Ends at level of
@ Lower 1/4 of vagina in women
® Apex of prostate in men

Has
® 3 lateral inflexions (left, right, left)
® Valves of Houston

Denonvilliers’ fascia separates the rectum from anterior structures

Relations (Fig. 3.16)

ANTERIOR~Pouch of Douglas; uterus;

_ bladder; prostate; seminal vesical;
vagina oe

LATERAL —
Levator
ani

POSTERIOR — Sacrum; coccyx;

middle sacral artery; lower sacral
nerve

Figure 3.16 Rectum and its spatial relations

Anal canal
ils Epithelium
® Lower half = squamous
@ Upper half = columnar (columns of Morgagni)
® This junction is separated by valves of Ball
oe 72 Chapter 3 Anatomy

2. Blood supply
® Upper 1/2 = superior rectal vessel
@ Lower 1/2 = inferior rectal vessel

3. Lymphatics
© Upper 1/2 = lumbar nodes
® Lower 1/2 = inguinal nodes

4. Relations
e Anterior = perineal body
® Posterior = coccyx
® Lateral = ischiorectal fossa

5. Haemorrhoids = dilatation of superior rectal veins

Appendix
1. Also known as vermiform appendix

2. Connects to the caecum

3. Base is 2.5cm below the ileocaecal valve

4, Lies posteromedial to caecum

5. Length = 2.5—23cm

6. Blood supply = ileocolic artery

7. Has 2 folds of peritoneal attachment

® leocaecal fold
@ Appendix mesentery

8. lleocaecal fold
® Passes from the front of the ileum to the appendix
® |s also known as bloodless fold of Treves

9. Appendix mesentery
®@ Descends from behind the ileum to the appendix
® Contains the ileocolic artery

Portal vein system

1. Drains blood from the alimentary tract (excluding the anus) to the liver

2. Formation
@ Inferior mesenteric vein joins the splenic vein above L3
® Superior mesenteric vein joins the splenic vein behind neck of pancreas at L1, giving rise to
the portal vein
® Portal vein divides into right and left branches

3. Collateral pathways between portal and systemic venous systems

® Oesophageal branch of left gastric vein and oesophageal vein of Azygos
system
® Superior rectal and inferior rectal veins
® Portal branches of liver and
i. Veins of diaphragm (bare area)
ii, Veins of abdominal wall (via falciform ligament)
 Accessory gastrointestinal and other organs 73

® Portal tributaries in mesocolon, mesentery, and retroperitoneal veins to

i. Renal veins
ii, Lumbar veins
iii, Phrenic veins

Meckel’s diverticulum
1, Remnant of vitello-intestinal duct (communication between midgut and yolk sac)

2. Always on anti-mesenteric border

3. Rules of 2
® Prevalence = 2%
Male : female = 2:1
2 inches (5 cm) long
Situated 2 ft (61cm) from ileocaecal junction

Accessory gastrointestinal and other organs

Liver
1. Largest organ in the body

2. Has 4 lobes
@ Right
@ Left
® Anterior quadrate
® Posterior caudate

3. Contains
® Falciform ligament
® Ligamentum teres (remnant of left umbilical vein)
@ Ligamentum venosum (remnant of ductus venosum)

4. Lesser omentum arises from

® Porta hepatis
® ligamentum venosum

5. Porta hepatis
@ 5cm long
® Contains (Fig. 3.17)

Porta hepatis

Hepatic
artery
POSTERIOR —
Portal vein

Figure 3.17 Content of porta hepatis

74 chapter 3 Anatomy

6. Venous drainage — 3 in total

@ Left
@ Right
® Central

7. Blood supply
e@ Left hepatic artery
® Right hepatic artery
® Cystic artery

Biliary system
1. Common hepatic duct
© Formed from fusion of right and left hepatic ducts
® 3.8cm long

2. Cystic duct = 3.8cm long

3. Common bile duct

© Formed from fusion of common hepatic duct and cystic duct
® 10cm long

4, Gall bladder
® Holds 50mL of bile
© Separates the right and quadrate lobes of the liver
® Epithelium = columnar

Pancreas
1. Weighs 80g

2. Contains islets of Langerhans which secrete

® Glucagon (from a cells)
® Insulin (from B cells)
® Somatostatin (from 6 cells)
® Pancreatic polypeptide (from F cells)

3. Is retroperitoneal

4. Is both an endocrine and exocrine organ

5. Relations (Fig. 3.18) '

6. Blood supply
@ Splenic artery
® Pancreatoduodenal artery

7. Development
® Ventral bud
i, It is smaller
ii, Forms part of the head and uncinate process
iii. It is drained by the duct of Wirsung (also known as the major pancreatic
duct)
® Dorsal bud
i. It is larger
ii. Forms the body, tail, and part of the head and uncinate process
ili, Contains the accessory duct of Santorini (also known as the accessory pancreatic duct)
which is non-functional
 Urinary system 75

ABOVE - Splenic artery

POSTERIOR —
Left kidney ANTERIOR —
suprarenal 2 Pancreas ve Stomach;
gland; lesser sac
diaphragm

POSTERIOR = IVC; portal vein (inferior and superior

mesenteric and splenic veins); aorta (superior
mesenteric and coeliac arteries)

Figure 3.18 Pancreas and its spatial relations

Spleen
1. Size = a cupped hand

2. Ligaments
® Gastrosplenic
i, Runs to greater curve of stomach
ii Carries short gastric and left gastroepiploic artery
@ Lienorenal
i. Runs to posterior abdominal wall
ii, Contains splenic artery and tail of pancreas

3. Accessory spleen tissue can occur in

®@ Ovary
@ Testes
®@ Omentum
@ Small bowel mesentery
® Tail of pancreas

Urinary system

Kidney
1. ls retroperitoneal

2. Right kidney is 1.26cm lower than the left

3. Relations (Fig. 3.19)

4. Vessel order at the hilum (front to back)
 Chapter 3 Anatomy

Vein
Artery
Pelvis of ureter

5. Supplied by sympathetic nerve fibres

6. Has 3 capsules
Renal fascia
Perinephric fat
True capsule

7. Renal fascia blends with

Above = diaphragm
Medially = IVC and aorta
Laterally = transversalis fascia
Inferiorly = tracts the ureter
8. The suprarenal glands are not in the renal fascia

~ ANTERIOR- Liver; 2nd part of

duodenum; ascending colon;
mach; descending colon;
ancreas; spleen

POSTERIOR — Diaphragm; quadratus lumborum; psoas;

tranversus abdominis; 12th rib; nerves (T12
intercostal/ lliohypogastric/ llioinguinal)

Figure 3.19 Kidney and its spatial relations

Ureters

1. Are 25.4cm long

2. Are valveless

3. Route
Pass anterior to the medial edge of psoas major
Separated from tip of transverse process (L2—L5) by psoas major
Cross into pelvis at the bifurcation of common iliac artery in front of sacroiliac joint
Run on lateral wall of pelvis
Run in front of internal iliac artery
Pass under uterine artery
 Urinary system 77

® Pass 1.5cm lateral to supravaginal cervix

® Cross into bladder at ischial spine
® Pierce cardinal and broad ligaments

4. Relations (Fig. 3.20)

LATERAL — Pelvic
side wall

POSTERIOR (in a caudal direction) — Psoas major; common

iliac artery bifurcation; internal iliac artery

Figure 3.20 The ureter and its relationship to other organs

5. Crossed by (in a caudal direction)

® Ovarian/testicular vessels
® Right colic vessels and ileocolic vessels on the right side
®@ Left colic vessels on the left side
® Uterine vessels

6. Blood supply (in a caudal direction) is from branches of the

®@ Aorta
Renal artery
Ovarian/testicular artery
Internal iliac artery
Inferior vesical artery

7. Narrowing occurs at 3 sites

® Junction with the renal pelvis
@ Pelvic brim
® Ureteric orifice
8. Common sites of ureteral injury during surgery are
® Lateral to the uterine vessel
® |n the tunnel of the cardinal ligament
@ Base of the infundibulopelvic ligament (as the ureters cross the pelvic brim at the ovarian
fossa)
@ The lateral pelvic wall (just above the uterosacral ligament)
 78 Chapter 3 Anatomy

Bladder
{ls ls extraperitoneal

24, Is intra-abdominal in children <3 years old

3. Ureteric orifices are 2.5 cm apart

Trigone is the triangular area bounded by

@ Ureteric orifices
® Internal meatus

Relations (Fig. 3.21)

"ANTERIOR -
| Pubic symphysis _

SUPERIOR — LATERAL —
Peritoneum; Bladder Levator ani;
intestine; obturator
uterus internus

POSTERIOR — Rectum; vasa

deferentia; seminal vesicles;
vagina; cervix

Figure 3.21 Bladder and its spatial relations

Urethra
ile In females
® |s 3.8cm long
® Lies 2.5cm behind the clitoris

2. In males
@ |s 25.4cm long
® |s divided into 3 portions (Box 3.2)
® Prostatic utricle
i. Opens into the colliculus seminalis (verumontanum)
ii, Is a blind tract
iii, Is the remnant of paramesonephric duct
Chpt 2 iv. Is the equivalent of the vagina

3. Has spiral grooves on the inside

 Male genital tract 79

Box 3.2 Portions of the male urethra

; Prostatic Membranous Spongy

® Posterior wall bears the urethral © Located in deep perineal pouch ® Also known as cavernous or
crest and prostatic sinus ® Contains external urethral penile portion
sphinter
® Narrowest part of urethra
Bulbourethral glands enter here

4. Epithelium changes between

® Transitional (near the bladder)
® Stratified columnar
® Stratified squamous (near the external urethral orifice)
5. Contains mucus-secreting urethral glands

6. Urethral sphincter
® Has two parts
i. Internal
= Located at the junction of the urethra and bladder
Composed of smooth muscle (as a continuation of the bladder’s detrusor muscle)
Under autonomic sympathetic control from the inferior hypogastric plexus
In males it prevents retrograde flow of semen in the bladder during ejaculation
In females it is not anatomically distinct, although smooth muscle fibres are still
present
ii. External
= Located at the junction of the urethra and bladder in females and after the prostate
in males
= Composed of skeletal muscle
®™ Under voluntary control via the perineal branch of the pudendal nerve (but not
exclusively)

Male genital tract

1. External genitalia consist of

@ Scrotum
Testes
Epididymides
Vasa deferentia
Penis, consisting of
i. A pair of corpus cavernosa
ii, Corpus spongiosum

2. Internal genitalia consist of

® Seminal vesicles
@ Ejaculatory ducts
® Prostate gland
®@ Bulbourethral glands (Cowper’s)

3. Scrotum
® ls pigmented and rugose
ee 80 Chapter 3 Anatomy

® Contains
i. Median longitudinal raphe
ii. Sebaceous glands
iii, _Dartos muscle
e@ Divided into 2 sacs
® Temperature is 2.5°C lower than body temperature

4, Epididymides
@ Consist of
i. Head
ii. Body
iii, Tail
® Measure 6m long
® Lined by ciliated epithelium
® Passage of sperm through them takes 8-14 days

5. Vasa deferentia
® Measure 45cm long
@ Join the spermatic cord
® Connect to the epididymides
® Similar length to
i. Femur
ii. Thoracic duct
iii. Spinal cord
iv. Distance from incisor to cardiac end of stomach

6. Seminal vesicles
® |rregular-shaped sacs
® Lie between base of bladder and rectum
® Measure 5cm long
® Functions
i. Reservoir for spermatozoa
ii, Secrete nourishing fluid for sperm

7. Ejaculatory ducts
® Measure 2.5 cm long
@ Eject sperm into urethra
® Connect vas deferens to urethra

8. Bulbourethral (Cowper’s) glands

® Situated at root of penis
@ Pea sized

Testes
1. The left testis lies lower than the right

2. Oval shaped

3. Measurements
@ Dimensions = 55 x 30mm
® Weight = 10-15g
® Volume = 15-30mL

4. Have 3 layers
® Tunica vaginalis
 Male genital tract 81

® Tunica albuginea
® Tunica vasculosa

Functions
® Produce spermatozoa
® Produce testosterone

Consist of 2 types of cell

® Sertoli cells
® Leydig cells

Structure
@ Divided in to 300 lobules
Each lobule has 1-3 seminiferous tubules
Each tubule = 61cm (2ft) long
Seminiferous tubules anastomose at rete testes

. Seminiferous tubules
@ Lined with germinal epithelium
@ Make up 90% of testes
® Have a basement membrane that acts as a blood barrier

. Testicular artery anastomoses with vas artery (the vas artery is a branch of the inferior
vesical artery)

10. Lymph drainage

®@ Para-aortic lymph nodes
® Cervical nodes

1 _ . Nerve supply is via T10

12. Development (fetal life)

® 3 months — reach iliac fossa
@ 7 months — traverse inguinal canal
® 8 months — situated at external ring
® 9 months — descend in scrotum

13. Embryological remnants

® Appendix testes is the remnant of the paramesonephric duct
@ Appendix epididymis is the remnant of the mesonephros

. Sertoli cells
@ Situated within seminiferous tubules
@ Nourish spermatozoa
@ Produce inhibin and oestrogen
® Contain follicle-stimulating hormone (FSH) receptors

ib), Leydig cells

@ Situated between seminiferous tubules
® Produce testosterone
®@ Contain luteinizing hormone (LH) receptors

Prostate
ile Measures 4 X 3cm

2s Pyramidal in shape

oF Relations (Fig. 3.22)

 82 Chapter 3 Anatomy

SUPERIOR -
Bladder neck

ANTERIOR — Pubic
symphysis;
retropubic space
LATERAL — Prostate (cave of Retzius);
Levator ani prostatic plexus;
puboprostatic
ligament

INFERIOR —
External
urethral
sphincter

Figure 3.22 Prostate and its spatial relations

4, Has 2 capsules
@ True capsule
® False capsule, which is the extraperitoneal fascia (continues with bladder and Denonvilliers’
fascia)

5. Blood supply = inferior vesical artery

6. Prostatic plexus
® Lies between the 2 capsules of the prostate
® Receives the dorsal vein of the penis
® Drains into
i. Internal iliac vein
ii. Valveless vertebral veins of Batson

Female genital tract

ik External genitalia
® Collectively known as the vulva
© Extend from
i. Anteriorly — mons pubis
ii, Posteriorly — perineum
iii, Laterally — labium majora
® Consist of
i. Mons pubis
ii, Labia majora
iil, Labia minora
iv. Vestibule
v. Clitoris
 Female genital tract 83

. Mons pubis is the pad of fatty tissue that lies above the symphysis pubis

. Labia majora
® Extend from mons pubis to perineum
®@ Analogous to the scrotum
® Contain
i, Hair-bearing skin
ii. Sebaceous glands
iii. Smooth muscle (tunica Dartos)
iv. Nerve endings (free and corpuscles = Ruffini/Pacini/Merkel/Meissner)
® Insertion point of round ligament
® Nerve supply
i. lliohypogastric nerve
ii. llioinguinal nerve
iii. Genitofemoral nerve
iv. Posterior femoral cutaneous nerve
v. Pudendal nerve

. Labia minora
© Hairless skin folds
® Give rise to
i. Prepuce
ii. Frenulum
iii. Fourchette
® Contain sweat and sebaceous glands

. Vestibule
® |s the area enclosed by labia minora
® Contains
i. Urethral orifice
ii. Vaginal orifice
®@ Blood supply
i. Azygos artery of vagina
ii, Pudendal artery

. Clitoris
® Contains erectile tissues
® Consists of
i. Aglans
ii. A shaft that is attached to the pubis
iii, Paired crura that are attached to the inferior pubic rami
@ Ischiocavernosus muscles
i. Overlie the crura of the clitoris
ii. Originate from ischial tuberosity
© Bulbospongiosus (also known as bulbocavernosus) muscle
i. Originates from perineal body
ii. Inserts into clitoral shaft
iii. Overlies vestibular bulb and Bartholin’s glands

. Bartholin’s glands
® A pair of glands that lie
i. Between the perineal membrane and bulbospongiosus muscle
ii, At the tail end of the vestibular bulb
iii. Deep to posterior labia majora
 Chapter 3 Anatomy

Pea sized
Duct = 2.5cm long
Drains at 5 ’clock and 7 ’clock positions between the hymen and labium minus

8. Introitus
Is the vaginal orifice
Situated in the vestibule
Covered with hymen
Remnants of hymen are called carunculae myrtiformes

9. Vagina
Vaginal orifice is demarcated by the hymen (carunculae myrtiformes)
Length
i. Anterior wall = 7.5cm
ii, Posterior wall = 10cm
iii, Length is proportional to height of the individual
Cervix projects into anterior part of vaginal vault
Has no glands
Is kept moist by
i. Cervical glands
ii. Seepage of fluid from blood capillaries
Relations (Fig. 3.23)

~ ANTERIOR -
‘Bladder;
urethra

SUPERIOR - LATERAL —
Ureter Levator
: ani;;
pelvic fascia

POSTERIOR -— Anal canal; rectum;

peritoneum (upper 1/4 of vagina)

Figure 3.23 Borders of the vagina

Peritoneum covers only the posterior upper 1/4 of the vagina

Ureters lie above and lateral to the fornix, 1.5m away from the cervix
Blood supply
i, Uterine artery
ii, Vaginal artery
iii, Internal pudendal artery
iv, Middle rectal artery
 Female genital tract 85

® Lymphatic drainage (Box 3.3)

Box 3.3 Lymphatic drainage of the vagina

Upper 1/3 ofvagina | Middle

1/3ofvagina = Ms Lower 1/3ofvagina
® External iliac nodes © Internal iliac nodes ® Inguinal nodes
® Internal iliac nodes

© Gartner's duct cyst is a mesonephric remnant in the vagina

@ Vaginal fluid
i. pH=4
ii, High K* content
iii. Low Na* content
iv. Remains alkaline 6 h post coitus
® Vaginal wall is composed of 4 layers
i. Inner squamous epithelium
ii. Connective tissue
iii. Muscular layer (inner circular and outer longitudinal)
iv. Connective tissue
@ Epithelium is arranged in folds (arbour vitae)
®@ Vagina contains Doderlein’s bacilli (converts glycogen to lactic acid)
® Nerve supply is via the sacral plexus

10. Uterus
®@ Pear-shaped organ
® Weighs
i. Nulliparous = 50g
ii, Multiparous = 70g
iii. Term = 1kg
Measures 7.5 x 5 x 2.5cm
Consists of
i. Fundus
ii, Body
iii, Isthmus
iv. Cervix
@ Ante-flexed or retroflexed
i. Flexion of uterus at the level of the internal os
ii, Is usually 170°
® Anteversion or retroversion
i. Axis of cervix on vagina
ii. Is usually 90°
® Relations (Fig. 3.24)
Lymphatic drainage (Box 3.4)
®@ Uterus is made up of 3 layers of tissue
i. Endometrium
ii. Myometrium
iii, Perimetrium
® Endometrium consist of 2 layers
i. Functional layer
ii, Basal layer
®@ Cervical endometrium is not shed during menstrual cycle
 Chapter 3 Anatomy

Myometrium is composed of 3 layers of muscle

i, Inner circular
ii. Middle oblique
iii. Outer longitudinal
Perimetrium is made up of peritoneum
Nerve supply is via sacral plexus
Blood supply
i. Basal layer — straight arterioles
ii. Functional layer — spiral arterioles

ANTERIOR — Uterovesical
pouch; intestines;
superior surface of
bladder

POSTERIOR — LATERAL —
Pouch of Broad
Douglas; ligament;
intestines ureter

Figure 3.24 Uterus and its and its spatial relations

Box 3.4 Lymphatic drainage of the uterus

PT
® Via round ligament to inguinal node
as
® Via broad ligament to external iliac node
© Via ovarian vessel to para-aortic node

11. Cervix
Epithelium consists of
i, Supravaginal portion = columnar cells
ii, Vaginal portion = stratified squamous cells
Cervical mucosa displays
i. Arbour vitae
ii, Spinnbarkeit
Lymphatic drainage (Box 3.5)
12. In pregnancy
Lower segment of uterus is composed of
i, Isthmus = 70%
ii, Cervix = 30%
Internal os lies in the cervix
Shortening of the upper segment is called retraction
 Female genital tract 87

Box 3.5 Lymphatic drainage of the cervix

© Via broad ligament to external @ Via uterine vessels to internal ® Sacral node
lliac node iliac node

®@ Decidua
i, Is endometrium under the influence of progesterone
ii, Has high glycogen content
iii, Produces prolactin and insulin-like growth factor (IGF)
® Braxton Hicks ,
i. Can occur as early as 8 weeks
ii, 25mmHg of pressure is sufficient to cause cervical dilatation

1 w . Fallopian tubes
@ 10cm long
® Composed of
i. Isthmus — 2.5cem
ii, Amputlla—5cm
iii. Infundibulum — 2.5m
iv. Fimbriae
@ Have 4 layers
i. Lined by ciliated columnar epithelium
ii. Inner circular muscle
iii, Outer longitudinal muscle
iv. Peritoneum
@ Nerve supply is via ovarian plexus

14. Uterine ligaments consist of

@ Broad ligaments (is a double fold of perimetrium)
Round ligaments (run from cornua to labia majora)
Cardinal ligaments (run from cervix to lateral wall of pelvic cavity)
Uterosacral ligaments (run from cervix to periosteum of sacrum)
Pubocervical ligaments (run from cervix to pubic bone)

15. Infundibulopelvic ligaments

@ Are folds of broad ligament
® Extend from infundibulum to lateral wall of the pelvis
® Contain ovarian vessels

16. Ovaries
@ Measure 3cm x 2cm x 1cm
Weight 5-8 g
Irregular surface
Almond shaped
Have 4 layers
i. Germinal epithelium
ii. Tunica albuginea
iii, Cortex (contains ovarian follicles)
iv. Medulla (contains vessels)
® Ovarian support ligaments
i. Infundibulopelvic ligament
 88 Chapter 3 Anatomy a ae

ii, Broad ligament

iii, Ovarian ligament
Attached to back of broad ligament by mesovarium
Lie in the ovarian fossae
Nerve supply is via T10
Ovarian epithelium is cuboidal

17. Ovarian fossa (Waldeyer’s fossa)

® Shallow depression on the lateral wall of the pelvis
® Contains the obturator nerve
© Boundaries (Fig. 3.25)

‘SUPERIOR —
External iliac
vessel

Ovarian
fossa

POSTERIOR — ANTERIOR —-
Internal iliac Obliterated
vessels; umbilical
ureter artery

Figure 3.25 Boundaries of the ovarian fossa

18. Breasts
® Are modified sudoriferous glands which produce milk
® Overlie
i, 2nd-6th rib ;
i, Serratus anterior
iii, Pectoralis major
iv. Rectus sheath
® Structure
i. Have 20 lobules
ii, The lobules are drained to the nipple via lactiferous ducts
® Ligaments of Cooper
i, Separate the lobules
ii, Run from subcutaneous tissue to fascia of chest wall
® Glands of Montgomery
i. Lubricates areola
ii, Are modified sebaceous glands
® Tail of Spence is the superior lateral quadrant of the breast that extends towards
the axilla
 Vascular tree — arteries 89

® Blood supply
i. Axillary artery via
= Lateral thoracic artery
= Acromiothoracic artery
ii, Internal thoracic artery
iii. Intercostal arteries
® Nerve supply of the breast is from T4-T6
®@ Nerve supply to the nipple is from T4
® Lymphatic drainage
i. Axillary
ii, Parasternal
iii, Abdominal
©@ Develops from ectoderm

19. Homologous male structures

@ Skene’s gland = prostate
Bulbourethral gland (Cowper’s) = Bartholin’s
Prostatic utricle = vagina
Labia majora = scrotum
Clitoris = penis

Vascular tree — arteries

1. Aorta
@ Branches
i. Inferior phrenic arteries
ii. Coeliac trunk
iii, Suprarenal arteries
iv. Superior mesenteric artery
v. Renal arteries
vi. Gonadal arteries
Ss.i. Lumbar (4 paired lateral arteries)
viii. Inferior mesenteric artery
ix. Median (also known as middle) sacral artery
® Bifurcates at L4 into the 2 common iliac arteries
®@ Enters abdomen at the level of T12

2. Common iliac arteries

® Commence at the level of L4
End at L5/S1
Bifurcate at sacroiliac joints
Relations (Fig. 3.26)

3. External iliac arteries

®@ Branches
i. Inferior epigastric arteries
ii. Deep circumflex iliac arteries
® Relations (Fig. 3.27)

4. Internal iliac arteries

@ Also known as hypogastric arteries
® Arise at bifurcation of common iliac arteries (level of L5/S1)
 ANTERIOR — Superior hypogastric
plexus; small bowel

Common
iliac
artery

LATERAL — POSTERIOR — Sympathetic

trunk; obturator nerve;
pvoee aioe iliolumbar artery

Figure 3.26 Common iliac artery and its spatial relations

ANTERIOR at ORIGIN — Ureter; gonadal

vessels; genital branch of genitofemoral
nerve; deep circumflex iliac vein; round
ligament

External MEDIAL -—
LATERAL —
iliac = Femoral
Psoas major
artery vein

POSTERIOR — Psoas major

Figure 3.27 External iliac artery and its spatial relations

Are the main arteries of the pelvis

© Supply
i. Pelvic organs
ii, Buttocks
iii. Medial compartment of thighs \
® Relations (Fig. 3.28)
® Divide into 2 branches at the margin of the greater sciatic foramen (Box 3.6)
® Collateral circulations — anastomoses
i, Uterine and ovarian arteries
ii, Middle rectal and superior rectal arteries
 Vascular tree —arteries 91

iii, Obturator and inferior epigastric/medial circumflex femoral arteries

iv. Superior and inferior vesical arteries
v. Profunda femoris and inferior gluteal arteries
vi. Superior gluteal and lateral sacral arteries
vii. Lateral sacral and median sacral arteries
viii. lliolumbar and lumbar arteries
ix. Iliolumbar + superior gluteal and superficial iliac circumflex arteries

LATERAL —
External iliac Internal
vessels; : iliac | MEDIAL - Small
obturator nerve; artery
bowel
psoas major

POSTERIOR — Internal iliac vein;

lumbosacral trunk; piriformis

Figure 3.28 Internal iliac artery and its spatial relations

Box 3.6 Branches of the internal iliac artery

Brances of anterior branch ; Branches of posterior branch

Uterine ® |lio lumbar
Vaginal ® Lateral sacral
Vesical (inferior and superior) © Superior gluteal
Umbilical
Obturator
Gluteal
Rectal
“Internal pudendal

5. Femoral arteries
® Branches of external iliac
® Route
i. Run medial to femur
ii. Cross via the adductor hiatus (a hole in the tendon of adductor magnus)
iii, Enter into popliteal fossa
iv. Become the popliteal arteries
® Pass under inguinal ligament
 Chapter 3 Anatomy

® Lie
i. In the femoral triangle
ii, On the tendon of psoas major
®@ Branches (Fig. 3.29)

Profunda
femoris
Epigastric
Superficial om
t
pila Circumflex
Descending hee
genicular
Superficial
External
pudendal
} sep |

Figure 3.29 Branches of the femoral artery

6. Obturator arteries
®@ Arise from
i. Internal iliac (anterior division)
ii, Rarely
= External iliac
= Internal iliac (posterior division)
= Superior gluteal
@ Inferior epigastric
® Route
i, Pass anteroinferiorly on the lateral wall of the pelvis to the obturator foramen
ii. Leave pelvic cavity via obturator canal
iii, Rarely
= Pass lateral to femoral ring
™ Curve on the free margin of the lacunar ligament
® Branches (Fig. 3.30)

Iliac branch

=s
Insid tvi
Pubic

Vesical
branch

Outside
pelvis
Posterior |

Figure 3.30 Branches of the obturator artery

® Communicate with
i. llioltumbar
ii, Inferior epigastric
® Relations (Fig. 3.31)
 Vascular tree — veins 93

MEDIAL -
LATERAL—
Obturator Ureter; ductus
Obturator
artery deferens;
fascia
peritoneum

INTERIOR —
Obturator
nerve

Figure 3.31 Obturator artery and its spatial relations

7. Internal pudendal arteries

® Supply the external genitalia
e Are the terminal branches of the anterior division of the internal Iliac arteries
® Smaller in females compared with males
@ Route
i, Exit pelvis via greater sciatic foramen
ii, Curve around sacrospinatous ligament
iii. Enter ischio-anal fossa via lesser sciatic foramen
iv. Travel in the pudendal (Alcock’s) canal
@ Branches (Fig. 3.32)

Internal
pudendal

Deep artery Anterior bulb

Inferior rectal Perineal | ESTE Darsat amen)
labial of clitoris of clitoris of vestibule

Figure 3.32 Branches of the internal pudendal artery

8. Homologous male and females structures

@ Vaginal artery = inferior vesical artery in male
® Uterine artery = middle rectal artery in male

Vascular tree — veins

1. IVC
@ Commences at level of L5
® Terminates at level of T8
@ Relations (Fig. 3.33)

2. Gonadal veins
@ Right drains directly in to IVC
® Left drains to left renal vein
 94 Chapter 3 Anatomy

ANTERIOR — Root of ileal mesentery; 3rd part

of duodenum; head of pancreas; bile duct;
portal vein; 1st part of duodenum; posterior
abdominal peritoneum; bare area of liver

POSTERIOR — Lumbar artery; renal artery;

sympathetic chain; suprarenal gland; inferior
phrenic artery

Figure 3.33 IVC and its spatial relations

3. Greater saphenous veins

® Large superficial veins
® Originate from dorsal vein of big toe
®@ Route
i. Pass anterior to the medial malleolus
ii, Run over posterior border of medial epicondyle of femur
iii. Enters fascia lata via saphenous opening on the anterior aspect of the thigh
iv. Join femoral vein in femoral triangle
® Receive
i. Tibial veins
ii, Femoral vein branches
4. Thoracoepigastric veins
® Connect femoral and axillary veins
® Run lateral to the superficial epigastric veins

Lymphatic system
Chpt 4
1. Thoracic duct
® Originates from cisterna chyli at the level of T12
® Drains into the left subclavian vein
@ Measures 45cm

2. Right lymphatic duct

® Arises anterior to scalenus anterior
® Drains into the right subclavian vein
® Measures 10mm

3. Drainage of abdominal lymph glands (Fig. 3.34)

 Neuroanatomy 95

Figure 3.34 Abdominal lymph gland drainage

Neuroanatomy

Brain
1. Brain consists of 4 principal parts
® Brain stem consisting of
i. Midbrain
ii, Pons
iii. Medulla oblongata
@ Cerebellum
® Diencephalon consisting of
i. Thalamus
ii, Hypothalamus
iii. Pineal gland
® Cerebrum

2. Cerebrum
® The superficial layer is the grey matter and is called cerebral cortex
® Consists of
i. Gyri
ii. Sulei
© Corpus callosum is white matter that connects the cerebral hemispheres
®@ Each hemisphere is divided into 4 lobes
i. Frontal
ii, Parietal
iii. Temporal
iv. Occipital
@ Precentral gyrus
i. Located anterior to the central sulcus
ii, Is the primary motor area
® Postcentral gyrus
i. Located posterior to the central sulcus
ii. Is the primary somatosensory area

3. Basal ganglia
@ Are several groups of nuclei in each cerebral hemisphere
® Consist of
i. Corpus striatum
ii. Substantia nigra
iii. Red nuclei
iv. Subthalamic nuclei
 96 Chapter 3 Anatomy

© Corpus striatum is made up of

i. Caudate nucleus
ii, Lenticular nucleus
® Lenticular nucleus is made up of
i. Putamen
ii. Globus pallidus

4. Cerebrospinal fluid (CSF)

® Circulates in the subarachnoid space
@ There are 4 CSF-filled cavities within the brain
i. 2 lateral ventricles
ii, Third ventricle
iii, Fourth ventricle
® Measurements
i. Total CSF volume in body = 80-150mL
ii, Rate of production = rate of absorption = 20mL/h
6 Produced
i. By choroid plexus
ii, Via filtration of blood plasma
® Flow of CSF (Fig. 3.35)

Lateral i Aqueduct of Fourth Subarachnoid

ventricles

Figure 3.35 CSF flow

® Reabsorption occurs via

i. Arachnoid villi in the superior sagittal sinus
ii Choroid plexus

Cranial nerves
1. Cranial nerves — there are 12 pairs (Table 3.7)

Somatic pathways
1. Somatic motor and sensory pathways (Fig. 3.36)
e Motor
i. Pyramidal tract
ii, Extrapyramidal pathway
® Sensory
i. Posterior column
ii, Spinothalamic column

2. Spinothalamic tract
®@ Formed by 3 neurone sets
i. Pseudounipolar neurones in the dorsal root ganglion
ii, Tract cells (i.e, secondary neurones in the substantia gelatinosa or the nucleus proprius)
iii, Several nuclei in the thalamus (i.e. third order neurones)
® The pathway decussates at the level of the spinal cord in the anterior white commissure
 : Neuroanatomy 97

Table 3.7 Cranial nerves

Cranial nerve Origin Runs via Exits via

Olfactory Olfactory foramina

Optic Optic canal
Oculomotor Midbrain Lateral wall of Superior orbital fissure
cavernous sinus
Trochlear Midbrain Cavernous sinus Superior orbital fissure
Trigeminal Pons Cavernous sinus Ophthalmic nerve — Superior
orbital fissure
Maxillary nerve — Foramen
rotundum

Mandibular nerve — Foramen ovale

Abducens Pons Cavernous sinus Superior orbital fissure

Facial Cerebellopontine Internal acoustic Stylomastoid foramen

angle canal and facial canal

Vestibulocochlear Cerebellopontine Internal acoustic canal

angle

Glossopharyngeal Medulla Jugular foramen

Vagus Medulla Carotid sheath Jugular foramen

Accessory Foramen magnum Jugular foramen

Hypoglossal Medulla Lies on carotid Hypoglossal canal

sheath

Posterior column tracts

Posterior grey horn

Central canal Posterior spinocerebellar

tracts
Lateral
corticospinal tracts
Anterior spinocerebellar
tracts

Anterior grey horn (with Lateral

cell body of motor spinothalamic tracts
neurone)

Anterior spinothalamic
Anterior corticospinal
tracts
tracts

Figure 3.36 Somatic motor and sensory pathways in the spinal cord

® Consists of two tracts

i. Lateral spinothalamic tract (transmits pain and temperature)
ii, Anterior spinothalamic tract (transmits touch)
® Type of impulse modality conducted
i. Pain
 98 Chapter 3 Anatomy

ii. Temperature
iii. Touch
iv. Pressure
Pathway (Fig. 3.37)

a Splncthalamic track Postcentral gyrus

Figure 3.37 Spinothalamic pathway

3. Posterior column
Also known as dorsal column-medial lemniscus pathway
Formed by 3 neurone sets
i. First set = Meissner’s corpuscles
ii, Second set = gracile and cuneate nucleus (forms the medial lemniscus)
iii. Third set = ventral posteromedial nucleus of the thalamus
Types of impulse modality conducted
i. Proprioception
ii. Discriminative touch
iii, 2-point tactile discrimination
iv. Pressure
v. Vibration
Composed of
i. Fasciculus gracilis
ii, Fasciculus cuneatus
This pathway is tested with Romberg’s test
Pathway (Fig. 3.38)

Figure 3.38 Posterior column pathway

4. Corticospinal tracts
Consist of
i, Lateral corticospinal tract — 90% (Fig. 3.39)
ii. Anterior corticospinal tract — 10% (Fig. 3.40)

5. Extrapyramidal pathway consists of

Rubrospinal tract
Tectospinal tract
Vestibulospinal tract

Spinal nerves
1. Meninges
Are connective tissue covering the brain and spinal cord
 Neuroanatomy 99

Left precentral gytus Internal capsule 90% decussate in medulla #§ Right lateral corticospinal
to contralateral side tract

Figure 3.39 Lateral corticospinal pathway

Left precentral gyrus Internal capsule 10% stay on ipsilateral sidepy U°f afer io! Soneospins|

Figure 3.40 Anterior corticospinal pathway

® Composed of 3 layers
i. Dura matter (runs from brain to 2nd sacral vertebrae)
ii, Arachnoid
iii, Pia matter

2. Spinal cord
® Extends from medulla oblongata to vertebral level
i. In adults — L1
ii, In infants — L3/L4
® Conus medullaris
i, Is the conical portion of the spinal cord
ii, Ends at L1
iii. Gives rise to filum terminale
@ Filum terminale
i. Is the extension of the pia matter
ii. Ends at the coccyx
®@ Cauda equina are nerve roots that arise inferior to the conus
medullaris
® Potential spaces
i. Epidural space — between wall of vertebral canal and dura
ii, Subdural space — between dura and arachnoid
iii, Subarachnoid space — between arachnoid and pia matter

3. Spinal nerves
@ There are 31 pairs
i. Cervical — 8
ii, Thoracic — 12
iii. Lumbar — 5
iv. Sacral —5
v. Coccygeal — 1
® Have 2 roots
i. Posterior (dorsal) root — contains sensory fibres
ii Anterior (ventral) root — contains motor fibres
@ Posterior root has a ganglion
i 100 Chapter 3 Anatomy

Peripheral nerves
1, Nerve plexuses
Cervical (C1—CS5)
Brachial (C5—T1)
Lumbar (T12-L5)
Sacral (L4—-S5)

Lumbar plexus
Gives rise to
i. lliohypogastric nerve (L1)
ii, Ilioinguinal nerve (L1)
iii, Genitofemoral nerve (L1—L2)
iv. Lateral femoral cutaneous nerve (L2-L3)
yv. Obturator nerve (L2-L4)
vi. Femoral nerve (L2-L4)
Originates from the anterior primary rami of L1-L4
Traverses the psoas major and emerges from its lateral borders except for the
i. Obturator nerve (emerges from the medial border)
ii, Genitofemoral nerve (emerges from the anterior aspects of the muscle)

lliohypogastric nerve
Originates from the anterior ramus of L1 (which also contains some fibres from 112)
Emerges on the lateral border of psoas major
Perforates the transversus abdominis muscle
Branches
i. Lateral cutaneous
ii, Anterior cutaneous
Communicates with the ilioinguinal nerve (which also originates from the anterior
ramus of L1)

Genitofemoral nerve
Emerges from the anterior surface of psoas major
Branches
i. Femoral branch (lumboinguinal)
ii. Genital branch
Femoral branch travels
i Lateral to external iliac artery
ii, Beneath inguinal ligament
Genital branch innervates (via the deep inguinal ring)
i, Cremaster muscle
ii. Scrotum
iii, Mons pubis
iv. Labia majora

. Obturator nerve
Arises from L2—L4
Emerges from the medial border of psoas major
Route
i, Passes behind common iliac vessels
ii, Lateral to internal iliac vessels and ureter
iii, Runs along lateral wall of lesser pelvis
iv. Runs above and in front of the obturator vessels
v. Enters the thigh via the obturator canal and divides into anterior and posterior divisions
 Neuroanatomy 10

® Branches
i. Anterior
ii, Posterior
® Both anterior and posterior branches are divided by
i. Obturator externus muscle
ii, _Adductor brevis muscle
®@ |nnervations
i. Medial aspect of thigh
ii, Knee joint
iii, Adductor muscles of lower limb
e@ Adductor muscles of lower limb innervated by the obturator nerve include
i. External obturator
ii, Pectineus
iii, Adductor longus
iv. Adductor brevis
y. Adductor magnus
vi. Gracilis

6. Femoral nerve
e@ Largest branch of lumbar plexus
® Arises from L2-L4
® Emerges from lateral border of psoas major
®@ Route
i. Passes between psoas major and iliacus muscles
ii. Runs behind the iliac fascia
iii. Divides into 2 divisions beneath the inguinal ligament which straddle the lateral
circumflex femoral artery
@ Branches
i. Anterior
ii, Posterior
@ Anterior femoral branch consists of
i. Intermediate anterior cutaneous nerve
ii, Medial anterior cutaneous nerve
®@ Posterior femoral branch consists of
i. Saphenous nerve
ii. Vastus lateralis
iii, Vastus medialis
iv. Vastus intermedius
® Innervates
i. Hip joint
ii, Knee joint
iii, Anterior compartment of thigh
@ Anterior compartment of thigh muscles innervated by the femoral nerve include
i. Quadriceps
ii. Sartorius
iii, Pectineus

7. Saphenous nerve
@ Branch of femoral nerve
® Route
i. Descends in the femoral triangle
ii, Enters adductor canal
 102 Chapter 3 Anatomy

iii, Continues with long saphenous vein

iv. Crosses anterior to the medial malleolus (where it is palpable)

8. Sacral plexus
S1-S4
Lies between the piriformis muscle and the pelvic fascia
In front of it are
i. Internal iliac vessels
ii, Ureter
iii. Sigmoid colon
Gives rise to
i. Superior gluteal nerve (L4—S1)
ii, Sciatic nerve (L4—-S3)
iii. Inferior gluteal nerve (L5-S2)
iv. Posterior cutaneous nerve (S1—S3)
y. Pudendal nerve (S2-S4)

9. Posterior cutaneous nerve

Innervates
i. Perineum
ii, Skin of posterior thigh and leg
Route
i. Exits pelvis via the greater sciatic foramen
ii. Descends beneath gluteus maximus with inferior gluteal artery
iii, Runs down the back of the thigh beneath the fascia lata
iv. Pierces the deep fascia at the knee and accompanies the small saphenous vein

10. Superior gluteal nerve

Innervates
i. Gluteus medius
ii. Gluteus minimus
iii. Tensor fascia lata
Route
i. Leaves the pelvis via the greater sciatic foramen above piriformis
ii. Accompanies the superior gluteal vessels

11. Inferior gluteal nerve

Innervates the gluteus maximus :
Leaves the pelvis via the greater sciatic foramen below piriformis

12. Sciatic nerve

L4-S3
Longest single nerve in the body
Innervates
i. Nearly the entire skin of the leg
ii, Obturator internus
iii. Biceps femoris
iv. Semitendinosus
v. Semimembranosus
vi. Adductor magnus
vil. Hip joint
Route
i, Exits the pelvis via the greater sciatic foramen below piriformis
 Neuroanatomy 103

ii. Descends between greater trochanter of femur and tuberosity of ischium

ii. Divides at lower 1/3 of posterior thigh into 2 branches
Branches
i. Tibial
= Passes through the popliteal fossa
@ Innervates
= All muscles of the foot except extensor digitorum brevis
@ Knee joint
® Ankle joint
= Skin over lateral aspect of foot
= Branches
= Sural nerve (provides the cutaneous innervation)
® Plantar nerve
ii, Fibular (or common peroneal) divides into 2 branches
= Deep (innervates extensor digitorum brevis)
= Superficial
The division can take place from any point between the sacral plexus to the lower 1/3 of the
thigh
Accompanied by
i. Posterior femoral cutaneous nerve
ii. Inferior gluteal artery
Crossed by long head of biceps femoris
Covered by gluteus maximus

13. Pudendal nerve

Arises from S2-S4
Route
i. Passes between piriformis and coccygeus muscles
ii, Leaves the pelvis via the greater sciatic foramen
iii. Crosses the ischial spines
iv. Re-enters pelvis via lesser sciatic foramen
v. Runs along the pudendal vessels in the ischiorectal fossa
vi. Contained in the obturator internus fascia called pudendal (Alcock’s) canal
Branches
i. Inferior anal nerve (arises at greater sciatic foramen)
ii. Perineal (superficial)
iii. Dorsal nerve of penis/clitoris (traverses the deep perineal pouch)
Innervates
i. Penis
ii, Scrotum
iii. Clitoris
iv. Bulbospongiosus
v. Ischiocavernosus
vi. Anus

Autonomic nerves
1. Autonomic plexuses
Coeliac
i. Formed by coeliac ganglia
ii. Supplied by greater splanchnic nerve and vagus nerve
Superior mesenteric
ea 104. Chapter 3 Anatomy

Aortic
Inferior mesenteric
Superior hypogastric — lies at the bifurcation of the aorta
Inferior hypogastric
i. Two plexuses, each located on either pelvic side wall
ii. Together form the pelvic hypogastric plexus

2. Splanchnic nerve
Preganglionic sympathetic fibres form
i. Greater splanchnic nerve (T5-T9)
ii. Lesser splanchnic nerve (T10-T 11)
iii. Least splanchnic nerve (112)
iv. Lumbar splanchnic nerve (S1—S4) — joins superior hypogastric plexus
v. Sacral splanchnic nerve (L1—L4) — joins inferior hypogastric plexus
Preganglionic parasympathetic fibres form
i. Pelvic splanchnic nerve (S2—S4) — joins inferior hypogastric plexus

3. Pelvic splanchnic nerve

Also known as nervi erigentes
Located on the side of the rectum
Provides motor innervation to
i. Beyond the left 1/3 of the transverse colon
ii. Uterus
iii. Bladder
Provided sensory innervation to
i. Bladder
ii. Urethra
iii, Rectum
iv. Anal canal
v. Cervix
vi. Upper vagina
vii. Prostate

4. Inferior hypogastric plexus postganglionic sympathetic innervations

Motor
i. Seminal vesicles
ii. Prostate
iii. Anal sphincter :
iv. Urethral sphincter
Sensory
i, Upper rectum
ii Body of uterus

Endocrine anatomy

1. Hypothalamus
Located
i. Below the thalamus
ii. Above the brain stem
Forms the floor of the 3rd ventricle
Includes
 Endocrine anatomy 105

Coeliac Vagus

Superior
mesenteric
plexus

Inferior
mesenteric

Superior
hypogastric

Inferior Inferior
hypogastric hypogastric
plexus

Pelvic
splanchnic
nerve

Figure 3.41 Nervous plexus pathways

 Sites
106 Chapter 3 Anatomy

i, Optic chiasm
ii, Tuber cinereum
iii, Infundibular stalk (connects to posterior pituitary)
iv. Mamillary bodies
v. Posterior perforated substance
® Has 2 portions
i. Posteromedial (has sympathetic innervation)
ii, Anterolateral (has parasympathetic innervation)

2. Pituitary gland
® Also known as hypophysis
@ Pea sized
® Sits on sella turcica (pituitary fossa) in the sphenoid bone
® Covered by a dural fold (sella diaphragm)
® Has 3 parts
i. Anterior lobe (adenohypophysis) — develops from Rathke’s pouch
ii, Posterior lobe (neurohypophysis)
iii, Pars intermedia
®@ Develops from ectoderm
e@ Borders (Fig. 3.42)

[ ABOVE-
Optic
chiasm

BELOW —
Sphenoid
bone

Figure 3.42 Boundaries of the pituitary

© Blood supply to anterior pituitary lobe is via the infundibulum (Fig. 3.43)

Forms primary =
Superior plexus at base Hypophyseal SEMS Anterior
hypophyseal ce} portal veins secondary hypophyseal
artery plexus vein
hypothalamus

Figure 3.43 Vascular network of the anterior pituitary

 Endocrine anatomy 107

® Blood supply to posterior pituitary lobe (Fig. 3.44)

Internal carotid — Inferior Plexus of

hypophyseal infundibular Posterior
artery. hypophyseal vein
artery process

Figure 3.44 Vascular network of the posterior pituitary

® Anterior lobe composed of 3 cell types

i. Chromophobe
ii. Eosinophilic
iii. Basophilic
® Adenohypophysis secretes 6 hormones
i. Gonadotrophins (FSH and LH)
ii, Prolactin
iii. Growth hormone
iv. Thyroid-stimulating hormone (TSH)
y. Adrenocorticotrophic hormone (ACTH)
vi. Melanocyte-stimulating hormone
® Neurohypophysis stores and secretes 2 hormones, which are produced by the
hypothalamus
i. Oxytocin
ii, Antidiuretic hormone (ADH)

3. Pineal gland
® Secrets melatonin
® Often calcified
® Attached to roof of 3rd ventricle
® Covered by a capsule formed by pia matter

4. Thyroid gland
@ ‘st endocrine organ to appear at day 24 of embryonic development
® Weights 30g
®@ Blood supply = 120mL/min
@ Arterial supply
i. Superior thyroid (branch of external carotid artery)
ii. Inferior thyroid (branch of subclavian artery)
iii. Thyroid ima (branch of aortic arch/ brachiocephalic artery)
® Venous drainage
i. Superior thyroid (drains to internal jugular vein)
ii, Middle thyroid (drains to internal jugular vein)
ii. Inferior thyroid (drains to left brachiocephalic)
@ |s made up of
i, Isthmus (overlying 2nd and 3rd tracheal ring)
ii, Lateral lobes (extends to 6th tracheal ring)
iii. Pyramidal lobe (also known as the Lalouette’s pyramid)
@ |s enclosed in pretracheal fascia
 108 Chapter 3 Anatomy

Thyroid follicles contain 2 cell types

i. Follicular
ii. Parafollicular (C cells)
3 principal hormones are secreted
i. Thyroxine (T4)
ii, Triiodothyronine (T3)
iii, Calcitonin (from C cells)
Relations (Fig. 3.45)

ANTERIOR - Strap muscles;

sternocleidomastoid; anterior
jugular vein

POSTERIOR — Larynx; trachea; carotid

sheath

Figure 3.45 Thyroid gland and its spatial relations

5. Parathyroid glands
There are usually 4 (10g each)
Pea sized
Yellowish-brown in colour
Contain 2 cell types
i, Chief
ii. Oxyphilic

6. Carotid sheath
Extends from base of skull to 1st rib and sternum
Contains
i. Internal carotid artery (medial)
ii, Internal jugular vein (lateral)
iii. Vagus nerve
iv. Deep cervical lymph node
Nerves that pierce the sheath
i. Glossopharyngeal
ii, Accessory
iii. Hypoglossal

7. Suprarenal (adrenal) glands

Lie above the kidneys
Measure 3cm * 5cm
Weigh 5g
 Fetal skull 109

® Have 2 regions
i. Cortex
= Derived from mesoderm
™ Subdivided into 3 zones
ii, Medulla
= Derived from ectoderm
® Contain chromaffin cells
@ Adrenal cortex zones
i, Zona glomerulosa (secretes mineralocorticoids)
ii. Zona fasciculata (secretes glucocorticoids)
iii. Zona reticularis (secretes androgens)
® Chromaffin cells
i. Are sympathetic postganglionic cells
ii, Secrete catecholamines (adrenaline (epinephrine) and noradrenaline (norepinephrine))
® Blood supply
i. Renal artery
ii, Phrenic artery
iii. Aorta
® Venous drainage
i. Right suprarenal drains into the IVC
ii. Left suprarenal drains into the left renal vein
@ Fetal adrenals produce surfactant
@ Nervous supply
i. Receives preganglionic sympathetic fibres
ii. No parasympathetic supply

Fetal skull

1. Fetal skull bones (9 in total)

® 2-*< frontal
®@ 2% parietal
® 2% temporal
® 2 sphenoidal
® 1 * occipital

2. Fetal skull sutures (8 in total)

1 x frontal
® 1 x sagittal
® 2% coronal
® 2 x lambdoidal
® 2 X squamous (lie between parietal and temporal bones)

3. Fetal skull fontanelles (6 in total) (Box 3.7)

® 1 x anterior
® 1 X posterior
® 2% sphenoidal
@ 2x mastoid

4. Designations
@ Vertex is the area encompassed by the anterior fontanelle, posterior fontanelle and the
2 parietal eminences
 110 Chapter 3 Anatomy

® Occiput is behind the posterior fontanelle

® Sinciput is the area in front of the anterior fontanelle, divided into
i. Brow (area above root of nose)
ii, Face (area below root of nose)

&, 5. Dimensions
Chpt 9.10 ® Diameter
i, Biparietal = 9.5cm
ii, Bitemporal = 8.5cm
iii, Suboccipitobregmatic (presenting in an occipital position) = 9.5cm
iv. Occipitofrontal (presenting in a vertex position) = 11.5cm
v. Mentovertical (presenting in a brow position) = 14cm
vi. Submentobregmatic (presenting in a face position) = 9.5cm
@ Circumferences
i, Subocipitobregmatic x biparietal (presenting in a vertex position) = 28cm
ii. Occipitofrontal x biparietal (presenting in a occiput posterior position) = 33cm
iii. Mentovertical x biparietal (presenting in a brow position) = 35.5cm

Box 3.7 Fetal skull fontanelles

Anterior (Bregma) Posterior 5 capes ees

(anterolateral) (posterolateral)
© Bordered by frontal ® Bordered by parietal ® Bordered by frontal, © Bordered by parietal,
and parietal bones and occipital bones parietal, temporal and temporal and occipital
© Diamond shaped ® Closes at 2 months sphenoidal bones bones
® Closes at 18 months of life ®@ One on each side © One on each side
of life
CHAPTER 4

Physiology

CONTENTS Male reproductive system 150

Acid—base balance 111 Musculoskeletal system 152
Calcium homeostasis 115 Nervous system 154
Cardiovascular system 122 Lymphatic system 161
Respiratory system 128 Skin 161
Digestive tract and nutrition 136 Special senses 163
Urinary system 141 Fetal and placental tissues 165
Female reproductive system 144 Physiological changes in pregnancy — quick glance 172

Acid—base balance

Fluids
1. H,O balance
® Total body volume = 42L (60% total body weight) (Fig. 4.1)
® Total blood volume = 5.6L (plasma + RBC)
@ Fluid losses occur by 4 routes (exact amount depends on ambient temperature, humidity,
and intake)
i. Lungs — 400 mL/day of water is lost in expired air
ii, Skin — 1 L/day
iii. Faeces — 100mL/day
iv. Urine — 1.5 L/day (minimum UO/day = 400 mL)
@ Maintenance fluid requirement = 30 mL/kg/day

2. Hormones that regulate extracellular fluid (ECF) volume

® Directly
i. ADH
® Indirectly
i. Atrial natriuretic peptide (ANP)
ii, Renin—angiotensin system — this primarily regulates plasma osmolarity and indirectly
blood volume via aldosterone
® Minor regulators with some effect
i. Glucocorticoids
ii, Catecholamines

3. Osmosis
® Movement of water from low solute concentration to a higher one via a semi-permeable
membrane
 112 Chapter4 Physiology

Intracellular = Extracellular =
28L

sigh =
Interstita
\ntracellu \ar 40.5L
= 28L

Figure 4.1 Distribution of total body fluid volume

® Opposed by hydrostatic power

1 osmol/L depresses freezing point by 1.86°C
® Osmolarity
i. Defined as number of osmoles of solution per litre of solution (Osm/L)
ii. Is a measure of solute concentration
® Osmolality isa measure of osmoles of solutes per kilogram of solvent (Osm/kg)

4. Plasma osmolarity
® Total plasma osmolarity = 300 mOsm/L
® Consist of
i. Na* = 140mOsm/L (Na* is the main contributor to plasma osmolarity)
ii, Cl = 140mOsm/L
ii, KT =4mOsm/L
iv. Anion = 4mOsm/L
v. Glucose = 5mOsm/L
vi. Urea = 5mOsm/L

5. Starling’s law of the capillaries

© Refers to fluid movement across capillary membrane as a result of filtration
© Starling’s forces shows the relationship between hydrostatic and oncotic pressures (Box 4.1)

Box 4.1 Starling’s forces

_ Oncotic pressures (mmHg) Hydrostatic pressures (mmHg)

® Blood (BOP) = 26 © Arterial (BaHP) = 35
® Interstitial (IOP) =14 ® Venous (ByHP) =6

© Interstitial (IHP) = 0

@ Net filtration pressure (NFP) = pressure promoting filtration (BHP + IOP) — pressure
promoting reabsorption (BOP + IHP)
i, NFP arterial end = (35 + 1) — (26 + 0) = 10 mmHg
ii, NFP venous end = (16 + 1) — (26 + 0) =-9mmHg

6. Oedema (Box 4.2)

® Signifies increased fluid in interstitial space
® Anasarca is generalized oedema with subcutaneous tissue swelling
 Acid—base balance 113

© Pathophysiology of oedema
i. Increased hydrostatic pressure
ii, Reduced plasma oncotic pressure
iii, Lymphatic obstruction
iv. Sodium retention
v. Inflammation

Box 4.2 Causes of oedema

Lymphatic obstruction : Sodium retention

Inflammatory ® Increased renin—angiotensin secretion
Neoplastic
Post-surgical
Post-irradiation

Acid—base balance
1. Main organs involved in regulating acid-base balance
@ Respiratory system
Kidney
Blood
Bone
Liver (generates HCO} and NH; by glutamine metabolism)

2. Anion gap (Box 4.3)

® |s the difference between the concentrations of the body’s cations and anions
® Normal values range between 8 and 16 mEq/L

Box 4.3 Causes of altered anion gap

® Lactic acidosis (methanol; salicylate; paraldehyde) © Bromide

® Ketoacidosis ® Myeloma
® Hypoalbuminaemia

3. Henderson—Hasselbach equation
@ CO,@HCO;+ H*
@ fH" is generated reaction shifts to the left
i. Generates CO,
ii. Consumes HCO;
® lf HCO; is lost reaction shifts to the right
i. Generates H*
ii. Consumes CO,
@ A net gain in H” is the same as a net loss in HCO;

4. pH
® |sa logarithmic relationship
@ |s the negative logarithm (with base 10) of hydrogen ion concentration (— logy [H+])
© pH = pK + logio [HCO3 ]/[CO2]
5. Normal maternal arterial values (Box 4.4)

6. Normal fetal values (Box 4.5)

 114. Chapter 4 Physiology

Box 4.4 Normal maternal arterial blood values

Tee
© > 97%
nh
© 100 mmHg
a
© 40 mmHg © -2to2
© 4kPa

@ 24 mEq/L
a@ 734-144 @ 12 gm/dL

Box 4.5 Normal fetal blood values

@ Venous = 75% ® Venous = 35 @ 8-10 kPa @ Vein =-1to?

@ Arterial = 25% @ Artery = 25 @ Artery =-2.5 to 10

|
pH Haemoglobin
@ Vein = 7.17-7.48 @ 18 gm/dL
@ Artery = 7.05-7.38

7. Respiratory compensation
® Occurs only in metabolic disorders
® ls instantaneous
@ Cannot compensate for primary respiratory disorders

8. Metabolic compensation
@ |s via kidneys
© Compensates for
i. Respiratory disorders
ii. Metabolic disorders not originating from the kidneys
® Slow process

9. HCO;
® Is alkaline
® |s manufactured in
i, Distal convoluted tubule (DCT)
ii, Collecting duct
® Proximal convoluted tubule (PCT) is not involved with acid—base balance
@ DCT cells
i, Have carbonic anhydrase
ii, Produce CO, (CO, reacts with water to form carbonic acid [H,CO3], a reaction
catalysed by carbonic anhydrase. HCO; is an unstable organic acid, which rapidly
dissociates into H* and HCO3)
CO, + H,O > H,CO;—> H* + HCO;
iii, HCO; enters general circulation
iv. H* enters urine and is buffered with
m NH;
m HPO}
v. NHj is produced by the kidneys and increases in acidosis
 Calcium homeostasis 115

10. In long-term acidosis

eH’ enters cell (due to high extracellular fluid concentration of H*)
@ kK’ is driven out of the cell to maintain electrical neutrality
®@ Hyperkalaemia occurs

11. Base deficit/excess

@ |s the amount of acid or alkali required to restore 1L of blood to a normal pH at a
i. pCO, of 5.3kPa
ii, Temperature of 37°C
Is calculated using the serum bicarbonate concentration and pH values
Base excess = 0.93 x [HCO3- 24.4 + 14.8 (pH — 7.4)]
Normal range is —2 to +2 mEq/L
A negative base excess indicates metabolic acidosis
A positive base excess indicates metabolic alkalosis
Actual base excess
i. Is the base excess value of blood
ii. ls not a true representation of the base excess of the total ECF
® Standard base excess
i. Is the base excess value calculated when the haemoglobin is at 5 g/dL
ii Gives a better representation of the base excess of the total ECF
®@ Total body bicarbonate deficit = 0.3 x base deficit x body weight (in kg)

Acid—base changes in pregnancy

1. In the fetus
© Cord compression leads to respiratory acidosis
® Placental insufficiency leads to metabolic acidosis
®@ Anaerobic metabolism leads to increased lactate
@ Shift to anaerobic metabolism occurs when OQ) saturation <25%

2. Electrolyte changes in pregnancy

®@ Osmolarity decreases by 10mOsm/L (in response to progesterone)
® Decreased HCO; (in response to decreased CO,)
® Decreased Na’ (in response to fall in HCO} and resetting of the plasma osmolarity)

Calcium homeostasis

Calcium
1, Ca’* functions
Bone formation
Muscle contraction
Enzyme co-factor
Blood clotting (necessary for the function of some of the coagulation cascade complexes)
Secondary messenger
Stabilization of membrane potentials

2. Distribution of Ca”*
@ Total body calcium is 1kg of which 99% is located in the skeleton
® Extracellular (plasma) Ca**
i. lonized (45%)
ii, Bound (55%)
 116 Chapter4 Physiology

® Ca’*is bound to
i, Plasma proteins
th 1HOvE
iii, HCO;
@ Acidosis causes increased ionized calcium
® Daily requirement
i. Adult = 1 g/day
ii. Pregnant = 1.5 g/day

3. There are 3 major pools of Ca”* in the body

@ Extracellular compartment (plasma)
i. The concentration of ionized calcium in ECF is 12000 times the Ca** concentration
within the intracellular compartment
® |ntracellular compartment
i. Ca** is sequestrated almost exclusively out of the cytosol and within the endoplasmic
reticulum and mitochondria. It can only be released by certain stimuli or cell damage
ii. Intracellular free Ca?* concentrations fluctuates from 100nM to 1uM
@ Bone

4. Ca’* modulation is via

@ Parathyroid hormone (PTH)
®@ Parathyroid hormone-related peptide (PTHrP)
® Calcitonin

5. Ca’* absorption from GIT via

® Active uptake — Na*/Ca** ATPase
® Transcellular transport — Calbindin
@ Endocytosis — Ca’*—calbindin complex via TRPV6 membrane Ca?* channel

6. Phosphate functions
® |mportant in intracellular metabolism (ATP synthesis)
® Phosphorylation of enzymes
® Forms phospholipids in membranes

Calcium regulatory hormones

ie Veils.
Peptide hormone (consist of 84 amino acids and has many isoforms)
Acts on G-protein receptors '
Secreted by parathyroid gland
Half life = minutes
Store supplies last for 90 min
Functions
i. Increases Ca**
ii. Decreases PO}
iii. Calcitonin antagonist
Does not cross placenta
@ Acts on 3 body components (Box 4.6)

2. PTHrP
@ Made by
i. Most tissues
ii. Cancer cells
® Functions
i. Similarto PTH
 Calcium homeostasis 117

ii, Does not increase vitamin D levels

iii, Regulates chondrocyte proliferation
iv. Important for placental Ca?* transport

Box 4.6 Action of PTH

© Increases bone resorption ® Increases Ca** absorption from ® Increases Ca?* and PO}
DCT absorption
® Decreases PO; re-absorption
from PCT
® Increases vitamin D production
via increasing 10-hydroxylase
Promotes calcitriol formation

3. Calcitonin
@ Isa polypeptide (consists of 32 amino acids)
@ Secreted in response to high levels of PO and Ca”*
®@ Produced by C cells (parafollicular cells) in the thyroid gland
@ Decreases circulating Ca** levels in 3 ways
i. Prevents osteoclast action
ii. Decreases reabsorption of PO and Ca’* in PCT
iii. Decrease Ca** absorption in GIT
4. Phosphaturic hormone
@ Functions
i. Increases PO? in urine
ii, Decreases PO? in blood
® Counteracts actions of vitamin D
@ Predominantly made by osteoblasts

5. Vitamin D
@ ls apro-hormone
@ 2major forms
i. Vitamin D, (ergocalciferol)
ii. Vitamin D; (cholecalciferol)
@ Made in
i, Skin
ii Placenta
iii. Decidua

6. Calcitriol = 1,25(OH),D;
® |s the active form of vitamin D found in the body
® Controls
i, Osteoblast and osteoclast differentiation
ii. Increases Ca’* uptake from GIT
iii. Increases Ca>* and PO? reabsorption from kidneys
@ Functions
i. Has anti-tumour activity
ii, Inhibits release of calcitonin
© Synthesis
i, 7-dehydro-cholesterol (skin) > UV light > vitamin D;
ii. Vitamin D; (liver) > 25-hydroxylase > 25(OH)D;
ii, 25(OH)D3 (kidney) > 10-hydroxylase — 1,25(OH),D;
 118 Chapter4 Physiology

® 25(OH)D3
i, Half life = 1.5 months
ii. ls a form of stored vitamin D
® 1,25(OH),D; half life = 0.25 days
® Deficiencies cause
i, 2° hyperparathyroidism (renal osteodystrophy)
ii, Rickets
iii, Osteomalacia
iv. X-linked rickets

Calcium disorders
1. Hyperparathyroidism
® There are 3 types (Box 4.7)

Box 4.7 Types of hyperparathyroidism

2° hyper-PTH 3° hyper-PTH
® Causes hypercalcaemia © Response to decreasing Ca** ® Secondary to 2° hyper-PTH
® Due to benign tumours levels ® Chronic process

® 1° hyperparathyroidism is due to
i. Parathyroid adenoma (80%)
ii. Primary parathyroid hyperplasia (15%)
iii, Parathyroid carcinoma (2%) — can occur as part of familial endocrinopathies; all of which
are autosomal dominant traits
H Multiple endocrine neoplasia (MEN) 1
@ MEN 2A
= |solated familial hyperparathyroidism
@ 2° hyperparathyroidism is due to
i. Kidney disease
ii, Decreased vitamin D
iii. Decreased serum Ca**
® 2° hyperparathyroidism results in renal osteodystrophy by
i, Increased Ca’* resorption from bones
ii, Reduced glomerular filtration rate (GFR) by 50%

2. Pathological calcification :
® |s the abnormal tissue deposition of Ca** salts with smaller amount of other mineral salts
® tis a common process
@ 2 forms
i. Dystrophic calcification
= Deposition occurs locally in dying tissue or areas of necrosis
= Occurs despite normal serum levels
= Occurs despite normal calcium metabolism
ii, Metastatic calcification
= Deposition in normal tissues
® Due to hypercalcaemia

3. Hypercalcaemia
® Causes of hypercalcaemia
i. Hyperparathyroidism
ii, Renal failure
 Calcium homeostasis 119

™ Leads to accumulation of PO} and

= Secondary hyperparathyroidism
iii, Vitamin D-related disorders
™ Sarcoidosis (causes dysregulation of vitamin D production with an increase in its
extrarenal production)
= Vitamin D excess
= Williams’ syndrome (idiopathic hypercalcaemia of infancy)
iv. Destruction of bone tissue
= Primary bone tumours
= Skeletal metastasis (breast cancer)
= |mmobilization
= Accelerated bone turnover (Paget’s disease)
vy. Drug induced
& Vitamin A intoxication
= Thiazide diuretics
= Lithium
= Oestrogens
vi. Endocrinopathies
& Thyrotoxicosis
™ Phaeochromocytoma
® Classic clinical features (Box 4.8)

Box 4.8 Clinical features of hypercalcaemia

cio
® Renal calculi
eo
® Osteitis fibrosa © Constipation e Depression
®@ Nephrocalcinosis ® Osteoporosis © Vomiting ® Memory loss
® Osteomalacia ® Peptic ulcer ® Psychoses, paranoia
® Rickets © Pancreatitis ® Coma

® Proximal muscle
weakness
© Keratitis
® Conjunctivitis

@ Treatment includes
i. Rehydration
ii. Pamidronate disodium (is a bisphosphonate drug that inhibits osteoclastic bone
resorption)
iii. Calcitonin
iv. Plicamycin

4, Hypocalcaemia
@ s defined as the presence of low serum calcium in blood
i. lonized Ca** < 1.1mmolV/L
ii, Total Ca?* < 2.1mmol/L
® Aetiology
i, Hypoparathyroidism
ii. Vitamin D deficiency
iii. Hypomagnesaemia
iv. Acute pancreatitis
v. Citrated blood transfusion
Se 120 Chapter4 Physiology

® Clinical features include

i. Perioral tingling
ii. Paraesthesia
iii, Tetany
= Carpopedal spasm
= Trousseau’s sign
= Chvostek’s sign
iv. Cardiac arrhythmias
v. ECG changes
& Prolonged QT interval
B Prolonged ST interval
vi. Subcapsular cataract
@ Causes of hypoparathyroidism
i. Surgical or post-radiation
ii, Idiopathic
iii. Neonatal
iv. Familial
v. Autoimmune (DiGeorge’s syndrome)
vi. Deposition of metals (iron, copper, aluminium)
= i, Hypomagnesaemia

Bone and osteoporosis

1. Bone
@ Remodelling cycle takes 90-200 days
® Turnover occurs at bone surfaces
i. Periosteal
ii. Endosteal
® Total surface area = 1000-5000 m?
Osteoblast modulators
L lee
ii, Oestrogen
iii, Glucocorticoids
iv. Thyroid hormone
® Osteoclast modulators
i. TNF
ii, IL-1/IL-6 ’
iii. GM-CSF
@ Peak bone mass density occurs at the age of 25

2. Osteoclast
@ Has no PTH receptors
® Osteoclast is a product of osteoblast
® Osteoblast has PTH receptors

3. Biochemical markers of bone turnover

@ AIPO,
® Type 1 collagen (urine)
® Hydroxyproline (urine)
@ Pyridinolines (urine)
@ TRAP

4. Osteoporosis
® lsabone disease characterized by
 Calcium homeostasis 121

i. Reduced bone mineral density

ii, Disruption of bone microarchitecture
® Prevalence in age >50 years old
i. Male = 20%
ii, Female = 50%
® Diagnosis based on T-scores
i. BMD <1SD = normal
ii, BMD 1-2.5SD = osteopenia
iii, BMD >2.5SD = osteoporosis
® Aetiology (Box 4.9)

Box 4.9 Causes of osteoporosis

® Smoking ® Diabetes mellitus © |mmunosuppresive © Hyperthyroidism

® Alcohol ® Coeliac disease drugs © Hyperparathy roidism
® Malnutrition ® Steroids ® Hypogonadal states
© |mmobilization © Proton pump inhibitor ® Cushing's
® Pregnancy
® Lactation
e J Oestrogen
® Hyperprolactinaemia

Haematological [| ‘Metabolic
® Lymphoma ® Haemochromatosis
® Myeloma ® Glycogen storage
® Sickle cell disease
® Homocystienuria
® Porphyria

@ Risk factors
i. BMI <19kg/m?
ii. Family history of maternal fractures before the age of 75
iii. Untreated premature menopause
iv. Chronic medical disorders
v, Prolonged immobility

5. Treatment of osteoporosis includes prescription of

® Calcium (1g)
@ Vitamin D (8001U)
® Bisphosphonates
i. If >75 years it can be given without a dual energy X-ray absorptiometry
(DEXA) scan
ii. If 65-75 years give if osteoporosis confirmed on DEXA
iii. If <65 years give if low bone mineral density (BMD) or high risk factors
Hormone replacement therapy (HRT) or raloxifene (SERM)
Teriparatide (a form of PTH) — used in women aged >65 years with low BMD
Strontium (promotes osteoblasts and inhibits osteoclasts)
Calcitonin
Calcitriol
Testosterone
SF 122 Chapter 4 Physiology

Calcium and pregnancy

1. Pregnancy
@ \sahypocalcaemic (although the free ionized calcium levels remain the same) state caused by
i. Active transplacental transport of Ca’* to the fetus
ii. Increased renal loss of Ca** (due to increased renal GFR)
iii. Decreased serum albumin
@ |s associated with an
i, Increased calcitriol
ii. Increased PTH
iii, Increased calcitonin

2, Fetus
® Contains 21-33 ¢ calcium
Is hypercalcaemic compared to the mother (ratio 1.4 : 1)
Ca**and PO} is actively transported
Ossification occurs in 3rd trimester
Produces PTH from 12 weeks

Cardiovascular system

Cardiac
1. The cardiovascular system consists of
@ The heart
® Blood vessels
®@ Blood

2. Cardiac anatomy
® Heart weighs = 250g
® Approximately same size as the person’s fist
® Composed of 3 layers
i, Epicardium — is part of the pericardium
ii. Myocardium
iii, Endocardium
®@ Has 4 valves
i. Mitral (bicuspid valve)
ii. Tricuspid (composed of 3 cusps)
iii, Aortic (semilunar valve)
iv. Pulmonary (semilunar valve)

3. Cardiac cycle
® Electrical impulse travels via (Fig. 4.2)

LEAVIN Bundle of His Purkinje fibres

Figure 4.2 Cardiac electrical impulse pathway

@ Divided into 3 phases

i, Relaxation (0.45)
ii. Ventricular filling (0.1 s)
iii. Ventricular contraction (0.3s)
 Cardiovascular system 123

@ Last for 0.8s

® lsovolumetric contraction phase
i. Both atrioventricular and semilunar valves are closed
ii. Volume in ventricular chamber is constant

4. Central venous pressure

@ Wave forms
i. A wave = atrial systole
il, 2X wave = occurs at the end of atrial systole
iii. C wave = ventricular systole
iv. V wave = atrial filling against closed tricuspid valve
v. Y descent occurs following tricuspid valve opening
® Normal value = 0-10 mmHg

5. Heart sounds (Fig. 4.3)

@ ‘st = Atrioventricular valve closure (occurs at the beginning of ventricular systole)

a
0.8

5
= ale
= S
£
i
Ventricle z
Atrium oa

Diastole

120 ap
E
vo
i=
=I
/ Ko)

44
V 40 =

1st HS 2nd HS 3rd HS 4th HS

ECG

[2|
lsovolumetric contraction lsovolumetric relaxation

Cardiac cycle

Figure 4.3 Cardiac cycle

 Chapter 4 Physiology

® 2nd = Semilunar valve closure

i. Occurs at the end of ventricular systole
ii, Usually split
® 3rd
i. Occurs at beginning of ventricular diastole
ii, Due to rapid ventricular filling
iii. Common in pregnancy and young adults
® 4th
i. Atrial systole
ii, Absent in atrial fibrillation (AF)

6. ECG
@ PR interval
i. {5 0:1=0.2's
ii. Beginning of P to beginning of Q
@® QRS=0.12s
® QT interval = 0.3-0.4s (depends on HR) (Box 4.10)

Box 4.10 QT interval

Increased QT interval Decreased QT Interval

® Hypokalaemia ® Hyperkalaemia
® Hypocalcaemia ® Hypercalcaemia
® Quinidine © Digoxin

7. Cardiac chambers (Fig. 4.4)

® Saturations
i. Mixed venous saturation = 60%
ii, Left side saturation = 96%
® Atrial pressure
i. Right = 1-7 mmHg
ii, Left = 10-15 mmHg
® Right ventricle pressure
i. Systolic = 35 mmHg
ii, Diastolic = 4mmHg

eteatrium
Left
atrium

Systole = Systole =
35mmHg 140mmHg
Diastole = 4 Diastole =
mmHg 10mmHg
* Right ° Left
ventricle ventricle

Figure 4.4 Cardiac chamber pressures

 Cardiovascular system 125

Left ventricle pressure

i. Systolic = 140 mmHg
ii. Diastolic = 10mmHg
Pulmonary artery pressure = 35/15mmHg

8. Stroke volume (SV)

Is the volume ejected by the ventricles during systole
SV = end systolic volume (ESV) — end diastolic volume (EDV)
i. ESV =120mL
ii, EDV = 40mL
Is 80 mL
Ejection fraction (EF)
i. Is 0.67
ii, EF = SV/ESV

9: sae output (CO)

CO= SV (stroke volume) x HR
Resting CO
i. Male = 5.5L/min
ii, Female = 4.5 L/min
Cardiac index = CO/body surface area = 3.2L/min/m?
Starling’s law
i. Force of contraction is proportional to fibre length
ii. Fibre length is proportional to stretch of ventricular muscle (ventricular dilatation)
iii. Ventricular dilatation is proportional to venous return
Venous return (pre-load) depends on
i. Intrathoracic pressure
ii. Total blood volume
iii. Gravity
iv. Calf muscle action
v, Venous tone
After-load depends on arterial resistance

10. Cardiac autonomic control is via

Baroreceptors
i. Are inhibitory
ii, Are of 3 types (Box 4.11)

Box 4.11 Baroreceptors

Carotid sinus : Floor

of4thventricle
® Located at bifurcation of ® Located at aortic arch ® Sensitive to CSF pressure
common carotids ® Sensitive to partial pressure of ® Cushing's reflex: T CSF pressure
®@ Innervated by glossopharyngeal O,/CO, and pH — 7 BP
nerve

@ Chemoreceptors consist of
i. Carotid body
= Located at bifurcation of carotid artery
= Sensitive to pO2, pCO, and pH
ii, Central chemoreceptor (sensitive to CO;)
 126 Chapter 4 Physiology

11. Coronary circulation

® Heart receives 4-5% of CO
® Coronary flow
i. Rate at rest = 80mL/min
ii. Is greatest during diastole
® Myocardial oxygen consumption = 8mL per 100g of tissue

Blood vessels
1. Blood vessel wall is made up of 3 layers
@ Tunica interna
® Tunica media
i. Thickest layer in artery
ii. Consist of smooth muscles
® Tunica externa — thickest layer in vein

2. Veins have valves

3. Capillaries have a single layer of tunica interna

4. Blood pressure (BP)

@ BP = systemic vascular resistance (SVR) x CO
@ Depends on
i. Blood volume
ii. Viscosity
iii. Elasticity of vessel walls
iv. Length of blood vessels
v. Diameter of blood vessels
< i. Hormones
® Angiotensin-converting enzyme (ACE)
@ ADH
® Adrenaline

5. Mean arterial pressure (MAP)

MAP = Diastolic pressure + x (systolic pressure — diastolic pressure)

6. SVR depends on the following factors:

@ Neurogenic (via the central sympathetic outflow paths) ,
® Metabolic
be Wale
i, (ey
ii, COs;
iv. Kt
® Endocrine
i. Adenosine
ii, Prostaglandin
iii. Serotonin
iv. Kinin
v. Catecholamines

7. Blood flow
® Follows Poiseuille’s law
® |s proportionalto
i. Pressure
 Cardiovascular system uv

ii. Radius
ili, 1/viscosity
iv. 1/length
® Viscosity increases when haematocrit >45%

Blood
1. Blood is composed of
® Plasma (55%)
® Blood cells (45%)

2. Blood cells
@ There are 3 types
i. Erythrocytes
ii, Leucocytes
iii. Thrombocytes
® Are formed by haemopoiesis
® Are derived from stem cells

3. Erythrocytes
® Structure
i. Biconcave disc
ii. Diameter = 8mm
iii. Do not have nucleus
@ Lifespan = 120 days
Contain haemoglobin

4. Blood groups
@ |s the classification of blood based on the presence or absence of inherited antigenic
substance on the surface of RBCs
® 2 main systems
i. ABO —has 4 groups (Table 4.1)
ii. Rhesus — 80% of Caucasians are Rhesus positive
@ Other blood groups include
i. Kell system
ii, Lewis system

Table 4.1 ABO system

Blood group oO A B AB

Antigen = a b a/b

Antibody in plasma a/b b A 3

Compatible donor O A,O B, O A, B, AB, O

Incompatible donor A, B, AB AB, B AB, A -

5. Leucocytes
@ Make up 1% of blood cells
® Contain nuclei

6. Thrombocytes
® Release serotonin, which causes vasoconstriction
® Form a platelet plug
 128 Chapter4 Physiology

T.in Cardiovascular changes in pregnancy

Obs
Gyn
Ke Cardiac changes in pregnancy
Chpt 6.1 Cardiac output rises by 40%
i. From 4.5 to 6L/min
ii, Plateaus at 24-30 weeks
Heart rate increases by 20%
Stroke volume increases by 30%
Peripheral vascular resistance decreases by 5%
BP decreases 10%
Vasodilation (due to progesterone)

Distribution of CO in pregnancy
Uterus — 400 mL/min
Kidney — 300 mL/min
Skin — 500 mL/min
Gl/breast — 300 mL/min
In labour CO increases by 2 L/min

ECG changes in pregnancy

Left ventricular hypertrophy and dilatation
The apex is shifted anteriorly and to the left
Left axis deviation 15°
Inverted T-waves in lead 3
Q-wave in lead 3 and aVF
Non-specific ST changes

Haematological changes in pregnancy

Plasma volume rises by 50%
i. From 2600 to 3800mL
ii. No further increase after 32 weeks
Total volume of RBCs rises by 18% (1400 mL to 1650 mL)
Leucocytes increase
Increase in clotting factors
Haemodilution — physiological anaemia
Haematocrit decreases

Endothelial changes in pregnancy

® Vasodilatation due to '
i, Increased nitric oxide (NO)
ii. Decreased asymmetrical dimethylarginine (ADMA)
iii, Increased PGI, (prostacyclin)
@ Pro-coagulant state

Puerperium
® Increase diuresis in the first 48 hours post delivery
@ Clotting factors remain high

Sa

Respiratory system

Respiratory tree
1. The pharynx is divided into 3 parts
Nasopharynx
 Respiratory system 129

® Oropharynx
@ Laryngopharynx

2. The pharynx measures 130mm in length

3. Nasopharynx contains
® Eustachian tube opening
® Pharyngeal tonsils (adenoids)

4. Oropharynx
® Contains palatine tonsils
®@ Separated from the oral cavity by
i. Uvula
ii. Pillars of fauces

5. Pillars of fauces consist of

@ Anterior fold — palatoglossal arch
© Posterior fold — palatopharyngeal arch

6. The larynx
@ Also known as the voice box
@ Has 4 significant cartilages
i. Epiglottis
ii. Thyroid cartilage (Adam’s apple)
iii. Cricoid cartilage
iv. Arytenoid cartilage

7. Trachea
@ Measures 120mm in length
® Has 16-20 incomplete cartilage rings

8. Bronchi
@ Bifurcation at carina
® Has incomplete cartilaginous rings
@ Right bronchus is more acute in angle

9. Lung anatomy
® Right lung has 3 lobes
® Left lung has 2 lobes
® Lobules contain alveoli
@ Alveolar and capillary wall is composed of a single layer of epithelium

10. Pulmonary vascular resistance (PVR) depends on

@ Lung volume
i, Small lung volume — PVR is high
ii, Initial increase in lung volume — PVR falls
iii, Further increase in lung volume — PVR rises exponentially
@ Pulmonary vascular tone (via nitric oxide action)
@ Hypoxia leads to pulmonary vasoconstriction
Pulmonary artery and venous pressure

11. Muscles of ventilation

® Consist of
i. Diaphragm
ii, Intercostals muscles (11 pairs)
iii. Accessory muscles (sternocleidomastoid, platysma, and scalene muscles)
@ Supplied by phrenic nerve from C3, C4, and C5
 130 Chapter4 Physiology

Mechanics of breathing
1. Airis a mixture of
@® 0,=21%
® N, = 78%

2. Types of respiration
® Physiological respiration
® Cellular respiration
i. Is metabolic process in which an organism obtains energy
ii. O, + Glucose > CO, + H,O + ATP
Chpt 5 F F Siearh A
fe 3. Physiological respiration consist of
@ Ventilation
® Pulmonary gas exchange
© Gas transport
® Peripheral gas exchange

4. Ventilation
® |s movement of air into and out of the lungs
® Occurs as a result of pressure difference
® Consists of
i. Inspiration (an active process)
ii. Expiration (a passive process)
© Factors affecting ventilation
i. Airway compliance
ii. Airway resistance
® Minute ventilation (MY) is
i. Tidal volume (TV) X respiratory rate (RR)
ii. The total volume of gas entering the lung per minute
® Alveolar ventilation (AV) is
i. (TV — dead space volume) x RR
ii, 4.2 L/min
iii. The volume of gas per minute that reaches the alveoli
® Dead space ventilation (DSV) is
i, The volume of gas per minute that remain in the airways
ii. The volume of gas per minute not involved with gaseous exchange

5. Inspiration '
® |s based on Boyle’s law
® Occurs as follows (Fig. 4.5)

i stal| ‘ ‘ | ‘ Boyle's law — gas moves

tThoracic cavity volume +Thoracic cavity pressure from high to low pressure

Figure 4.5 Mechanism of inspiration

6. Intrapleural pressure (IP)

® Prevents the tendency of the lung to collapse due to its elastic recoil
®@ Resting IP = -5cmH,O
 Respiratory system 131

@ Falls during inspiration

@ Becomes positive during forced expiration (can reach up to +30 cmH,0)
7. Control of ventilation is under
®@ Nervous control — respiratory centre in brainstem
@ Chemical control
i. Central — medulla oblongata
ii, Peripheral (aortic and carotid body)
®@ Bezold-Jarisch reflex
i. Causes hypopnoea and bradycardia
ii, Is due to increase in parasympathetic activity
iii. Is caused by veratrum alkaloids, nicotine, and antihistamines
@ J-receptors (proprioceptors)
i. Are innervated by vagus nerve
ii, Stimulation causes a reflex increase in breathing

8. Gaseous exchange
@ Takes place at the respiratory surface
® ls governed by Fick’s law (describes diffusion), which states that respiratory surfaces must
have a
i. Large surface area
ii, Thin permeable surface
iii. Moist exchange surface

9. Factors affecting gaseous exchange

@ Temperature (Charles’ law— high temperature causes increase in Coase increased velocity
causes increased pressure)
® Composition (Dalton’s law— the total pressure of a mixture is that of all the partial
pressures added together)
@ Diffusion gradient
i. pO, (Box 4,12)
ii, pCO, (Box 4,13)

Box 4.12 pO, diffusion gradient

a© 160 mmHg
Es ess
© 150 mmHg ® 100 mmHg @ 13.3 kPa
© 21kPa © 19.8 kPa © 14kPa

© 40 mmHg

Box 4.13 pCO, diffusion gradient

© 0.3 mmHg ® 40 mmHg @ 5.3 kPa ® 45 mmHg

© 0.03 kPa @ 5.3 kPa © 6.1 kPa

Exhaled air :

© 4kPa
 132 Chapter4 Physiology ;

Box 4.14 Lung compliance changes

E Lung complicance is increased in Lung compliance is decreased in

® Obstructive lung disease ® Restrictive lung disease
© Expiration @ Pulmonary oedema
® Old age © Acute respiratory syndrome (ARDS)

10, Lung compliance (Box 4.14)

@ |s defined as the change in lung volume per unit change in pressure
@ |s 200mL/cmH,O
®@ Governed by Laplace’s law (P = 2T/r)
i. Transpulmonary pressure (P) is proportional to wall tension (T)
ii, Transpulmonary pressure (P) is inversely proportional to radius (r)
iii. Transpulmonary pressure is required to prevent alveolar collapse
@ Pulmonary surfactant
i. Reduces wall tension and thus compliance
ii. Secreted by lung type 2 pneumocytes
iii, Composed of dipalmitylphosphatidylcholine and cholesterol
® Elastance
i. Is defined as 1/compliance
ii. Measures elastic recoil of lung

11. Airway resistance

® Is governed by Poiseuille’s law (R = 8V/r4)
i. Resistance (R) is proportional to length (l) of tube
ii. Resistance (R) is inversely proportional to radius (r) of tube
® Factors that influence diameter of airways
i. Respiratory secretions
ii, Lung volumes (high volumes cause decreased resistance due to radial traction)
iii, Smooth muscles of respiratory tree
® Closing volume is
i, The volume at which airways collapse
ii. Between FRC and RV
iii, Increases with age

Respiratory function '

1. Lung volumes
® Residual volume (RY) is
i, The volume that remains in the lungs following maximal expiration
Hh APSE
® TVis
i. 7mL/kg
ii, or approximately 500 mL
® Inspiratory reserve volume (IRV) is
i. The volume that can be inspired above the TV
ales
® Expiratory reserve volume (ERV) = 1.5L
® Vital capacity (VC)
i. Is the volume of gas that can be inhaled from forced expiration to inhalation
ii, VC =IRV + ERV + TV
iii, VO = 3.5L
 Respiratory system 133

® Inspiratory capacity (IC) = TV + IRV

@ Functional residual capacity (FRC) (Box 4.15)
i, Is the volume of gas left in the lung at the end of quiet respiration
ii, FRC = RV + ERV
iii, FRC = 2.5-3L
® Total lung volume (TLY)
i. TLV =VC + RV
i, TLV=5L

Box 4.15 FRC changes

_FRCisincreasedby
© Obstructive lung disease Restrictive lung disease
® Continuous positive airway pressure (CPAP) Pregnancy
Anaesthesia
Following surgery

2. Alveoli
® Total alveolar volume = 2L
® Alveolar ventilation = 350mL
@ Basal O, consumption = 250mL/min
® ©) capacity = 20mL/100mL blood

3. Spirometry (Box 4.16)

® Forced vital capacity (FVC) is the total amount of air that can be forcibly exhaled after
inspiration
® Forced expiratory volume in 1 second (FEV,) = 3L
® FEV,/FVC = 75%-80%
®@ Peak expiratory flow rate (PEFR) = 600 mL/breath
® Respiratory rate = 10-18 breaths/min

Box 4.16 Spirometry changes in lung disease

Obstructive lung disease Restrictive lung disease.

® Total lung volume T ® All lung volumes are reduced
© FRCT ® FEV1/FVC T or normal
° VT
@ PEFR J
® FEVI/FVC L

4. Dead space
® ls the volume of inspired air that is not involved in gaseous exchange
® 3 types
i. Anatomical (is approximately equal to body weight in pounds) = 150mL
ii. Alveolar (those ventilated but not perfused)
iii, Physiological
@ Physiological dead space (PDS) is
i. Anatomical dead space + alveolar dead space
ii, 2-3 mL/kg
;
} Respiratory changes in pregnancy
1 1. Respiratory changes in pregnancy are due to progesterone (Fig. 4.6)
134. Chapter4 Physiology

~ Total Respiratory
lung volume minute
decreases by volume rises
200mL by 40%

Expiratory Oxygen
reserve consumption
decreases rises by 20%

Tidal volume
rises by 30—
40%

Nh Pulmonary tpO2 to 14
kPa
foe
unchanged hanges
chang

Figure 4.6 Pulmonary changes in pregnancy

@ Anatomical
i. Engorged turbinates
ii. Bronchiole relaxation
iii, Decreased airway resistance
Mechanical
i. Oxygen demand increases by 20%
ii. Increased TV
iii, VC = same
iv. RR = same
y. Lung compliance = same
vi. Decreased chest compliance
vii. Decreased RV by 200mL
viii. Decreased ERV
ix. Decreased total lung volume by 200 mL
x. Increased IRV
xi. Breathing more diaphragmatic than thoracic ;
xii, FEV, = same
xiii. PEFR = same
Gases
i, Decreased pCO, to 30mmHg
ii. Increased pO, to 14kPa

Maternal and fetal oxygen transport

1. General facts
Cyanosis occurs when deoxyhaemoglobin >5 g/dL
Decrease in O), saturation by 1% causes an increase in ventilation by 600 mL/min
Only 1% of O, in blood is dissolved in plasma
Haematocrit of venous blood is 3% higher than that of arterial blood
Carbon monoxide has 240 times more affinity for haemoglobin than oxygen
2. Fetal and maternal values (Table 4.2)
 Respiratory system 3

Table 4.2 Fetal and maternal gas values

Maternal Fetal

pO, (mmHg) Artery 80-100 (9-13 kPa) 25

Placental pool 45
Venous 35
pCO,(kPa) Artery 4.7-6.0 (35-45 mmHg) 49-10.7
Venous 3.5=7.9

pH Artery 7.34-7.44 7.05-7.38

Venous 7.A/—=7A8

Base excess (mmol/L) Artery 3 1013 Si) 1K)

Venous -1to9
Hb (g/dL) 12 ly/
Blood O, content (mL/100 mL) 15 25
O, saturation (%) Artery >97% 25
Venous 75

3. O, dissociation curve
® ls sigmoid shaped
i, At pO, >60mmHg the curve is flat (which means O, content of blood does not change
significantly with increase in pO,)
@ Px is
i. The pO, in blood at which the Hb is 50% saturated
ii, 26.6mmHg
@ Left shift, indicating higher affinity for O, (decrease in Psg), is caused by
i. Carbon monoxide
ii, Fetal Hb
iii, Decreased 2,3-DPG
@ Right shift, indicating decreased affinity for O, (increase in Psp — which means that larger
pressures are required to maintain an O, saturation of 50%), is caused by
i. Hyperthermia
ii. Acidosis
iii, Hypercapnia

4. Properties of haemoglobin
@ Bohr effect
i, States that in the presence of CO, the O, affinity for dissociation of respiratory pigment
decreases
ii, Shift of the oxyhaemoglobin dissociation curve to the right when the pH is low even
with a relatively high PO,
@ Haldane effect — states that deoxygenation of blood increases its ability to carry CO,

5. CO, transport
® In 3 forms
i, Solution (10%) — CO, is 24 times more water-soluble than O,
ii, Hydration (60%): CO, + H,O — H,CO3;> H* + HCO; — occurs in RBCs
iii. Carbamino compounds (30%)
®@ RBCs have carbonic anhydrase
® Plasma has no carbonic anhydrase
 136 Chapter4 Physiology

® Chloride shift
i. HCO3leaves the RBCs and moves into plasma
ii, Cl moves into RBCs from plasma to maintain electrical neutrality
® Majority of CO, is transported in plasma as HCO;
® His buffered in RBCs
6. 2,3-diphosphoglycerate (2,3-DPG) (Box 4.17)
® Isa product of glycolysis

Box 4.17 2,3-DPG changes

¢ 2,3-DPG increases in 2,3-DPG decreases in

Exercise © Acidosis
High altitude
Elevated androgens
Elevated thyroxine
Elevated growth hormones

Digestive tract and nutrition

Digestive tract
1 Two sets of teeth develop in the course of a lifetime
® Deciduous (‘milk’ teeth) — total of 20 (start to erupt at 6 months of age)
® Permanent teeth — total of 32 (start to erupt at 6 years of age)

Salivary glands
® 3 pairs of exocrine glands empty into the mouth
i, Parotid (duct opens at 2nd upper molar)
ii, Submandibular (ducts open on either side of frenulum of tongue)
iii, Sublingual (ducts open on floor of mouth)
®@ Produce 1.5L of saliva per day
® Saliva contains amylase

. Digestive tract is made up of 4 layers

® Mucosa :
@ Submucosa
i. Contains blood vessels, nerves, and lymph
ii. Has Meissner’s (submucosal) plexus
iii. Responsible for secretions
® Muscular layer
i. Has Auerbach’s (mesenteric) plexus
ii, Responsible for contractions
® Serosa —is a continuation of the peritoneum

Gastric secretions
® 3Lare produced per day
® Consist of
i, HCl (pH 1.5-3.5)
ii. Pepsinogen
iil. Intrinsic factor (for the absorption of vitamin B,.)
 Digestive tract and nutrition 137

. Digestion has 3 phases

Cephalic phase
Gastric phase
i. Gastrin is secreted
ii, Continues until stomach is emptied and pH falls to 1.5
Intestinal phase causes the production of 3hormones
i. Gastric inhibitory peptide (GIP) — inhibits gastric motility and secretion
ii, Secretin — inhibits gastric secretion
iii. Cholecystokinin (CCK) — inhibits gastric emptying
Gastric emptying
i. Takes 2-6 hours
ii, Protein stays the longest period of time in the stomach
Intestinal emptying takes 3-5 hours
Chyme is digested food

. Small Intestine
Epithelium contains microvilli (brush border)
pH = 7.5
Produces 3L of intestinal secretions per day
Food movement is via
i. Peristalsis
ii. Segmentation
lleum is
i. The only site of absorption of vitamin B, and bile salts
ii. Critical in fluid and Na* conservation
Jejunal contents are isotonic
Small bowel motility is 3 times slower in ileum compared to the jejunum

. Resection of ileum causes

@ Loss of bile salts that is not met by increased synthesis
Reduction in bile salt pool
Bile salts loss into the colon causes
i. Reduction in salt and water reabsorption
ii. Diarrhoea (which may be treated with cholestyramine)
Increased intestinal transit
Short gut syndrome
Renal calculi
Cholelithiasis

. Large intestines
Secretes mucus
Does not produce enzymes
Has commensal bacteria that produce
i. Some vitamins of the vitamin B family
ii, Vitamin K
Efficiency of salt and water resorption = 90%
Transit time = 24-150h
Flatus is made up of
i. Hydrogen
ii, Methane
iii, CO,
 138 Chapter 4 Physiology

9. Bile
@ 1L produced per day
@ |s alkaline
® Contains
i. Bile salts
ii. Bile pigments
iii, Cholesterol
® Bile salts
i. Are essential for absorption of fat and fat-soluble vitamins
ii. Are bile acids conjugated to glycine or taurine
iii. The 2 major bile acids are
™ Cholic acid
=® Chenodeoxycholic acid
@ Enterohepatic circulation of bile salts is essential to maintain bile
salt pool

10. Bilirubin
® Isa bile salt
® Product of haemoglobin breakdown
® Lipophilic
® Converted to
i. Stercobilin (excreted in faeces)
ii. Urobilinogen (excreted in urine)

11. Physiological jaundice

® Common between day 3 and 7 of life
®@ Due to
i. Immature liver enzymes
ii. Haemolysis of fetal RBCs
® Can cause kernicterus (deposition of bilirubin in basal ganglia)

12. Pancreatic juices

® 1.5L produced per day
® Contain
i. Water
ii, Sodium chloride
ili, Sodium bicarbonate
iv. Enzymes :
= Trypsinogen
= Chymotrypsinogen
= Proelastase
= Amylase
m@ Lipase
® Are alkaline

Nutrition
1. Calories
® Energy provided
i, Carbohydrate = 4.2 kcal/g
ii, Protein = 4.2 kcal/g
iii, Fat = 9kcal/g
 Digestive tract and nutrition 139

®@ Requirement (is about 30 kcal/kg/day)

i. Non-pregnant = 2200 kcal/day
ii, Pregnant = 2400 kcal/day
ili, Lactating = 2800 kcal/day

2. Daily recommended intake

® Carbohydrate = 400 g/day
@ Fat = 100g/day
® Salt = 6g/day
® Folic acid = 400 g/day
® Protein
i. Non-pregnant = 1.5 g/kg body weight/day
ii, Pregnant = 2g/kg body weight/day

3. Nitrogen requirements
® 1g of nitrogen is contained within 6.25g of protein
® 6.25¢ of protein is contained within 36g of wet weight tissue
® Normal urinary nitrogen excretion is 14 g/day
® Nitrogen intake
i. Basic nitrogen requirements — 0.1 g/kg/day
ii, Nitrogen requirements in hypermetabolic state — 0.2 g/kg/day
iii, Nitrogen intake of >14 g/day has no benefit
@ Nitrogen loss
i. Daily = 2 g/day
ii, Menstruation = 2g/month

4. Iron
® ron requirement
i. Non-pregnant = 2.8 mg/day
ii. Pregnant = 6mg/day
® ron deficiency anaemia is characterized by
i. Iron <12 umol/L
ii. TIBC saturation <15%
iii. Microcytic
iv. Microchromic
® Total body iron = 40 mg/kg body weight

5. Vitamins and minerals

@ Vitamins A, D, E, and K (the ADEK group of vitamins) are fat soluble
@ Vitamin and mineral daily recommended requirements (Table 4.3)
®@ Vitamin deficiencies and overdoses (Table 4.4)

GIT changes in pregnancy

1. Changes in pregnancy
® Vomiting
®@ Heartburn/reflux (due to the relaxation of gastro-oesophageal
sphincter)
® Delayed gastric emptying
® Constipation (due to relaxation of intestinal smooth muscles by
progesterone)
® Gingivitis (due to increased vascularity in gums)
 140 Chapter4 Physiology

Table 4.3
ee ee en ee eS eee eee ee
Vitamin Requirement/day (g/day) Minerals Requirement/day (g/day)

A (retinol) 800 a 800

B, (thiamine) 1000 lron 12
B, (riboflavin) 1500 Na* 3000
B (niacin) 15000 Clr 3500
B, (pyridoxine) 2000 Kt 1000
Biz (cobalamin) 2 lodide 0.1
C (ascorbic acid) 30000 Zinc 150

D (calciferol) 10 Mg?* 300

E (tocopherol) 10000

Table 4.4

Vitamin Deficiency Toxicity

A Keratomalacia (at dose >3000 g/day)

Night blindness Hypervitaminosis A
B B, Beriberi No known toxicity
Wernicke—Korsakoff syndrome

By Ariboflavinosis No known toxicity

B; Pellagra Liver damage

B; (pantothenic acid) Paraesthesia No known toxicity

Be Microcytic anaemia (at dose >100 mg/day)

Peripheral neuropathy Impairment of proprioception
B, (biotin) Dermatitis No known toxicity
Enteritis

By (folic acid) Macrocytic anaemia No known toxicity

By» Megaloblastic anaemia No known toxicity

Scurvy (at dose >2 g/day) Vitamin C
megadosage
Rickets (at dose >50 |tg/day)
Osteomalacia Hypervitaminosis D

Haemolytic anaemia in newborn

infants

K (phylloquinone) Bleeding diathesis No known toxicity

 Urinary system 141 oe

Urinary system

Urinary tract
1. Kidney consist of
© Functional units — nephrons
® Collecting ducts (collect urine from nephrons)

2. Nephrons
® Each kidney contains about 1 million nephrons
® ls made up of 4 regions
i, Bowman’s capsule (surrounds glomerulus)
1 [SI
iii. Loop of Henle
iv. DCT

3. Urine is formed by 3 processes

® Glomerular filtration
® Selective tubular reabsorption
@ Tubular secretion (secretion of H* and K” ions)

4. Glomerulus
® ls amass of capillaries in Bowman’s capsule
@ Contains 2 arterioles
i. Afferent
ii, Efferent (smaller in size)

Saal
® Reabsorbs
i. Water (passively)
ii. Solutes (actively)
80% filtrate is reabsorbed
Glucose (when plasma levels are in the physiological range) is completely reabsorbed
@ Renal threshold (the maximum limit of solute that can be reabsorbed) reduces in pregnancy

6. Loop of Henle
@ Solute reabsorption occurs at ascending loop
e Water reabsorption occurs at descending loop
@ Ascending limb is impermeable to water
® Concentrates urine

ih PXenr
@ Only 5% of filtrates reach the DCT
@ Plays a role in water absorption
®@ |s under the influence of
i. ADH
ii. Aldosterone

8. The juxtaglomerular apparatus is composed of specialized cells situated in

@ Ascending loop of Henle (macula densa) — measures Na* concentration
@ Afferent arteriole (juxtaglomerular cells) - modified endothelial cells, which are pressure
sensitive

9. Renal functions
®@ Urine production
 142 Chapter4 Physiology

@ Synthesis of
i. Glucose
ii. Erythropoietin (EPO)
iii, Vitamin D

10. General functional measurements

® Renal blood supply
i, Receives 25% of CO
ii, 1.2 L/min
® Renal plasma flow (RPF) = 660 mL/min
® Creatinine clearance = 120mL/min
@ GFR = 120mL/min
i. Proportional to body surface area
ii. Is 10% less in females
® Filtration fraction = GFR/RPF = 0.18

11. Ureter has 3 layers

@ Outer fibrous
® Middle muscular
® Inner transitional epithelium

12. Bladder
® Stimulated at 300mL of volume
® Nerve supply via Lee—Frankenhauser plexus

13. Micturition
® Voiding is under voluntary control mediated by the pontine reticular formation in the
cerebellum
® Bladder contractility is dependent on sacral spinal reflex
® Urethral function is controlled by pudendal nerve
® Micturition cycle involves 3 phases
i, Storage
ii, Initiation
iii. Voiding
® |n bladder filling
i. Ascending impulses pass from (Fig. 4.7)

Sacral root S2- Lateral

spinothalamic Higher centres
tract

Figure 4.7 Ascending impulses from bladder during bladder filling

ii, Descending impulses inhibit detrusor contraction via the sympathetic nervous system
(Box 4.18)
® Bladder initiation phase begins with
Chpt 1 i. Relaxation of pelvic floor
 Urinary system 143

ii. Suppression of descending inhibitory impulses via parasympathetic system (acting on M2

and M3 muscarinic receptors in the bladder)
@ Voiding phase begins when rising intravesical and falling urethral pressures
equalize

eoyet 4. Normal urodynamic values

Residual volume = <50mL
1st sensation = 200mL
Voiding volume = 400mL
Bladder capacity = 600 mL
Flow rate > 15mL/s
Pressures
i. Negligible rise in detrusor pressure on filling (< 15cmH,O)
ii, Maximum voiding detrusor pressure < 50cmH,O
iii. Intraurethral at rest (with sphincter contracted) = 50-100 cmH,O
iv. Absence of systolic detrusor pressure during filling

Urinary system changes in pregnancy

1. Changes of urinary system in pregnancy
@ Increase uterine size causes
i. Increased frequency
ii, Nocturia
@ Lowered renal threshold leads to glycosuria
@ Increased kidney size by 1cm
i. Due to renal hypertrophy
ii, No hyperplasia
®@ Mild renal pelvis and ureteric dilatation (due to progesterone and obstruction by gravid
uterus)
® Increased renal blood flow (from 1.2 to 1.5 L/min)
@ Increased GFR (from 140 to 170 mL/min)
@ Decreased filtration fraction (GFR/RPF)

2. Renal metabolic changes in pregnancy

® Decreased HCO; (in response to decreased CO,)
Decreased Na’ (in response to fall in HCO;)
Decreased osmolarity by 10mmol/L (in response to progesterone)
Decreased urea (from 4.3 to 3.1 mmol/L)
Decreased creatinine (from 73 to 47 pmol/L)

3. Retention of urine is common in labour

4. Postnatal changes
® Urine output increases for 7 days postpartum
® Urinary tract infection (UTI) occurs in 2-4% of women in the puerperium

5. Neonate — passage of urine is expected within 24 hours post delivery

Box 4.18 Detrusor inhibitory sympathetic impulses

® Located in bladder neck and urethra ® Located on detrusor muscle

® Increase outlet urethral resistance ® Cause detrusor smooth muscle relaxation
 144 Chapter4 Physiology

i DS

Female reproductive system

Folliculogenesis
1. Folliculogenesis
Defined as growth and development of follicle from the earliest ‘resting’ stages through to
ovulation
2 main phases
i. Pre-antral — independent of FSH
ii. Antral (Graafian) — dependent on FSH
Is based on 2-cell 2-gonadotrophin hypothesis for oestrogen production
i, In response to LH, thecal tissues produce androgens, which can then be converted to
oestrogen in granulosa cells via FSH-induced aromatization
ii. Granulosa cells are dependent on androgens from theca cells to make oestrogens
iii. FSH is important in early folliculogenesis
iv. LH optimizes final stages of follicle maturation and promotes growth of dominant follicle

2. Theca cells
Secrete
i. Androgens
ii, Progesterone
Do not secrete testosterone as they lacks 17B-HSD
Have only LH receptors

3. Granulosa cells
Secrete
i, Oestrogen
ii, Progesterone
Contain P450 aromatase
Have LH and FSH receptors

4, Stages of ovarian follicle development (Fig. 4.8)

eS SES

Figure 4.8 Ovarian follicle developmental stages

5. Primordial follicles
Consist of a primary oocyte surrounded by
i. A single layer of granulosa cells
ii, Basal lamina
Formed at 6 months gestation
Number of primordial follicles at
i. 6 months gestation = 5-7 million
ii. Birth = 2 million
iii, Puberty = 300000 to 500000 (only about 500 will be selected to ovulate)
 Female reproductive system 145

6. Primary follicle
® Is the stage when the granulosa cells in the primordial follicle change from flat to cuboidal
® Zona pellucida forms around the ovum
@ FSH receptors develop
@ |s independent of gonadotrophin stimulation

7. Secondary follicle
® ls the stage when primary follicle attains a second layer of granulosa cells
® Occurs at day 5 of cycle
® Follicle mitotic activity is high
@ Theca cells are recruited to surround the granulosa cells and form 2 layers
i. Theca interna
ii, Theca externa
® A capillary network exists between the 2 theca layers

8. Pre-antral follicle
® Is asecondary follicle in its late stages of development
®@ Histologically contains
i. Oocyte
ii. Zona pellucida
iii. 9 layers of granulosa cells
iv. Basal lamina
v. Theca interna
vi. Capillary network
vii. Theca externa

9. Graafian follicle
® Also known as
i. Tertiary follicle
ii, Antral follicle
Is marked by the formation of a fluid-filled cavity between the granulosa cells
Corona radiata = granulosa cells immediately surrounding the ovum
Dependent on FSH
Grows to a size of >1.¢m
Secretes oestrogen

10. Preovulatory follicle

® sa Graafian follicle in its late stages of development
® 5 to7 preovulatory follicles will enter the menstrual cycle and compete to become the
dominant follicle
Follicles with low FSH receptors will stop developing and undergo atresia
® Dominant follicle will undergo ovulation
® Usually only 1 follicle per cycle undergoes ovulation while the rest will undergo atresia

11. Size of follicle at ovulation =~ 20mm

12. Time length of folliculogenesis

@ Lasts for about 375 days (i.e. from resting follicle stage to ovulation)
® Coincides with 13 menstrual cycles
@ Follicular growth (from pre-antral follicle stage to ovulation) takes 90 days

Oogenesis
1. Oogenesis
® Process by which mature ova are formed
 146 Chapter 4 Physiology :

© Consist of
i, Oocytogenesis
ii. Ootidogenesis
iii, Maturation
® Stages of development (Fig. 4.9)

; Primary Secondary

Figure 4.9 Stages of ovum development

2. Primordial germ cells

@ Migrate from yolk sac to the ovaries
@ Mature to oogonia

3. Oogonia
® Consist of 46 chromosomes (diploid)
@ Reach a maximum of 6-7 million by 16-20 weeks of intrauterine life
® Divide by mitosis
i. To form primary oocyte
ii, At 3rd month of gestation (2nd trimester of pregnancy)

4. Primary oocyte
® Contains 46 chromosomes (diploid)
@ Surrounded by primordial follicle
® Undergoes meiosis 1 at 5th month gestation
® Meiosis 1 is not completed until ovulation (arrested at prophase 1)
@ At ovulation primary oocyte completes meiosis 1 forming
i, Secondary oocyte
ii. 1st polar body

5. Dictyate
® \sa prolonged resting phase in oogenesis '
® Starts late in fetal life and ends (due to LH surge) before ovulation

6. Secondary oocyte
Contains 23 chromosomes (haploid)
Is the primitive ovum
Surrounded by secondary follicle
Enters meiosis 2
Meiosis 2 is not completed until fertilization occurs (arrested at metaphase 2)
At fertilization secondary oocyte completes meiosis 2 forming
i, Ovum
ii, 2nd polar body

Reproductive cycle
1. Reproductive cycle
® Lasts 28-30 days
 Female reproductive system 147

@ 1st day
i. Is the onset of menstruation
ii, Oestrogen and progesterone levels are at their lowest

. Menstrual cycle
@ Is the proliferation and shedding of the functional layer of endometrium
® Has 3 phases
i. Menstruation (day 1-5)
ii. Proliferation (day 6-15)
ili. Secretion (day 16-28)
® Menstruation
i. Blood loss is 50-150mL
ii. Is due to withdrawal of progesterone
@ Proliferative phase
i. Also known as the follicular phase
ii. Is under the influence of oestrogen produced from the Graafian follicle
@ Secretory phase
i. Also known as luteal phase
ii. Is under the influence of the corpus luteum
iii, Is the interval between ovulation and menstruation
iv. ls relatively constant and lasts approximately 14 days

. Hormonal changes during the ovarian cycle

@ Day 1
i, Low levels of oestrogen/progesterone stimulate gonadotrophin-releasing hormone
(GnRH) increase
ii, GnRH stimulates FSH increase
iii. FSH stimulates secondary follicle to secrete oestrogen
@ Day 14
i. High oestrogen
B Inhibits release of FSH
m Initiates release of LH
ii, LH initiates ovulation
® Post-ovulation
i. Corpus luteum secretes progesterone
ii. Increased progesterone levels cause decreased LH levels
® Dominant follicle survives fall in FSH by responding to LH

. Rules for hormones through ovarian/menstrual cycle

@ FSH — intercycle rise
e@ LH
i. Rises slowly through follicular phase
ii, Has a mid-cycle surge
iii. Then rapidly declines to low levels
® Oestradiol rises up to mid-cycle, falls, then peaks in the luteal phase
Progesterone levels start low then has one peak in the luteal phase

. Ovulation
@ ls the process in which an ovarian follicle ruptures and releases an ovum
@ Defines the transition from follicular to luteal phase
® Occurs 18 hours after peak of LH
® Signs
i. Mid-cycle pelvic pain (Mittelschmerz)
 148 Chapter4 Physiology

ii, Fluid in the pouch of Douglas

© Ruptured follicle becomes the corpus luteum

6. Corpus luteum
® Develops
i From ruptured Graafian follicle
ii, During luteal phase of menstrual cycle
® Produces oestrogen and progesterone
® Has LH receptors
© Fate if fertilization occurs (Fig. 4.10)

A: Degenerated only after :

Jj placenta takes over function a eae

Figure 4.10 Fate of corpus luteum if fertilization occurs

i. Persists for 6 months

ii. Function is replaced by placenta at 3rd month
® If fertilization does not occur, corpus luteum becomes corpus albicans and menstruation
begins (Fig. 4.11)

sn after 14 Corpus albicans Menstrual period

lays to

Figure 4.11 Fate of corpus luteum if fertilization does not occur

7. Corpus albicans
. ®@ J|samass of fibrous scar tissue
Obs ® |s the degenerated corpus luteum if fertilization does not occur
Chpts 2.6
a2.10 Menarche and menopause
1. Menarche
® ls the time of first menstruation
® Occurs around the age of 10-16
® Average age is 12.3 years in African girls and 12.8 in Western (Caucasian) girls
® Occurs due to changes in puberty
i. Sufficient body mass has to be achieved (minimum of 48kg with 17% of it being fat)
ii, Activation of the GnRH pulse generator
iii, Ovarian oestrogen-induced growth of uterus
iv. Fluctuating oestrogen levels
® Does not signal that ovulation has occurred
i, 1st year post-menarche — 80% of cycles are anovulatory
ii, 3rd year post-menarche — 50% of cycles are anovulatory
iii, Sth year post-menarche — 10% of cycles are anovulatory
 Female reproductive system 149

level
Gonadotrophin

Progesterone
Oestradiol

Sex
level
harmone

| | Secretory
Menses Menses
| | endometrium
| |
I Proliferative | y
| endometrium |
| | °
Endometrium |
1

is Follicle Cocyle Corpus Corpus'luteum

& | growth | released luteum regression
res
2 I epic |
> I J Ip : |
z}co1
3

3
es) |

|
© = C
N

|
>)
] ~> |

1 Menses 5 Proliferative 43 1) Secretory 28 Menses

hase ; hase
Days of cycle i Sinan .

Figure 4.12 The hormonal and endometrial axis of the human menstrual cycle
Reproduced from Training in Obstetrics and Gynaecology, by Sarris, Bewley, and Agnihotri, © Oxford University Press,
(2009).

® Nubility = anthropological term for a state of regular ovulation

@ Primary amenorrhoea is diagnosed when menarche fails to occur
i. 3 years after thelarche (beginning of breast development)
ii. by the age of 16 in the presence of normal secondary sexual characteristics
iii. by the age of 14 in the absence of other secondary sexual characteristics

2. Menopause
® Occurs between 45 and 55 years of age
@ Average age in the UK is 51 years
@ Age of menopause is reduced by
i. Cigarette smoking (by 12 months)
ii, Hysterectomy with ovarian conservation (believed to be by about 4 years)
iii. Uterine artery embolization (5% risk of premature menopause)
® Premature menopause
i, Occurs in approximately 1% of women
ii, Occurs before the age of 40
iii. Incidence is higher in identical twins
iv. 5% of identical twins reach menopause by the age of 40
@ The process can take between 6 months to 3 years to complete
®@ Biochemical changes
i. Fall in oestradiol
 150 Chapter4 Physiology

ii, Decreased levels of inhibin

iii, Rise in LH and FSH (FSH >301U/dL)
@ The predominant oestrogen during the menopausal years is oestrone
® Symptoms (Box 4.19)

Box 4.19 Symptoms of the menopause

Urogenital tract Skeletal Psychological

® Hot flushes ® Urinary urgency ® Osteopenia ® Mood disturbance
© Migraine ® Urinary frequency © Osteoporosis ® Memory loss
@ Urethral syndrome @ Insomnia
® Vaginal atrophy

© Decreased libido
@ Dyspareunia

Male reproductive system

1. Spermatogenesis (Fig. 4.13)

Spermatozoa are produced in the seminiferous tubules
Mature spermatozoa move into the lumen
Takes 70-80 days to produce
New cycle every 16 days
Under the influence of FSH
Consists of
i. Spermatocytogenesis (creation of secondary spermatocyte from spermatogonium)
ii. Spermatidogenesis (creation of spermatid from secondary spermatocyte)
iii. Spermiogenesis

2. Spermatocytogenesis
® Spermatogonium undergoes mitosis to produce primary spermatocyte
® Primary spermatocyte
i. Contains 46 chromosomes (diploid) ;
ii, Undergoes meiosis 1 to produce secondary spermatocyte

3. Secondary spermatocyte
® Contains 23 chromosomes (haploid)
® Undergoes meiosis 2 to produce 4 spermatids

Primary Secondary
spermatocyte spermatocyte Spermatid

Figure 4.13 Developmental stages of sperm

 Male reproductive system 151

. Spermiogenesis
@ |s the maturation of spermatids
® Under the influence of testosterone
® Spermatid structural changes
i. Axoneme forms
ii. Golgi apparatus becomes the acrosome
iii, Centriole of cell becomes the tail of sperm
iv. DNA becomes highly condensed
v. Excessive cytoplasm is removed as residual bodies
® Spermiation = release of mature spermatozoa from Sertoli cells into the lumen of the
seminiferous tubule

. Spermatozoa structure
@ Head (contains acrosome)
® Body (contains mitochondria)
@ Tail

. Hormonal control
® GnRH
i. Released at the age of 10
ii. Produces FSH and LH
© tsi
i. Acts on seminiferous tubules
ii. Stimulates spermatogenesis

i. Acts on Leydig cells

ii. Stimulates testosterone production
@ Testosterone — inhibits GnRH and LH
®@ Inhibin
i. Produced by Sertoli cells in response to increased spermatozoa
ii, Inhibits FSH

. Semen
® Combination of secretions from
i. Seminal vesicles
ii, Prostate
iii. Bulbourethral (Cowper's) glands
iv. Hyaluronidase — aids passage of sperm through cervical mucus
@ Normal semen analysis values (based on WHO 2010 criteria)
i. Volume = 1.5mL (range = 1.4-1.7mL)
ii, Each mL contains 50-150 million spermatozoa (normal 215 million/mL) (range =
12-16 million/mL)
iii, Total sperm per ejaculate = 39 million (range = 33-46 million)
iv. Vitality is > 55%
v. Leukocyte: < 1 million/mL
vi. 300 million sperm produced/day
vii. pH = 7.2-7.6
viii, Spermatozoa survive for 3-4 days
ix. Total motility: > 38% (with progressive motility > 31%)
x. Normal morphology: > 3%
® Seminal fluid composition
i. Carnithine
ii, Inositol
iii. Glycerophosphocholine
oe 152 Chapter4 Physiology

iv. Phosphatase
y. Fructose
vi. Citric acid

8. Spermatozoa journey
® Semen coagulates in vagina
® Cervical passage
i. Glycoprotein molecules arrange in parallel lines
ii. Sperm form reservoir in cervical crypt
® Capacitation
i. Is the biochemical removal of sperm surface glycoprotein
ii, Initiates whiplash movement of sperm tail
iii. Occurs in uterus via uterine fluid
® Acrosome reaction — allows sperm to penetrate the zona pellucida

Musculoskeletal system

1. The musculoskeletal system consists of

® Bones (206)
Joints (230)
@ Ligaments (900)
® Muscles (639)
® Tendons (about 4000)

Bone
1. Bones are formed from
® Collagen
® Inorganic materials
i. Collagen
ii. Phosphate
® Water

2. Hormones responsible for bone development

® Growth hormone
Thyroid
Parathyroid
Oestrogen
Testosterone

3. Bone ossification
® 2 types
i. Membranous
ii. Direct
Primary centre is in the diaphysis
® Secondary centres in epiphysis

4. Bone has 2 types of tissue

® Compact (also known as cortical)
i. Hard and dense
ii, Composed of sheets (lamellae)
iii, Arranges in concentric cylinders called Haversian systems
iv. At the centre of the cylinder is the Haversian canal
v. Osteocytes lie in the lacunae within the lamellae
 Musculoskeletal system 153

vi. Canaliculi (small canals) radiates from the lacunae

® Cancellous
i. Composed of an irregular honeycomb of thin plates (trabeculae)
ii, Contains red bone marrow

5. There are 5 main types of bone

® Long
i. Shaft has compact bone
ii. Epiphysis has cancellous bone
e@ Short
i. Mainly cancellous bone
ii. Cortex (outer shell) is compact bone
@ Flat — made up of 2 parallel plates of compact bone surrounding a layer of cancellous bone
® Irregular
® Sesamoid
i, Forms in areas of pressure
ii. Found in tendons

6. Bone healing
@ Haematoma forms initially
® Macrophages phagocytose the haematoma
® Osteoblast lay down new bone (callus)
® Osteoclast reshape bone and form a central medullary canal

Muscles
1. Muscles — there are 3 groups
® Skeletal — voluntary/striated muscle
@ Smooth
i. Involuntary/visceral muscles
ii, Spindle shaped cells
iii. Cells are connected by gap junctions
@ Cardiac
i. Branched fibres
ii, Cells are connected via intercalated disc

2. Skeletal muscle
@ There are 2 types of skeletal muscle fibre (Box 4.20)
Box 4.20 Types of skeletal muscle fibre

® Slow twitch fibre © Fast twitch fibre

® Red © White
® Contains high levels of myoglobin © Contains large reserve of glycogen
® Aerobic ® Anaerobic

e@ Architecture (Fig. 4.14)

Action and
| myosin

Figure 4.14 Architecture of a muscle fibre

 154 Chapter4 Physiology

3. Myofibrils
® Contains
i. Actin (thin filament)
ii. Myosin (thick filament)
® Are enclosed in
i. Epimysium (covers the whole muscle)
ii. Perimysium (covers the bundle)
® iii. Endomysium (covers a single muscle cell)

4. Muscle contraction
® Skeletal muscle contraction is associated with troponin (Fig. 4.15)
@ Smooth muscle contraction is associated with calmodulin — contraction occurs following
phosphorylation of myosin

Displacement of
Ca®* bind to troponin tropomyosin and Actin and myosin Myosin slides on actin
onactin exposure of myosin- cross-link
binding site on action

Figure 4.15 Skeletal muscle contraction mechanism

5. Muscle fuels
Phosphocreatine
Glycogen
Blood glucose
Fatty acids

Musculoskeletal changes in pregnancy

1. Muscle relaxation

2. Relaxation of sacroiliac joints

3. Separation of pubic symphysis

® Normally, space between joint in pregnancy is up to 9mm
© lf >10mm there is significant separation

4. Muscle relaxation in pregnancy occurs via

® Progesterone through
i, Suppression of mRNA production for oxytocin, oxytocin receptor, and prostaglandin F
(FP) receptor
i, Increase in cAMP
iii. Decrease in number of gap junctions
© NO through expression of eNOS by the syncytiotrophoblast
Chpt 5
5. Postnatal changes — it takes 3 months for muscle tone to normalize

Nervous system
Chpt 3
Nervous tissue
1. Nervous system is divided into
® Anatomical divisions
 Nervous system 155

i. Central nervous system (CNS) — includes brain and spinal cord

ii. Peripheral nervous system (PNS) — consist of cranial and spinal nerves
® Physiological divisions
i, Autonomic nervous system (ANS)
ii, Somatic nervous system (SNS)

. Cells of the nervous system consist of

® Neurones
® Glial cells

. Neuronal structure consists of

® Cell body (contains Nissl bodies — characteristic of neurones)
® Dendrites
®@ Axon
® Presynaptic terminal

. Glial cells
@® Are
i. Non-neuronal cells
ii, Non-excitable cells
® Functions
i. Provide support and nutrients to neurones
ii. Forms myelin
@ There are 4 types of glial cell in the CNS
i. Astrocytes
ii. Oligodendrocytes
iii. Microglia
iv. Ependyma
@ There are 3 types of glial cell in the PNS
i. Schwann
ii, Satellite
iii. Enteric glial

. Ependyma
@ |s an epithelial membrane lining the cavities in the brain and spinal cord
® Formed of ependymal cells
@ Includes choroidal epithelial cells

. Nerve fibre
@ |s the name given to an axon of a nerve cell
®@ 2 types of fibre are present
i. Myelinated
ii. Non-myelinated
®@ Divided into A, B, and C fibres (Box 4.21)
Myelin sheath is formed by
i, Oligodendrocytes in the CNS
ii, Schwann cells in the PNS
® Architecture
i. Axons are organized into bundles called fascicles
ii. Nerves consist of grouped fascicles
® Covering
i. Endoneurium — covers individual groups of axons
ii, Perineurium — covers groups of fascicles
iii, Epineurium — covers the nerve
a 156 Chapter4 Physiology ie

Box 4.21 Nerve fibres

a
CE ae
© Largest diameter fibre @ Myelinated ® Has smallest diameter
® Has shortest absolute refractory © Conductance speed = 15 m/s © Unmyelinated
period @ Found in ANS © Has longest absolute refractory
© Myelinated period
® Conductance speed = © Conductance speed = 2 m/s
12-130 m/s © Associated with pain
© Associated with touch, pressure, ® Visceral motor fibres to heart
joint position, and temperature and smooth muscles
® Motor innervation to skeletal
muscles

7. Axonal degradation pathway (Fig. 4.16)

Wallerian Debris clean-up

Chromatolysis Transneuronal
degeneration (is by
Myelin (neuronal cell degeneration
loss of axonal 1) Microglia
degeneration body changes) is 1) Retrograde
strutures distal 2) Macrophages
reversible 2) Anterograde
to lesion) 3) Schwann cells

Figure 4.16 Axonal degradation pathway

Action potential
1. Plasma membranes
® Exhibit membrane potential '
i, Membrane potential is an electrical voltage difference across the membrane
ii. Resting membrane potential is — 70 mV (the minus sign indicates that the inside of the
cell is negative in relation to the outside)
@ sa good electric insulator (impermeable to ions)
® Has 2 structures to transfer ions
i, lon pump
ii, lon channel

2. lon channels
® There are 2 types
i, Leak (age) channels (always open)
ii. Gated channels
® Gated channels depend on 4 stimuli
i. Voltage
ii, Chemicals
 Nervous system 157

iii, Mechanical pressure

iv. Light

3. Resting membrane potential

@ Arises due to
i. Unequal distribution of ions across plasma membrane
ii, Permeability of plasma membrane to K" is higher than to Na*
® ls calculated by the Goldman equation

4. Potential
®@ There are 2 types
i. Graded potential (due to the presence of chemical, mechanical, or light-gated ion
channels)
ii, Action potential
@ {t can cause the plasma membrane to be
i. Hyperpolarized = membrane potential more negative
ii. Depolarized = membrane potential less negative

Depolarization Repolarization
= (Nat inflow) (K+ outflow)
2
le) OQ eee 46 hee SSeS Se ee ee SS Se
2
€
=
3
e
gie)
So

5 -55 - Threshold -
re
£
(3)
|
pe -70—____— Resting membrane potential ol
Stimulus

Time in milliseconds (ms) After-hyperpolarization

Figure 4.17 Action potential

5. Action potential (Fig. 4.17)

@ |s generated on an all-or-none principle
® Consists of
i. Depolarization
ii. Repolarization
Lasts 1ms
Involves 2 types of voltage-gated ion channel (Na* and K* channels)
Depolarization is due to rapid opening of voltage-gated Na* channels
Repolarization is due to
i. Slow opening of voltage-gated K* channels
ii. Closure of voltage-gated Na* channels
@ After-hyperpolarization
i. Is hyperpolarization that occurs after the repolarization phase of an action potential
ii. Due to open voltage-gated K* channels
 158 Chapter 4 Physiology

6. Refractory periods
@ |s the time in which an excitable cell cannot generate another action potential
@ There are 2 types
i. Absolute — refers to the time period during which a second action potential cannot be
created irrespective of stimulus
ii. Relative — refers to time during which a second action potential can be created only by a
large stimulus

7. Propagation of action potentials

@ Types of impulse conduction
i. Non-myelinated = continuous propagation
ii, Myelinated = saltatory conduction (jumps from one node of Ranvier to another)
® Speed of propagation depends on
i. Fibre size (large fibres conduct at faster speeds)
ii, Presence of myelin

Neurotransmitters
Chpt 5 1. Neurotransmitters
e Are stored in vesicles in the presynaptic terminals
® Include (Box 4.22)

Box 4.22 Neurotransmitters

® Excitatory (glutamate Noradrenaline © Endorphins

and aspartate) Adrenaline @ Enkephalins
® Inhibitory (GABA and Dopamine ® SubstanceP
glycine) Serotonin © CCK
® Gastrin

® Nitric oxide
® Carbon monoxide

2. Transmission at synapses
@ Release of neurotransmitters is as follows (Fig. 4.18)

tintracellular Ca?* Transmitter binds

Depolarization of Causes voltage- to neurotransmitter
triggers exocytosis
presynaptic dependent Ca?* of synaptic vesicles receptor on
membrane channels to open postsynaptic
into synaptic cleft
membrane

Figure 4.18 Neurotransmitter release pathway

 Nervous system 159

® Removal of neurotransmitter from synaptic cleft is via

i. Diffusion
ii, Enzymatic degradation
iii. Reuptake into cells

3. Impulse conduction and synaptic transmission is altered by

® pH
i, Alkalosis — increases excitability of neurones
ii, Acidosis — results in depression of neuronal activity
@ Neurotransmitter agonists/antagonists
Receptor site antagonists (e.g. curare)
e@ Anticholinesterase agents
i, Neostigmine
ii. Physostigmine

Brain
1. Brain
® Cerebral blood flow is
i. 50mL per 100¢ of brain tissue
ii, 15% of cardiac output
iii, 750 mL/min
® Comprises 2% of body weight
® Consumes 20% of oxygen at rest
® Fuels
i, Glucose
ii. Liver glycogen — only after conversion to glucose via glycogenolysis
iii. Muscle protein — only after gluconeogenesis
iv. Ketone bodies
® Cannot use fatty acids
® Has an absolute requirement for glucose
i. During normal food intake uses 100 g/day
ii, During starvation needs 25 g/day
Does not have receptors for insulin
For adequate cerebral perfusion MAP must be >70 mmHg

Reflexes
1. Reflexes
@ Are involuntary (autonomic) response(s) to (a) stimuli(us)
® 2 types
i. Somatic
ii, Autonomic

2. Reflex arc
® |saneural pathway that mediates a reflex action
@ Includes 5 functional components (Fig. 4.19)

: Control centre
‘Sensory neurone (brain or spinal Motor neurone Effector
cord)

Figure 4.19 Reflex arc

 160 Chapter4 Physiology

3. 2 types of reflex arc

Monosynaptic (always ipsilateral) include
i. Stretch reflex
ii. Tendon reflex
Polysynaptic
i. Flexor reflex
ii, Crossed extensor reflex

4. Reflex receptors
Stretch reflex receptor = muscle spindles
i, Causes muscle contraction
ii. Muscle spindle monitors change in muscle length
Tendon reflex receptor = Golgi tendon organ
i. Causes muscle relaxation
ii Golgi organ monitors change in muscle tension

Autonomic nervous system

Chpt 5 1. General characteristics
All preganglionic fibres are cholinergic
Postganglionic fibres
i. Parasympathetic = cholinergic
ii. Sympathetic = adrenergic except for the sweat glands, which are
cholinergic
iii. Absent in adrenal gland because the chromaffin cells of the adrenal medulla are in a
developmental sense postganglionic cells

Sympathetic system is composed of

Preganglionic nerve fibres arising from vertebral levels T1 to L2
Sympathetic ganglia
i. Paravertebral (also known as sympathetic trunk)
ii, Prevertebral
Postganglionic nerve fibres

Sympathetic trunk
Is a paired structure lying on either side of the spinal cord
Each chain has 22 ganglia
i. Cervical — 3
ii, Thoracic — 11
iii, Lumbar — 4
iv. Sacral — 4

Sympathetic prevertebral ganglion consists of

Coeliac ganglion
Superior mesenteric ganglion
Inferior mesenteric ganglion

Parasympathetic system consists of

Preganglionic nerve fibres arising from
i, Cranial nerves — 4 in total (oculomotor, facial, glossopharyngeal, and vagus)
ii. Vertebral levels S2-S4
Parasympathetic ganglia (contained within the wall of the visceral organs)
Postganglionic nerve fibres
 Skin 161
aa a ee ee re ee Ey ee ee

Lymphatic system

1. The lymphatic system is composed of

®@ Lymphatic capillaries
®@ Lymphatic vessels
®@ Lymphatic tissues
® Lymphatic ducts (thoracic duct and right lymphatic duct)

2. Flow of lymph is
®@ Always towards the heart
® Directed to at least one lymph node before reaching a lymphatic duct
@ Maintained by
i. Valves
ii, Pressure
@ Muscular contraction
= Pulsating artery
iii. Suction — negative pressure created by the contracting heart

3. The composition of lymph is comparable with that of plasma

4. Lymphatic tissue is found in

@ Lymphatic nodes
® Spleen
@ Thymus

5. Lymph nodes
® Have several afferent vessels
®@ Have only one efferent vessel
® Contains
i, Lymphocytes
ii. Macrophages

6. Lymphatic functions
® Immune system
® Collect excessive fluid
® Transport of fat-soluble (digested) food (fatty acids)

Skin

1. The skin is composed of 2 layers

® Epidermis
@ Dermis

2. Epidermis
® Composed of stratified squamous epithelium
® Consists of 4 cell types
i. Keratinocytes — formation cycle last 3-4 weeks
ii, Melanocytes
iii. Langerhans cells
™ Produced by bone marrow
B Area type of immune cell
iv. Merkel cells — involved in sensation of touch
® Consists of 4 layers (Fig. 4.20)
 162 Chapter 4 Physiology

Stratum Stratum
granulosum spinosum

Figure 4.20 Layers of the epidermis from superficial to deep

3. Dermis
® Contains
i. Hair follicles
ii, Blood vessels
iii, Glands
iv. Nerves
® Papillae in the dermis give rise to surface ridges such as fingerprints

4. Skin gets its colour from 3 pigments

® Melanin
® Carotene
® Haemoglobin

5. The skin contains 2 types of glands

® Sebaceous (associated with hair follicles)
® Sweat

6. Sweat glands are of 2 types (Box 4.23)

Box 4.23 Types of sweat glands

© Produce watery secretions ® Produce viscous secretions

® Present all over body @ Associated with sexual excitement
® Present in axilla; pubic area; areola

Tea 7. Changes in pregnancy (Fig. 4.21).

Chpt 8.23

Increased skin
pigmentation
Chloasma (due to
increased
Linea nigra
bine tg (darkened linea
hormone
te
production)

Increased activity
Changes in of sebaceous and
sweat glands (due
pregnancy to increased
thyroid hormone)

Figure 4.21 Skin changes in pregnancy

 Special senses 163

ee ere Se A ee ee ee ee
Special senses

1. Sight
® The eye is composed of 3 layers
i. Sclera
ii. Choroids
iii, Retina
®@ Retina has 2 types of cells
i, Rods — mainly located at the peripheries
ii, Cones
® Sensitive to bright light and colour
= Make up the macula densa
2. Hearing
®@ The ear is enclosed in the temporal bone
® Divided in to 3 parts
i. Outer ear
ii. Middle ear
iii. Inner ear
@ Middle ear consists of
i. Tympanic cavity
ii, Eustachian tube
@ Tympanic cavity contain 3 bones
i. Malleus
ii. Incus
iii. Stapes
® Inner ear has 2 openings to the middle ear
i. Oval window
ii. Round window
® Stapes attaches to the oval window
® Inner ear consist of
i, Labyrinth
= Bony
® Membranous
ii. Semicircular canals
@ Labyrinth is filled with
i. Perilymph — contained between bony and membranous labyrinth
ii. Endolymph — contained within the membranous labyrinth
3. Taste
@ The tongue is divided into 3 zones
i. Front
= Sweet
@ Salt
ii Lateral — Sour
iii, Rear — Bitter
® Innervation supplied by 3 nerves
i. Facial
ii, Vagus
iii, Glossopharyngeal
4. Olfaction
@ Smell is detected by olfactory sensory neurones in the roof of the nasal cavity, known as the
olfactory epithelium
 164 Chapter 4 Physiology

® Olfactory sensitivity is dependent on the proportion of olfactory epithelium to respiratory

epithelium in the nasal cavity
i. Humans have about 10cm? of olfactory epithelium
ii. Dogs have 170cm’ of olfactory epithelium
@ Journey of an odour molecule (Fig. 4.22)

Olfactory Cribrifrom Mitral cells in Olfactory Brain

receptor cells plate olfactory bulb nerve

Figure 4.22 Journey of an odour molecule via the nasal passage

5. Touch
@ Has 2 main components
i. Touch
ii. Pressure
@ There are 4 main mechanoreceptors in humans
i. Meissner’s corpuscles
ii. Pacinian corpuscles
iii. Merkel’s disc (detects pressure and sustained touch)
iv. Ruffini corpuscles (sensitive to skin stretch)
@ Meissner’s corpuscles
i. Are encapsulated unmyelinated nerve endings
ii. Sensitive to light touch
iii. Do not detect pain (pain is exclusively detected by free nerve
endings)
iv. Situated in the papillae of skin
v. Also found in genital area
@ Pacinian corpuscles
i. Are sensitive to pressure and vibrations
ii, Situated deep in the skin

6. Pain
® |s defined as an unpleasant sensory or emotional experience associated with actual or
potential tissue damage
@ Can be classified into 2 groups
i, Somatogenic ,
ii. Psychogenic
® Somatogenic pain can be further divided into
i. Nociceptive
ii. Neuropathic
® Nociceptive pain
i, Can be divided into superficial and deep pains
ii. Superficial nociceptive pain is localized pain arising from skin or superficial tissues
iii. Deep pain can be divided into deep somatic and visceral pain
@ Deep somatic pain is
i. Poorly localized
ii, Dull and aching in nature
iii. Initiated by stimulation of nociceptors in ligaments, tendons, muscles, bones, fasciae, and
blood vessels

7, Changes in pregnancy (Fig. 4.23)

 a Fetal and placental tissues 165

Corneal
oedema

Change Change
in smell in taste

Changes
in
pregnancy

Figure 4.23 Special senses changes in pregnancy

Fetal and placental tissues

Amniotic fluid
1. Amniotic fluid volumes
@ 10 weeks = 30mL
12 weeks = 50mL
16 weeks = 190 mL
35 weeks = 900 mL
>35 weeks volume decreases

2. Amniotic fluid measurements

® Osmolality = 275mOsm/L
® Fluid exchange = 500 mL/day
@ Gases
i, pH = 7 (acidic)
ii, pO, = 2-15 mmHg
iii. pCO = 50-60 mmHg

3. Formation and clearance of amniotic fluid depends on (Box 4.24)

Box 4.24 Amniotic fluid formation and clearance

® Placenta
itedeinen
© Fetal swallowing
© Transport across fetal skin (fetal skin keratinises at © Fetal urine
22-25 weeks gestation) © Fetal lung secretions (200-400 mL/day)
© Placenta (intramembranous pathway)

4. Fetal urine
@ Urine first enters amniotic space at 8—11 weeks gestation
@ Urine production at
i. 25 weeks = 110mL/kg/day
ii, Term = 700-900 mL/day
@ Full development of renal system does not occur until several months post delivery

5. Fetal swallowing
® Starts at 12 weeks
@ 250mL/day
 166 Chapter4 Physiology

6. Amniotic fluid composition (Fig. 4.24)

® «-fetoprotein
i, Less than in fetal blood
ii, Peaks at 10-12 weeks
@ There is no fibrinogen
@ Bilirubin, which decreases in 3rd trimester

Hormones
1) Progesterone
2) Cortisol
3) Oestrogen
; Sone 4) Prolactin Antibacterial
ea Epithelia i 1) Zinc
~ (lung/dermis/fibroblast) p) Reni 2) Meade
oe 2) Glial ;
(in renal disease and NTD), 3) Peroxidase
3) Non-embryonic stem cells 4) Interferon-a

1) Albumin
Amniotic 2) Lecithin
fluid 3) Sphingomyelin
4) Bilirubin

Figure 4.24 Composition of amniotic fluid

Fetal membranes
1. The membranes consist of 2 layers
@ Amnion
® Chorion

2. Amnion
® Amniotic cavity is formed by day 7
® Has 5 layers
i, Cuboidal epithelium
ii. Basement membrane
iii. Compact layer
iv. Fibroblast layer '
v. Spongy layer (remnant of extra-embryonic coelom)
® Does not contain blood vessels, lymphatics, or nerves

3. Chorion has 4 layers

Cellular layer
® Basement membrane
® Reticular layer
® Trophoblast

Fetal lungs
1. Fetal respiration
® Measurements
i. First breath = 10-60 mL
ii, Tidal volume = 6mL/kg
iii, Functional residual capacity = 30 mL/kg
® Fetal lung development has 4 phases (Box 4.25)
 Fetal and placental tissues 167

Box 4.25 Phases of fetal lung development

Canalicular period {Terminalsa period ea

© 5-17 weeks gestation ® 16-25 weeks gestation © 24 weeks to birth ® Late fetal life to 8
® Primitive alveoli © Potential for gaseous years of age
© Low diffusing capacity exchange improves ® Final alveolar growth
at 24 weeks (due to ® Surfactant synthesis by ® A\lveolar-like
huge separation from type 2 pneumocytes structures present at
respiratory tissue and 32 weeks gestation
capillaries) @ At 34 weeks 15%
of adult number of
alveoli are present

2. Surfactant
® Increases lung compliance
® Predominant phospholipid is dipalmitoyl phosphatidylcholine (DPPC)
® Produced by type 2 pneumocytes
® Triggers to surfactant biosynthesis
i, Increase in cortisol at 32 weeks gestation
ii, Thyroid hormone
iii. Thyrotropin-releasing hormone
iv. Prolactin

3. First breath following delivery

®@ For lung inflation to occur
i. First inspiratory effort requires a transpulmonary pressure of 60cmH,O
ii Second inspiratory effort requires transpulmonary pressure of 40 cmH,O
@ Triggered by hypercapnia and hypoxia resulting from partial occlusion of umbilical cord
® ls promoted by
i. Tactile stimulation
ii, Decreased skin temperature

4. Respiratory distress syndrome (RDS)

@ Affects 10-15% premature babies
@ Aetiology = surfactant deficiency
® Risk factors
i. Male sex
ii, Caesarean section
iii. Perinatal asphyxia
iv. Maternal diabetes
v. 2nd twin in a twin pregnancy

5. Lung maturity is confirmed by amniotic fluid levels of

@ Lecithin : sphingomyelin ratio of 2: 1
® Lecithin = 10mg/100mL

Fetal circulation
1. Fetal circulation
® Only 10% of the CO enters the lungs
®@ Pathway
i. Umbilical vein to right atrium (Fig. 4.25)
ii. Right atrium to aorta can follow 2 pathways (Figs 4.26 and 4.27)
iii. Aorta to umbilical artery
 168 Chapter 4 Physiology eae

@ Therefore, 4 shunts are present in the fetal maternal circulation

i. Placenta— the entire placenta acts as a shunt to the maternal circulation as it is an
‘external’ unit not present in the non-pregnant woman
ii, Ductus venosus
iii, Foramen ovale
iv. Ductus arteriosus
® Ductus arteriosus patency is mediated by prostaglandins

= a Ee
Figure 4.25 Fetal circulation — umbilical vein to right atrium

: : Ascendin
Foramen
ne Left atrium Left ventricle
aorta i

Figure 4.26 Fetal circulation — right atrium to ascending aorta

Right Pulmonary Ductus Decending

ventricle artery arteriosus aorta

Figure 4.27 Fetal circulation — right atrium to descending aorta

2. Cardiopulmonary adjustments at birth

® Vasoconstriction of umbilical arteries
® Autotransfusion: blood from the fetal side of the placental system enters baby because
umbilical veins (which return blood from the placenta to the baby) do no constrict —
contributes 75-100 mL
@ Opening of pulmonary circulation due to decreased pulmonary vascular resistance by
i, Expansion of lungs at birth
ii, Pulmonary vasodilation
Closure of ductus venosus within 3 hours of birth
® Closure of foramen ovale due to
i. Increased left atrial pressure
ii, Decreased right atrial pressure
iii. Both of these changes in atrial pressure is due to decreased pulmonary vascular
resistance
® Closure of ductus arteriosus
 Fetal and placental tissues 169

3. Ductus arteriosus
® Functional closure
i. Occurs within a few hours of birth
ii, Functional closure is due to rapid rise in pO, at birth causing smooth muscle contraction
and fall in prostaglandin levels
@ Permanent closure occurs at 1 week of infant life

4. Hypoxia has 3 effects on the newborn

®@ Pulmonary vascular resistance remains high
® Ductus arteriosus remains patent
@ The patent ductus arteriosus maintains a right-to-left shunt

5. Fetal erythropoiesis
® Begins at 3 weeks gestation
® At 3 weeks gestation it occurs in
i. Placenta
ii. Yolk sac
@ At 4 weeks gestation it occurs in
i. Endothelium of blood vessels
ii, Liver
® Atend of 1st trimester it occurs in
i. Bone marrow
ii. Spleen

6. Fetal erythrocytes
e Early fetal erythrocytes are nucleated
®@ Reticulocyte count at term is 5% (in adults this is 1%)
@ Life span
i. Depends on fetal gestation
ii, At term = 80 days

Placenta
1. Structure
® |tis a discoid organ
Weighs approximately 600g at term
Diameter = 25cm
Thickness = 3cm
Surface area is
i. 5m? at 28 weeks of fetal life
ii. 14m? at term
® Blood flow = 1.5L/min
® Consumes 1/3 of O, supplied

2. Extravillous trophoblast invasion and conversion of spiral arterioles

® Trophoblasts differentiate from day 12
© Wave 1 occurs between 8 and 10 weeks gestation
i. Interstitial cells migrate to inner 1/3 of myometrium and form giant cells
ii. Endovascular migration down spiral arteries
® Wave 2 occurs between 16 and 18 weeks gestation
® Leads to
i, Loss of smooth muscle of spiral arterioles
ii Dilatation
iii. Loss of vasoreactivity
 170 Chapter4 Physiology : me

iv. Low-pressure vessels

v. High-capacity vessels

3. Vili
® Consists of
i. Syncytiotrophoblast
ii, Cytotrophoblast (is uninucleated)
iii. Mesenchyme
@ Types
i. Stem
ii, Intermediate
iii. Terminal (which is the functional unit)

4. Syncytiotrophoblast
® Has no mitotic activity
® Multinucleated
® Involved in hormonal synthesis

5. Mature placenta
® Vili are arranged as lobules
® There are 40-60 lobules (cotyledons)
@ Each lobule receives a spiral artery

6. Placental blood circulation

@ Pressures at the fetal maternal interface
i. Umbilical artery — 50 mmHg
ii, Umbilical vein - 20 mmHg
iii. Maternal spiral artery - 70 mmHg
iv. Intervillous space — 10 mmHg
@ Placental barrier is composed of (outermost to innermost part)
i, Syncytiotrophoblast (the only layer that comes into contact with maternal blood)
ii, Cytotrophoblast
iii. Extra-embryonic mesoblast — contains Hofbauer cells (these are macrophages that are
involved in restructuring of the stroma, in order to ensure plasticity during the
development of the villi)
iv. Fetal capillaries

7. Functions
® Maternal-fetal transport (Box 4.26) ;
® Hormone synthesis
i, human chorionic gonadotrophin (hCG)
ii. human placental lactogen (hPL)
iii, Placental growth hormone (secreted between 10 and 20 weeks)
iv. Progesterone
® Barrier to pathogens
Immunological interface

Box 4.26 Materno-fetal transport

ieee
R i
endocytosis
@ Urea © Glucose © Amino acid ® \gG (occurs from 35
® Free fatty acids weeks)
® Respiratory gases
 Fetal and placental tissues 171

8. Placenta cannot synthesize oestrogen de novo

© Works with fetal adrenals to synthesize dehydroepiandrosterone (DHEA)
® Fetal liver: DHEA — oestriol (utilized as a measure of fetal well being)
®@ Placenta : DHEA — oestradiol and oestrone

Miscellaneous fetal facts

1. The length of a twin pregnancy is 3 weeks shorter than in a singleton pregnancy

2. Fetal adrenal glands

® Have a fetal zone (occupying 80-90% of the volume of the cortex), which disappears soon
after birth
@ Are involved in the maturation (via cortisol production) of the lungs, liver, thyroid, and GIT
Are involved in the development of
i. Hypothalamic function
ii, Pituitary—thyroid axis
iii. Hepatic enzymes
@ Are involved in the sequential change of placental structure
®@ Promote thymic involution
@ |In some mammals are involved in the initiation of parturition, however, the contribution in
humans is unclear

3. Fetal movements are first felt (quickening) in

@ Primips at 18 weeks
® Multips at 16 weeks

4. Meconium
@ |sa thick greenish-black substance
®@ Formed during intrauterine life
® Consists of
i. Amniotic fluid
ii, Mucus
iii. Desquamated gastrointestinal mucosa cells (approximately 60% of meconium mass)
iv. Fatty acids
v. Bile salts
Usually passed from GIT within 48 hours of delivery
@ |n = 12% of births, meconium is present intrapartum due to
i, Post-dates
ii, Fetal distress which possibly causes fetal intestinal contraction and anal sphincter
relaxation (although this is widely believed, it has never been proven)
® Meconium in the lungs (meconium aspiration syndrome) occurs in 0.5—2 per 1000 live births
and causes
i. Mechanical lung obstruction
ii. Displacement of surfactant
iii, Pneumonitis (chemical inflammation)
iv. Decreased efficiency of gaseous exchange
® Complications of meconium aspiration syndrome include
i. _Pneumothorax
ii, Persistent pulmonary hypertension of the newborn

5. Neonatal skin
e 2 structures protect the neonatal skin during intrauterine life (Box 4.27)
® ls sterile in utero
 172 Chapter 4 Physiology af

e Milia
i. Are enlarged sebaceous glands
ii, Seen on nose and cheek

Box 4.27 Protective neonatal skin structures

® Isa fatty film that develops over the skin ® Fine covering of hairs
© Develops from week 20 of intrauterine life © Develops from week 20 of intrauterine life
® |t is shed at week 36 of intrauterine life

6. Fetal weight (Table 4.5)

e Average fetal weight gain
i. Before 28 weeks = 100 g/week
ii. After 28 weeks = 200 g/week

Table 4.5

Gestational age (weeks) Approximate fetal weight if on the 50th centile (g)

16 150

18 225

20 330

22 480

24 670

26 915

28 1200

30 1550

32 1950

34 2380

36 2810

38 3240 ;
40 3620

a Physiological changes in pregnancy — quick glance

yn

Chpts 6.1 1. Cardiovascular (Fig. 4.28)

aide ® Increased plasma volume by 40-50%
i. 2600 mL to 3800 mL
ii, No further increase after 32 weeks
® Increased red cell mass by 18%
i, 1400 mL to 1650 mL
® Increased CO by 40%
i. 4.5L/min to 6L/min
ii, Plateau at 24-30 weeks
 Physiological changes in pregnancy — quick glance

@ Increased HR by 20%
@ Increased stroke volume by 30%
®@ Increased O, consumption by 20%
i. Extra 30-50 mL/min
Decreased arteriovenous O) gradient
® Decreased peripheral vascular resistance by 5%
i. Systolic BP decreases by 5mmHg
ii, Diastolic BP decreases by 10 mmHg
iii. Large pulse pressure

Stroke volume
increases

Blood pressure
decreases
RBC rises by
18%
by 10%

Haemodilution
Heart rate Cardiovascular
= physiological
rises by 20% changes
anaemia

Figure 4.28 Cardiovascular changes in pregnancy

2. Pulmonary (Fig. 4.29)

®@ Oxygen demand increases by 20%
Decreased airway resistance
Increased TV
VC = same
RR = same
FEV, = same
PEFR = same
Lung compliance = same
Decreased chest compliance
Decreased RV by 200 mL
Decreased ERV
Decreased total lung volume by 200 mL
Increased IRV
Decreased pCO, to 30 mmHg
Increased pO, to 14kPa
Breathing becomes more diaphragmatic than thoracic
 174 Chapter4 Physiology

Total : Respiratory
tung volume — est minute
decreases by * : volume rises
200mL by 40%
Expiratory Oxygen
reserve consumption

decreases rises by 20%

Tidal volume
rises by 30—
40%

Respiratory Pulmonary tpO,ecto 14

rate — h
unchanged changes

Figure 4.29 Pulmonary changes in pregnancy

3. Distribution of increased maternal O, consumption in pregnancy

@ Fetus = 20mL/min
® \|ncreased CO = 6mL/min
® Increased renal work = 6mL/min
® \|ncreased maternal metabolic rate = 18 mL/min

4. Gastrointestinal (Fig. 4.30)

Gastro- "
oesophageal Rae Neer :
retuned rises by 11 kg

Gastric ;
emptying Nylon
inate Constipation
increases

Sphincter ;
P Gastrointestinal Se!
fone chan Gingivitis
decreases ges

Figure 4.30 Gastrointestinal changes in pregnancy

5. Liver (Fig. 4.31)

 Physiological changes in pregnancy — quick glance 175

CCK release
decreases

ALP increases by — Gall bladder

3x (dueto = contractility
“= placental: decreases
“preduction) | 1) Cholestasis
2) Gall stones

Liver
changes

Figure 4.31 Liver changes in pregnancy

6. Renal (Fig. 4.32)

Increased kidney size by 1cm
i. Renal hypertrophy
ii. No hyperplasia
Ureteric dilatation (due to progesterone and obstruction)
Increased renal blood flow (from 1.2 to 1.5L/min)
Increased GFR (from 140 to 170 mL/min)
Decreased filtration fraction (GFR/RPF)
Decreased plasma urea (from 4.3 to 3.1mmol/L)
Decreased plasma creatinine (from 73 to 47 umol/L)

Serum urea and

creatinine
ot Gupte falls
Glomerular
filtration rate Glycosuria
_ increases. —

Urinary uric
Renal acid
changes excretion
rises

Figure 4.32 Renal changes in pregnancy

7. Uterus (Fig. 4.33)

 176 Chapter4 Physiology

Uterine
weight rises
from 60g to
1.2kg

Uterine
changes

Figure 4.33 Uterine changes in pregnancy

8. Metabolic and drug metabolism (Fig. 4.34)

t Iron
demand and
absorption

t Volume of
distribution

Metabolic and
drug t Drug
metabolism excretion
changes

Figure 4.34 Metabolic changes in pregnancy

9, Haematological changes
® Increased erythropoiesis
i, Increased ERO
i, Increased hPL
® Physiological anaemia
® Increased white blood cell (WBC) count
® Gestational thrombocytopenia (due to haemodilution although increased platelet
production)
Hypercoagulant state due to increased coagulant factors (all except for factor XI and XII!)
Increased fibrinogen
Increased erythrocyte sedimentation rate (ESR)
Fibrinolytic system
i, Increased anti-thrombin 3
ii. Increased fibrin-degradation products (FDPs)
iii, Activity remains low in labour
iv, Returns to normal 1 hour after delivery of placenta
v. Placenta secretes plasminogen activator inhibitor (PAI-2), which inhibits fibrinolytic
system
 CHAPTER 5

-Biochemistry
ee
7)"

CONTENTS Proteins 188

Cell 177 Hormones 190
Carbohydrates 184 Prostaglandins 195
Fat 187 Starvation 196

Cell

Cell structure
1. The cell is the functional basic unit of all living organisms

2. Humans have = 10“ cells

3. There are 2 types of cell (Box 5.1)
@ Prokaryotic
® Eukaryotic

Box 5.1 Types of cells

: Prokaryotic cells . . Eukaryotic cells. aes

@ Are mainly bacteria ® Are mainly protista, fungi, plants, and animals
e@ Size = 1-10 um ®@ Size = 10-100 um
® Do not contain membrane-bound organelles ® Contain membrane-bound organelles
e Lack nucleus ® Have a nucleus
® Nuclear material lies in the cytoplasm ® Chromosome is usually a linear molecule with
® Chromosome is usually a circular molecule histone proteins
@ Can carry plasmids © Cell wall may or may not be present
® Most have cell wall (except for mycoplasma and ® Usually contain mitochondria
thermoplasma) ® Cell division occurs via mitosis or meiosis
© Lack mitochondria
® Cell division occurs via binary fission

4. All eukaryotic cells have

@ Plasma membrane
i. Made of a phospholipid bilayer
ii, It is semi-permeable
iii. Contains receptor proteins
 178 Chapter 5 Biochemistry “.

® Cytoplasm
i. Provides cellular shape and integrity
ii. Contains cytoskeletons (i.e. responsible for cytokinesis and
endocytosis)
iii. Contains organelles
® Nucleus
i. Is spherical
ii, Is the largest cellular organelle
iii. Surrounded by a nuclear envelope (i.e. a double membrane)
iv. Contains the nucleolus (that synthesizes ribosomal RNA)
v. Contains genetic material

5. Organelles within an eukaryotic cell

®@ Endoplasmic reticulum (ER) — there are two types
i. Smooth ER
ii, Rough ER (contains ribosomes on its surface)
® Golgi apparatus
® Mitochondria
i, Are the power house of the cell
ii. Contain genetic material inherited maternally
iii. Are self-replicating organelles
® Lysosomes and peroxisomes
i, Are rich in digestive enzymes
ii. Lysosomes internal pH value is 4.8

Cell signalling
1. Signal transduction
® |s the process by which an external stimulus to a cell is converted to a specific cellular
response, which includes
i Activation of genes
ii, Metabolic alterations
iii. Proliferation of the cell
® Can take milliseconds (for ion influx) to days (for gene
expression)
® Intracellular signal transduction is via second messengers
?
2. Signalling molecules
® Can be classified in to 6 groups
i, Hormones
ii, Growth factors
ili, Cytokines
iv. Chemokines
v. Neurotransmitters
vi. Extracellular matrix components (e.g. fibronectin)
® Acton cellular receptors, which can be divided into two classes
i. Cell surface receptors
ii, Intracellular receptors

3. There are 3 types of extracellular cell signalling

® Endocrine action (via bloodstream)
® Paracrine action (acts locally on neighbouring cells)
® Autocrine action (acts on cell producing the hormone)
 eS Cell 179

Cell surface receptors

1. There are 3 main classes of cell surface receptors
® lon-channel-linked receptors — consist of 2 types
i. Voltage gated
ii, Ligand gated
@ Enzyme-linked receptors
i. Consist of 6 types
ii, Activate tyrosine protein kinase
iii. Are receptors for growth factors
® G protein-coupled receptors
i, Also known as the ‘seven transmembrane domain receptors’ or serpentine receptors
ii. Activate G proteins (guanine nucleotide-binding proteins)
iii. Have 3 subunits (o, B, ¥)
iv. Found only in eukaryotes

2. Examples of cell surface receptors (Box 5.2)

Box 5.2

fon-channel receptors tein-couplec

® Nicotinic acetylcholine receptors ® Tyrosine kinase receptors ® Rhodopsin-like receptors
® GABA receptors ® Tyrosine phosphatase receptors ® Secretin receptors
® 5-HT receptors ® Guanylyl cylase receptors ® Metabotropic glutamate
© Glycine receptors © Histidine kinase receptors receptors
® Voltage-gated Na* channel @ Serine receptors ® cAMP receptors
® Voltage-gated Ca** channel
© Voltage-gated K* channel

3. Examples of G protein-coupled receptor subclasses (Box 5.3)

Adrenergic receptors
1, Adrenergic receptors (Table 5.1)
@ Are members of the G protein-coupled receptor superfamily
®@ Promote glycogenolysis and gluconeogenesis from adipose tissue and liver
@ There are 2 adrenergic receptor subgroups: a and B

2. B-antagonists (Box 5.4)

3. B-blockers with intrinsic sympathomimetic activity (ISA)
@ Have agonist and antagonist activity
@ Include
i. Oxprenolol
ii, Pindolol

4, Q-antagonists
@ Used in
i. Benign prostatic hypertrophy (BPH)
ii, Hypertension
® ,-antagonists include
i. Tamsulosin
ii, Prazosin
iii. Phentolamine
iv. Doxazosin
Se 180 Chapter 5 Biochemistry =

Box 5.3

Metabotropic glutamate
Rhodopsin-like receptor family Secretin receptor family receptor family

Chemokine receptors Secretin receptors © Glutamate receptors

Angiotensin II receptors Calcitonin receptors
Bradykinin receptors PTH receptors
Bradykinin receptors VIP receptors
Somatostatin receptors Glucagon receptors
Leukotriene receptors CRH receptors
Vasopressin receptors
Relaxin receptors
Thyrotropin-releasing hormone
receptors
Growth hormone receptors
Anaphylatoxin receptors
Melatonin receptors
Glycoprotein hormone receptors
(LH, FSH, and thyrotropin)
Eicosanoid receptors
Adrenergic receptors
Muscarinic acetylcholine receptors
Dopamine receptors
Histamine receptors
eeeee

Table 5.1 Adrenergic receptors

Adrenergic Mechanism Function

receptors

a Oh, Activation of phospholipase Smooth muscle contraction (ureter, urethral sphincter,

C (thus increasing IP3 and uterus, vas deferens, erector pili muscle)
diacylglycerol leading to Smooth muscle relaxation of GIT
increased intracellular Vasoconstriction of arteries and veins
calcium) Glycogenolysis
Gluconeogenesis
Oy Inactivation of adenylate
cyclase leading to decreased
intracellular cAMP
B B, Activation of adenylate Positive chronotropic effect on heart
cyclase, leading to increased Positive inotropic effect on heart
intracellular cAMP, which Increased conduction at atrioventricular node (AVN)
in turn activates protein Stimulates renin release
kinase A Lipolysis in adipose tissue

By Smooth muscle relaxation (bronchi, uterus, detrusor

muscle, GIT)
Contracts anal sphincter
Vasodilatory action
Anabolism in skeletal muscle
Stimulates renin release
Inhibit histamine release from mast cells
Reduces intraocular pressure

Bs Lipolysis in adipose tissue

Thermogenesis in skeletal muscle
 181

Box 5.4 Examples of B-antagonists

® Proponolol ® Atenolol ® Carvedilol

® Timolol ® Metoprolol ® Labetalol
® Sotalol ® Bisoprolol

® q)-antagonists include
i. Yohimbine
ii, Phentolamine

5. @- and B-agonists (Box 5.5)

Box 5.5 Examples of a and B agonists

e Phenylephrine ® Clonidine e Noradenathe ® Salbutamol

® Noradrenaline © lsoprenaline ® lsoprenaline
© Dobutamine ® Salmeterol
® Terbutaline
® Ritodrine

Acetylcholine receptors
1. Acetylcholine
@ ls aneurotransmitter found in the
i. Brain
ii, ANS
@ ls the only neurotransmitter used at the neuromuscular junction
® Receptors include
i. Nicotinic receptors
ii. Muscarinic receptors
@ Both preganglionic sympathetic and parasympathetic fibres are cholinergic
® All postganglionic parasympathetic fibres are cholinergic
© All postganglionic sympathetic fibres are adrenergic

2. Nicotinic receptors
@ Belong to the ionotropic receptor superfamily
® Form ligand-gated ion channels in the plasma membrane on the postsynaptic side of the
neuromuscular junction
® Do not make use of secondary messengers
® Consist of 2 subtypes
i, Muscle-type
ii, Neuronal-type
® Stimulation causes excitatory postsynaptic potential in neurones

3. Muscarinic receptors
@ Are members of the G protein-coupled receptor superfamily
® Consist of 5 subtypes (Box 5.6)
®@ Mechanism of action
i. M2 and M4 — act by decreasing intracellular cAMP
 182 Chapter 5 Biochemistry

Box 5.6 Subtypes of muscarinic receptors

© Exocrine glands © Heart © Blood vessels e CNS

e CNS @ Lungs
® Salivary glands

Box 5.7 Examples of nicotinic and muscarinic agonists and antagonists

Nicotinic agonist Nicotinic antagonist Muscarinic agonist

® Acetylcholine @ Pancuronium ® Acetylcholine ® Atropine
® Choline ® Tubocurarine @ Muscarine ® Scopolamine
® Nicotine ® Atracurium ® Pilocarpine © |pratropium
© Suxamethonium ® Tolterodine
© Oxybutinin
@ Darifenacin (M3)
® Tiotropium (M3)

ii, M1,M3 and M5 — act by upregulating phospholipase C and therefore inositol

triphosphate and intracellular calcium
@ Functions
i, Increase exocrine and endocrine secretions (e.g. salivary glands and stomach)
ii, Decrease HR
iii, Reduce cardiac contractility
iv. Smooth muscle contraction (e.g. bronchoconstriction)
v. Vasodilation
vi. Eye accommodation and pupillary constriction

4. Non-depolarizing blocking agents (act by blocking the binding of ACh to its receptor)
® Tubocurarine
® Vecuronium
® Pancuronium

5. Depolarizing blocking agents (act by depolarizing the plasma membrane of the skeletal
muscle fibre)
® Suxamethonium

Intracellular receptors
1, Intracellular receptors include
® Cytoplasmic receptors
® Nuclear receptors

2. Receptors that are exclusively intracellular include

® Steroid hormone receptors
e@ Thyroid hormone receptors
 ® Retinoic acid receptors
® Vitamin D3 receptors

Intracellular second messengers

1. There are 3 main groups
e-Cre
© Lipophilic messengers (e.g. diacylglycerol, inositol triphosphate (IP3), eicosanoids)
e NO
@ cAMP
i. Synthesized from ATP by adenylate cyclase
ii. Activation of protein kinase A
@ cGMP
i. Synthesized from GTP by guanylate cyclase
ii. Activates protein kinase G
iii. Relaxes smooth muscle
iv. Degraded by phosphodiesterases (sildenafil inhibits phosphodiesterase activity)

2. NO
® |s also known as endothelium-derived relaxing factor
@ |s biosynthesized from L-arginine
i. L-arginine > NO + L-citrulline
ii, Catalyst enzyme = nitric oxide synthase (NOS)
®@ Effects include
i. Vasodilatation
ii. Modulation of hair cycle
iii. Penile erection
@ 3 types of NOS
i. Endothelial (eNOS)
ii. Inflammatory (iNOS)
iii. Brain
e eNOS
i. Calcium-calmodulin dependent
ii. Half life = 10 s
iii, Acts on vascular smooth muscles
iv. Expressed by syncytiotrophoblasts
e iNOS
i. Secreted by bacterial cell wall and neutrophils following activation by tumour necrosis
factor (TNF) or interferon y
ii, Calmodulin independent
@ Mechanism of action (Fig. 5.1)

Re Aovican sk Phosphorylation of Inactivation of. Dephosphorylation Goth muuecle

tein Id G myosin light chain myosin light chain of myosin light cele
GMP. 1 lpia ai phosphatase kinase chain

Figure 5.1 Mechanism of NO action

a 184 Chapter 5 Biochemistry
2
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Carbohydrates

1. General facts
® Consist of carbon, hydrogen, and oxygen only
® Divided into
i. Monosaccharides (e.g. glucose, fructose, galactose)
ii. Disaccharides (e.g. maltose, sucrose, lactose)
iii. Oligosaccharides (e.g. the ABO blood group classification)
iv. Polysaccharides (e.g. amylose, glycogen)
Carbohydrate can be converted to fat
® Fat cannot be converted into glucose
ATP
i. Stores energy
ii. Hydrolyses to release energy
® Glucose
i. Has a molecular formula of C,H;,0¢
ii, ls the only substance that can undergo anaerobic metabolism
iii, Obligatory glucose requirement = 2 g/kg/day
iv. Physiological maximum amount of glucose that can be oxidized = 4 mg/kg/min
v. Energy provided = 4.2 kcal/g
vi. Have a low Km value (Km is an indicator of the affinity of the transporter protein for
glucose molecules; a low Km value suggest a high affinity)
® The brain has an absolute requirement for glucose
i. During normal food intake — needs 100 g/day
ii, During starvation — needs 25 g/day
® Maltose is formed from 2 units of glucose
® Lactose
i. Is broken down to galactose and glucose by the enzyme lactase
ii, Deficiency of lactase produces lactose intolerance
Sucrose is broken down to glucose and fructose by the enzyme sucrase
Lactate is converted to glucose via the Cori cycle

2. Glucose sources
® Glycogen
i, Stored in muscle (cannot release glucose into circulation due to deficiency in glucose
6-phosphatase) ’
ii. Stored in liver
iii, Stores last 24 hours
® Muscle protein conversion
® Breakdown of other carbohydrates

3. Glucose metabolism
® Anaerobic metabolism
i, Follows the glycolytic pathway
ii. End-product is lactate (a 3-carbon atom)
ili, Produces 2 mol ATP per mol glucose
iv. Occurs in the cytosol
® Aerobic metabolism
i. Comprises of glycolysis, pyruvate oxidation, tricarboxylic acid cycle (TCA) pathway and
oxidative phosphorylation
ii. Glucose is converted to pyruvate via glycolysis
 Carbohydrates 185

ii. Pyruvate (a 3-carbon molecule) is converted to acetyl CoA (a 2-carbon molecule)

™ Enzyme = pyruvate dehydrogenase (which is membrane bound)
® Irreversible reaction
iv. Acetyl-CoA enters TCA
v. TCA provides energy-rich molecules used in oxidative phosphorylation
vi. Yields 36-38 mol ATP per mol of glucose
vii. Occurs in the mitochondria

4. Glycolysis pathway (Fig. 5.2)

Converts glucose to pyruvate
® Occurs in aerobic and anaerobic conditions
®@ Undergoes double phosphorylation
®@ Also known as Embden—Meyerhof pathway

Glucose Glucose 6-phosphate Fructose 6-phosphate

2-Phosphoglycerate

Phosphoenol
Pyruvate Lactate
pyruvate

Figure 5.2 Glycolysis (Embden—Meyerhof) pathway

5. TCA pathway
® Also known as
i. Citric acid cycle
ii. Kreb’s cycle
e@ Pathway (Fig. 5.3)
i. Step 1: Acetyl CoA (2C) + oxaloacetate (4C) — citrate (6C); enzyme = citrate
synthase
ii, Step 2: Citrate (6C) — isocitrate (6C); enzyme = aconitase
iii. Step 3: Isocitrate (6C) + NAD* — ketoglutarate (5C) + CO, + NADH + H’; enzyme =
isocitrate dehydrogenase
iv. Step 4: Ketoglutarate (5C) + NAD* — succinyl CoA (4C) + CO, + NADH + H*;
enzyme = ketoglutarate dehydrogenase
v. Step 5: Succinyl-CoA (4C) + GDP — succinate (4C) + GTP; enzyme = succinyl-CoA
synthetase
vi. Step 6: Succinate (4C) + FAD — fumarate (4C) + FADH;; enzyme = succinate
dehydrogenase
vii. Step 7: Fumarate — malate; enzyme = fumarase
viii, Step 8: Malate (4C) + NAD* — oxaloacetate (4C) + NADH + H*; enzyme = malate
dehydrogenase
 186 Chapter 5 Biochemistry

Oxoloacetate
(4C)

Succinate Ketoglutarate
(4C) (5C)

Figure 5.3 Kreb’s cycle

6. Tissues that can undergo ANAEROBIC metabolism

RBC
i. Has no intracellular organelle
ii. Entirely depends on glucose
iii, Cannot use fat/ketones/amino acids
Retinal cells
Kidney medulla
Skeletal muscles

7. Cori cycle
Converts lactate (from anaerobic metabolism) back to glucose
Occurs in the liver ;
Importance
i. Produces ATP
i, Prevents build up of lactic acid

8. Blood glucose levels

Normal = 4 mM
Postprandial = 8 mM
Pregnancy = 3.2 mM
Coma = <3 mM
Glycosuria >11 mM

9. Features of gestational diabetes

Loss of insulin sensitivity
Hyperglycaemia
Increased plasma fatty acids
Increased plasma ketone bodies
 Fat 187

@ Fetal macrosomia
® Increased risk of developing type 2 diabetes in later life

Fat

1. General facts
® Energy provided = 9 kcal/g
® Requirements = 200 g/week

2. Triglycerides (TAGs, also known as triacylglycerol)

® Actas fuel store
@ Are dehydrated
® Consist of
i. 1 molecule of glycerol
ii. 3 molecules of free fatty acid
® Stored in adipocytes
® Transported by chylomicrons

3. Fatty acids
® Oxidation occurs in mitochondria
® Undergo B oxidation
® Metabolized to acetyl CoA
® Essential fatty acids are
i, Linoleic acid
ii. Linolenic acid
@ Unsaturated fatty acids
i. Linoleic acid (18 carbon atoms; double bond x2)
ii. Linolenic acid (18 carbon atoms; double bond *3)
iii, Arachidonic acid (20 carbon atoms; double bond 4)

4. Phospholipids
® Main component of cell membrane
® 3main groups
i. Lecithin
ii. Sphingomyelin
iii. Cephalins

5. Ketone bodies
@ Are by-products of fatty acid metabolism (fatty acid — acetyl CoA — ketone bodies)
® Synthesized in the
i. Liver
ii, Kidney
® Consist of
i. B-hydroxybutyrate
ii, Acetoacetic acid
iii, Acetone (excreted in urine and lung)
Are fuel for intermediate or prolonged starvation
® Ketone bodies (except for acetone) can be converted to acetyl CoA

6. Limitations of fat
® Not metabolized by brain (except ketone bodies)
® Not metabolized anaerobically
® Cannot synthesize glucose
 188 Chapter 5 Biochemistry

7. Adipose tissue
There are 2 types
i. White adipose tissue
ii. Brown adipose tissue
White adipose tissue stores energy
Brown adipose tissue
i. Has large number of uncoupled mitochondria which do not produce ATP
ii. Produces heat

Proteins

1. Amino acids
Molecules contain 2 functional groups
i. Amine
ii. Carboxyl
Are both acid and base at the same time
Zwitterions are neutral charged amino acid ions (i.e. at a certain isoelectric point the
number of positive and negative charges are equal)
i, Positive charge is from protonated amine group
ii. Negative charge is from deprotonated carboxyl group
Total number of amino acids in humans = 20
Essential amino acids = 10
i. Lysine
ii, Leucine
iii, Isoleucine
iv. Valine
v. Methionine
vi. Phenylalanine
vii. Tryptophan
viii. Threonine
ix. Arginine*
x. Histidine*
*Not strictly essential but depends on age and health status
7 subclasses (Box 5.8)

Box 5.8 Subclasses of amino acids

© Glutamate © Arginine ® Phenylalanine ® Methionine

© Aspartate © Histidine © Tryptophan ® Cysteine
@ Lysine ® Tyrosine

® Prolene © Therionine © Leucine

® Serine ® lsoleucine
® Valine
@ Alanine
e Glycine
 Proteins 189

® Amino acids as precursors

i. Tryptophan = serotonin
ii, Glycine > porphyrins
iii, Arginine > Nitric oxide
iv. Tyrosine + L-DOPA — dopamine and noradrenaline
2. Detoxification
® Begins before the urea cycle
i, Amino acid — glutamic acid + carbamyl phosphate
® Urea cycle occurs in the liver
i, Liver mitochondria (Fig. 5.4)
ii, Liver cytoplasm (Fig. 5.5)
@ Amino acid degradation can also produce uric acid and ammonia rather than urea

Se Arginosuccinate Aspartate

Figure 5.4 Urea cycle in liver mitochondria

Arginosuccinate Arginine — S eS

Figure 5.5 Urea cycle in liver cytoplasm

3. Proteins
@ Are made of polymerized amino acids
@ Peptide bonds link the amino acids in the polymer chain
® Protein structure has 4 distinct aspects (Box 5.9)
® Are divided into 3 classes
i. Globular proteins (are soluble and form enzymes)
ii. Fibrous protein (often structural)
iii. Membrane proteins (often serve as receptors)

Box 5.9 Protein structure

Primary structure Secondary structure Tertiary structure Quaternary structure

@ Is the amino acid ® 3-dimensional form of ® |s the overall shape @ |s the arrangement
sequence the primary structure of a single protein of multiple folded
® Has peptide bonds © Held by hydrogen molecule protein molecules
bonds ® Held by disulphide
bonds
® Controls the basic
function of the protein
oe 190 Chapter 5 Biochemistry

Examples of proteins
1. Haemoglobin
Chpt 1 Structure consist of
i. 1 haem ring
ii. 4 globin rings (i.e. 2 & and 2 B, y, or 6 subunits)
Gene location for subunits
i. = chromosome 16 (short arm)
ii. B = chromosome 11 (short arm)
Is synthesized in the mitochondria and cytosol of immature RBCs
Haem is metabolized to bilirubin and carbon monoxide by the liver
Haemoglobin is also found in non-erythroid cells
i. Dopaminergic neurones in substantia nigra
ii, Macrophages
iii. Alveolar cells
iv. Kidney mesangial cells
Subtypes (Box 5.10)

Box 5.10 Haemoglobin subtypes

® Gower 1 (G:€2) © HbF (o4y) © HbA (a8) @ HbS-sickle cell

® Gower2 (O€)) ® HbA» (082) ® HbC-variation in
© Portland (Cy¥) © HbF (oy) B chain
© HbH (B,)
© Barts (4)
@ HbE — variation in
B chain

® HbA, makes up 3% of adult haemoglobin

Fetal haemoglobin
i, Responsible for fetal oxygen transport from 12 weeks gestation
i, At birth makes up 50-95% of newborn's haemoglobin
iii, Levels decline in newborn at 6 months of age

2. Collagen
Secreted by ;
i, Fibroblasts
ii, Osteoblasts
Synthesized from pro-collagen
4 subtypes
i. Type 1 (bone/dermis/tendon)
ii, Type 2 (cartilage)
ili, Type 3 (fetal/cardiac/scar/synovium)
iv. Type 4 (basement membrane)
Type 1 collagen makes up 50% of total body protein

Hormones

‘hh Hormones are divide into

Endocrine
Exocrine
 Hormones 191

2. Hormones fall into 3 chemical classes (Box 5.11)

Box 5.11 Classes of hormones

Amine-derived hormones Peptide-derived hormones Ppepholpls dered aes |

: (steroids)
® Catecholamines © Vasopressin © Testosterone
® Thyroxine ® Insulin ® Cortisol
® LH
® FSH
© TSH

Lipids

Cholesterol Fatty acids Phospholipids

Arachidonic
Steroid
eroids asta
a

—_= es
Se
ee
i | } | | \

Figure 5.6 Lipid hormone family

Steroids
1. Cholesterol
»t6
Ring-based structure
Contains 27 carbon atoms
Transported by lipoprotein
ee
ii, HDL
Synthesized in the endoplasmic reticulum via HMG-CoA reductase pathway
Source
i. Acetyl-CoA
ii, Plasma membrane cholesterol
iii, Plasma lipoproteins
iv. Intracellular lipid droplets (esterified cholesteryl oleate)

2. General facts about steroids

Have 4 rings
i. 3 rings have 6 carbon atoms
ii, 1 ring has 5 carbon atoms
Steroid receptors
i. Area subclass of nuclear receptors
ii. Are associated with heat shock protein (HSP)
oo 192 Chapter 5 Biochemistry

e@ Hydrophobic
®@ 5 groups
i. Corticosteroids
™ Mineralocorticoids (aldosterone)
=™ Glucocorticoids (cortisol)
= Androgen (DHEA)
ii. Gonadal
® Progestogens (e.g. progesterone)
= Oestrogens (e.g. oestradiol)
= Androgens (e.g. testosterone)
® Acton nuclear receptors
® Increase gene transcription

3. Steroid synthesis (Fig. 5.7)

@ Cholesterol (C27) — progestin (C21) + androgen (C19) — oestrogen (C18)
® Enzymes include
i. Cytochrome P450 complex
ii. Hydroxysteroid dehydrogenase (HSD)
@ Rate-limiting step is conversion of cholesterol to progestin, involving the enzyme
cytochrome P450cscc (cholesterol side chain cleavage)
© Cytochrome P450cscc resides in inner mitochondria
@ Cholesterol cannot transverse the aqueous space between the mitochondrial membranes
unaided
i. Intracellular membrane transport aided by STAR (steroidogenesis acute regulatory)
protein and PBRs (peripheral benzodiazepine receptors)
® STAR resides in
i. Ovaries
ii, Testes

4, Cytochrome P450 complex

® Includes a variety of enzymes
i. 17-hydroxylase
ii, 21-hydroxylase
® 17-hydroxylase catalyses the following reactions
i, Pregnenolone > 17a-hydroxy-pregnenolone
ii. 170-hydroxy-pregnenolone + DHEA
iii. Progesterone — 17a-hydroxy-progesterone ’
iv. 170-hydroxy-progesterone — androstenedione
® 21-hydroxylase catalyses the following reactions
i. Progesterone — corticosterone
ii, 170-hydroxy-progesterone — cortisol

5. HSD
®@ 2 types
i. 3p
TA 8)
@ 3B-HSD
i. Converts a weak steroid to a strong steroid
ii, Catalyses the following reactions
™ Pregnenolone (C21) — pregnanedione (C21)
= 170-hydroxy-pregnenolone > 17ca-hydroxy-progesterone
= DHEA = androstenedione
® 17B-HSD catalyses the following reactions
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i, Androstenedione — testosterone
ii. Oestrone > oestradiol

6. Oestrogens
@ Phenol aromatic compounds
®@ Have 18 carbon atoms
@ P450 aromatase catalyses the following reaction
i. Testosterone — oestradiol
ii. Androstenedione — oestrone

7. Gonadal cells
® Leydig cells
i. Produce testosterone (Fig. 5.8)
ii. Have 17B-HSD

17a-
Eres hydroxypregnenolone

Testosterone Androstenedione

Figure 5.8 Testosterone production pathway in Leydig cells

© Theca cells
i, Produce androgens
ii, Cannot produce testosterone and oestradiol
iii. Does not have 17B-HSD
®@ Granulosa cells
i. Produce oestradiol
ii, Have 17B-HSD
® Luteal cells '
i, Produce progesterone
ii, Produce oestradiol

Examples of abnormalities of steroidogenesis

1. Lipoid congenital adrenal hyperplasia (CAH)
® Is an autosomal recessive condition resulting from mutations of genes for enzymes
mediating the biochemical steps of production of cortisol from cholesterol by the adrenal
glands (Fig. 5.9)

Increased Induces
ACTH hyperplasia of
levels adrenal cortex

Figure 5.9 Pathogenesis of CAH

 Prostaglandins 195

@ Defect in
i. STAR protein
ii, Cytochrome P450¢sce
iil, 21-hydroxylase (accounts for 95% of CAH)
® Results in
i. Failure of steroid production
ii, Accumulation of large lipid droplets (cholesteryl ester) in adrenal cortex
@ Depending on the type of CAH, it may be associated with
i. Ambiguous genitalia
ii. Natriuresis (due to 21-hydroxylase deficiency)
iii, Precocious puberty or failure of puberty
iv. Infertility due to anovulation (due to 21-hydroxylase deficiency)
v. Virilization (due to 21-hydroxylase deficiency)
vi. Hypertension (due to 11-hydroxylase deficiency)

Prostaglandins

1. General facts
@ Prostaglandins are
i. Produced by all nucleated cells except lymphocytes
ii. Hydrophilic
e@ Vasomotor functions (Box 5.12)

Box 5.12 Vasomotor functions of prostaglandins

® Thromboxane @ PGD
© Leukotriene ® PGE,
@ PGF,
@ Prostacyclin

®@ Other functions (Box 5.13)

Box 5.13 Non-vasomotor functions of prostaglandins

a
© Pyrogenic
aes
® Uterine contraction ® Inhibition ofplatelet aggregation
© Hyperalgesia ® Bronchoconstriction © Bronchodilation
@ Uterine contraction
® Increased gastric mucus
secretion
Gl smooth muscle contraction
(receptor subtype 1 and 3)
GI smooth muscle relaxation
(receptor subtype 2)
® Bronchoconstriction (receptor
subtype 1)
Bronchodilation (receptor
subtype 2)
 196 Chapter 5 Biochemistry

Thromboxane A,

jedale bi Prostaglandin Hy Seset catia Ey

pathway and F,

Lipoxygenase . os Prostacyclin

Figure 5.10 Prostaglandin synthesis pathway

2. Synthesis pathway (Fig. 5.10)

3. Prostaglandin dehydrogenase (PGDH)

® Metabolizes prostaglandins
®@ Found in
i. Lungs
ii, Ovary
iii. Testes
iv. Placenta

4. Prostaglandin receptors
® G-protein receptors
® Seven-transmembrane domain
@ EP receptor = PGE,
@ FP receptor= PGF,

5. Secondary messengers for

@ PGF, =|P3
@ PGE, = cAMP
6. Clinical applications
® Induction of labour (PGE, and PGF,)
® To prevent closure of patent ductus arteriosus (PGE,)
® Treatment of
i. Raynaud’s phenomena
ii. Glaucoma
iii. Limb ischaemia
iv. Erectile dysfunction (alprostadil)
v. Peptic ulcers (PGE,)

7. Prostaglandin antagonists include

® Non-steroidal anti-inflammatory drugs (inhibit cyclo-oxygenase)
® Acetylsalicylic acid (irreversibly inhibits cyclo-oxygenase)
® Corticosteroids (inhibit phospholipase A,)
® COX-2 selective inhibitors

Starvation

1. General facts
® The brain has an absolute requirement for glucose
i. During normal food intake — needs 100 g/day
 Starvation 197

ii, During starvation — needs 25 g/day

In starvation, the body is faced with an obligate need to generate glucose to sustain cerebral
energy metabolism; achieved by
i. Mobilizing glycogen stores
ii, Hepatic gluconeogenesis
2 L intravenous 5% dextrose provides 100 g/day of glucose
Death due to starvation occurs in 60 days

2. Metabolic response to starvation (Fig. 5.11)

Brain, RBCs, WBCs, and renal medulla can initially only use glucose for their metabolism
Starvation of 12 h or less leads to the following
i. Fall in insulin levels
ii, Rise in glucagon
iii. Conversion of 200 g of liver glycogen to glucose (glycogenolysis)
iv. Conversion of 500 g of muscle glycogen to lactate
y. Lactate is exported to liver and converted to glucose via Cori’s cycle
Starvation of >24h
i. Glycogen stores depleted
ii, Glucose synthesis from alanine and glutamine (gluconeogenesis)
iii. Protein catabolism of skeletal muscle up to 75 g/day
Starvation of >48 h
i. Fat (TAG) oxidation to meet energy requirements (lipolysis)
ii. TAG oxidation releases glycerol, which can be converted to glucose and fatty acids
iii. Fatty acids are converted to ketones in the liver
Starvation of 2-3 weeks
i. CNS adapts to using ketones as primary fuel source
ii. This conversion to a ‘fat fuel economy’ reduces muscle breakdown by up to 55 g/day
Reduction in resting energy expenditure up to 20 kcal/kg/day
i. Due to decline in conversion of T, to T3

24h
Gluconeogenesis

336h
48h Reduction in resting
Lipolysis energy expenditure
Primary fuel = ketone

Figure 5.11 Evolution of metabolic response to starvation

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CHAPTER 6

Endocrinology

CONTENTS Endocrine diseases 214

Sex hormones 199 Puberty 218
Hypothalamic hormones 203 Endocrine changes in pregnancy 220
Pituitary gland hormones 205 Placental hormones 220
Thyroid gland hormones 209 Labour 223
Adrenal hormones 210 Puerperium and lactation 224
Renin—angiotensin system 212 Fetal and neonatal endocrine system 226
Pancreatic hormones 213

Sex hormones

1. The ovary secretes 11 hormones (by definition a ‘hormone’ is a substance produced and
secreted by a gland or from cell(s)/tissues) into the blood stream that circulates and acts
at a target site remote from the source. Thus ovarian prostaglandins are strictly paracrine
substances (Fig. 6.1)

2. Androgens in females are produced by

®@® Ovary = 25%
@ Adrenal glands = 25%
@ Peripheral conversion of androstenedione = 50%

3. Markers of corpus luteum function are

® 17-hydroxyprogesterone (not secreted by placenta)
® Relaxin

4, Oestrogen
® 3 naturally occurring oestrogens
i. Oestrone (E1) — produced in menopause
ii. Oestradiol (E2) — primary oestrogen in non-pregnant women
iii, Oestriol (E3) — primary oestrogen in pregnancy
® Oestradiol is the most active of the natural oestrogens
® Produced by
i. Developing follicles in ovary
ii. Corpus luteum
iii, Placenta
iv. Liver
v. Adrenal glands
 a

oa 200 Chapter 6 Endocrinology

Activin
Oxytocin

SS

Follistatin

Prostaglanding
hormones
ormon pon

Figure 6.1 Ovarian hormones

vi. Breast
vii. Adipocytes
@ In plasma binds to
i. Sex hormone-binding globulin (SHBG)
ii, Albumin
® Metabolized in the liver to oestrone and oestriol (Fig. 6.2)
@ Excreted in the kidney as oestriol glucuronide
®@ Has 2 main receptors subtypes (other receptor subtypes exist)
i. © (found in endothelial cells)
i. B
® Work by genomic expression

Figure 6.2 Metabolism of oestradiol

5. Oestrogen functions
® Cardiovascular
i, Vasodilator (via an increase of NOS leading to an increase in NO)
ii, Prevents atherosclerosis
® Bone
i. Maintenance of bone density — decreases resorption of bone by antagonizing PTH
ii. Fusion of epiphyseal plates
® Increases clotting by
i. Increasing levels of factors Il, VII, IX, X, and plasminogen
ii, Decreasing anti-thrombin 3
iii, Increase platelet adhesiveness
© Gastrointestinal
i. Decrease motility of bowel
ii. Increases bile production
® Metabolic changes
i, Increases high-density lipoprotein (HDL) levels
 Sex hormones 201

ii. Decreases low-density lipoprotein (LDL) levels

iii. Decreases cholesterol levels
iv. Increases TAG synthesis
® Stimulates pigmentation of skin by increasing phaeomelanin
i. Nipple
ii, Areola
ili. Genital regions
® Proliferation of endometrium
@ Causes Na® and H,O retention by kidney
6. Progesterone
® Sources
i. Dioscorea mexicana (a type of plant)
ii. Corpus luteum
iii. Adrenal glands
iv. Placenta
® Stored in adipose tissue
@ In plasma binds to
i. Corticosteroid-binding globulin (CBG)
ii, Albumin
@ Metabolized in liver to pregnanediol
Excreted by kidney as pregnanediol glucuronide
@ Levels
i. Pre-ovulation = <2ng/mL
ii. Post-ovulation = 5ng/mL
iii. At term = 100-200 ng/mL
@ Atterm placenta produces 250mg/day progesterone

7. Progesterone functions
@ Uterus, cervix, and vagina
i. Converts proliferative to secretory endometrium
ii. Withdrawal of progesterone causes menstruation
iii. Thickens cervical mucus
iv. Inhibits uterine contraction until term
Increases core temperature following ovulation
Smooth muscle relaxant
Catabolic (thus causes an increase in appetite)
Increases aldosterone production (leading to Na” and H,O retention)
Reduces pressor responsiveness to angiotensin-2
Respiration
i. Increased ventilator response to CO,
ii, Decreased arterial and alveolar pCO,
@ Inhibits lactation during pregnancy
® Neuroprotective (is being investigated in treatment of multiple sclerosis; demyelination halts
during pregnancy)

8. Inhibins
® Are peptide members of transforming growth factor (TGF)-B family
® There are 2 forms of inhibin
i. Inhibin A
ii, Inhibin B
® Are secreted by ovarian granulosa cells
® Selectively inhibit FSH secretion but not LH secretion
oo 202 Chapter 6 Endocrinology

Produced in
i. Gonads
ii, Pituitary gland
iii. Placenta
Inhibin A is part of the quad screen test in the first trimester of pregnancy — elevated levels
of inhibin A, elevated B-hCG, decreased o-fetoprotein (AFP), and decreased oestriol are
suggestive of Down's syndrome

9. Activins
Are peptide members of TGF-B family
Are derived from
i. Ovarian granulosa cells
ii. Pituitary gonadotropes
Functions
i. Augment FSH action in the ovary
ii, Stimulate FSH secretion in the pituitary
iii. Inhibit prolactin, growth hormone, and ACTH responses

10. Relaxin
Produced by
i, Corpus luteum
ii. Placenta
iii. Breast
iv. Prostate
Relaxes pelvic ligaments in pregnancy
Plays a role in cervical dilatation
Inhibit contractility of myometrium

11. Testes secretes

3 main hormones
i. Testosterone
ii. DHT — strictly it is a paracrine hormone
iii, Oestradiol
Minor hormones
i. DHEA
ii. Androstenedione
iii, Oestrone
iv. Pregnenolone
v. Progesterone
vi. 170-hydroxypregnenolone
vii. 170-hydroxyprogesterone

12. Testosterone
Is an anabolic steroid
Secreted by
i. Testis (Leydig cells)
ii. Ovary (theca cells)
iii, Adrenals (zona reticularis)
iv. Placenta (cyto or syncytiotrophoblastic cells)
In serum exists
i. Freely (2% of testosterone)
ii, Bound to
= SHBG (60% of testosterone)
= Albumin (38% of testosterone)
 Hypothalamic hormones 203

® Effects of testosterone on tissue are via 2 mechanisms

i. By activation of nuclear androgen receptors
ii. By aromatization of testosterone to oestradiol (occurs in bone and brain)
® Is converted to DHT by 5a-reductase
® Excreted in urine as 17-ketosteroid

13. 5a-reductase
® Consist of 2 isoforms
® |s produced in
i. Skin
ii, Seminal vesicles
iii. Prostate
iv. Epididymis
vy. Brain
® Deficiency results in
i. Low DHT levels
ii, Increased testosterone levels
iii. Gynaecomastia
iv. Ambiguous genitalia at birth (DHT is necessary for development of male genitalia in
utero)

14. SHBG
® |saglycosylated dimer protein
Synthesized by liver
Gene located on chromosome 17
Levels are higher in females
SHBG levels are influenced by the following (Box 6.1):

Box 6.1 Causes of altered SHBG levels

SHBG increased by
© Oéestrogen ® Exogenous androgens
® Tamoxifen ® Progestin
© Phenytoin ® Glucocorticoids
® Thyroid hormone © Growth hormone
® Hypothyroidism
© Obesity

Hypothalamic hormones

1. Hypothalamic hormones (Box 6.2)

2. Paraventricular nucleus (PVN)

@ Adjacent to 3rd ventricle
® Within blood-brain barrier
@ Has 2 types of neurones
i. Magnocellular
ii. Parvocellular
@ Magnocellular neurones produce
i. Oxytocin
ii, ADH
 204 Chapter 6 Endocrinology

Box 6.2 Hypothalamic hormones

Paraventricular nucleus Arcuate nucleus Pre-optic nucleus Peri-ventricular nucleus

@ CRH © Dopamine ® GRH ® Somatostatin

@ TRH @ GHRH

Supraoptic and
paraventricular nuclei

® ADH
® Oxytocin

Parvocellular neurones produce

ib (Ne
ii, ADH
ii, TRH

3. Dopamine
Is a prolactin-inhibitory hormone
Has 5 receptor types
Produced in
i. Substantia nigra
ii, Arcuate nucleus
iii. Medulla of adrenal glands
Functions
i. Plays an important role in behaviour, cognition, and voluntary movements
ii, Inhibits prolactin
iii, Inotropic
iv, Chronotropic
vy. Induces vomiting via chemoreceptor trigger zone (metoclopramide is a dopamine
receptor antagonist)
Does not cross blood-brain barrier
Is metabolized by
i. Catechol-O-methyl transferase (COMT)
ii, Monoamine oxidase (MAO)

4. GnRH
Release is pulsatile .
i. GnRH pulsatile frequency is high in follicular phase
ii, GnRH pulsatile frequency slows in late luteal phase
Half life = 24 min
Gene is located on chromosome 8
Activity is low in childhood
Insulin increases GnRH activity
Prolactin decreases GnRH activity

5. Somatostatin
Is a GHRH inhibitor
Secreted by
i, Stomach
ii, Intestines
iii, Pancreatic cells (D-cells)
iv. Thyroid (parafollicular cells)
v. Periventricular nucleus
 Pituitary gland hormones 205

@ Functions are inhibitory

i. Inhibits growth hormone (GH)
ii. Inhibits TSH
iii. Suppresses release of gastrointestinal hormones
Gastrin
CCK
Secretin
Vasoactive intestinal peptide (VIP)
Motilin
Insulin
Glucagon
iv. Decreases gastric emptying, blood flow, and intestinal contractions
y. Suppresses release of pancreatic hormones

6. Thyrotrophin-releasing hormone (TRH)

@ Stimulates release of
i. Prolactin
is ool
Sin
@ Secreted by paraventricular nuclei

7. Melatonin
® ls synthesized from serotonin
Is associated with biorhythms
Inhibits gonadotrophins
Diurnal
Produced in
i. Pineal gland
ii, Retina
iii. Lens of eye
iv. GIT
vy. Suprachiasmatic nucleus
® Melatonin secretion increases in response to
i. Hypoglycaemia
ii, Darkness

Pituitary gland hormones

1. The 6 anterior pituitary hormones can be classified into 3 groups (Box 6.3)

Box 6.3 Classification of anterior pituitary hormones

Corticotrophin-related : Somatomammotrophin Glycoproteins —

: peptides : peptides ~ (have 2 subunits 0 and B)

@ ACTH ® Growth hormone @ TSH

@ MSH ® Prolactin & FSH)
® Gonadotrophin (LH

7 VES
Va
@ Isa glycoprotein
@ Released in response to GnRH
oo 206 Chapter 6 Endocrinology

@ Structure has 2 subunits

i. (gene located on chromosome 6)
ii. B (gene located on chromosome 11)
® Functions
i. Stimulates maturation of germ cells
ii. In females — stimulates ovary to produce Graafian follicle
iii. In males — induces Sertoli cells to synthesize and secrete inhibin
® High levels of FSH are due to
i. Premature menopause
ii, Reduced ovarian reserve
iii. Gonadal dysgenesis
iv. Castration
v. Swyer’s syndrome
vi. CAH
@ Half life = 3-4 hours
Receptors are only in granulosa cells

ch (ar!
@ |sa heterodimeric glycoprotein
® Structure has 2 subunits
i, (gene located on chromosome 6)
ii. B (gene located on chromosome 19)
® -subunit has 92 amino acids and is identical to the a-subunit of
i, Sel
te Ite
iii, hCG
® In females
i. Triggers ovulation
ii. Prevents apoptosis of corpus luteum
iii, Stimulates oestrogen and progesterone production
® In males — stimulates Leydig cells to produce testosterone
Low LH levels are due to
i. Kallmann’s syndrome
ii. Hypothalamic suppression
iii. Hypopituitarism
iv. Hyperprolactinaemia
® High levels of LH are due to
i, Premature menopause
ii, Gonadal dysgenesis
iii, Castration
iv. Polycystic ovary syndrome (PCOS)
v. Swyer’s syndrome
vi. CAH
® Surge
i. Is biphasic
ii, Ovulation occurs
= 36h after LH surge
B 16-26 h after peak of LH
iii. Causes
@ Prostaglandin production
™ Progesterone secretion from corpus luteum
= Resumption of meiosis by oocyte
 Pituitary gland hormones 207

® Half life = 20min

® Gonadotrophins reach 2 peaks at
i. 20 weeks in fetal life
ii, 1-2 months in infancy
@ LH and testosterone increases in the first 3-6 months of life
@ Receptors are found in
i. Granulosa cells
ii. Theca cells

4. Prolactin
® l|sa peptide hormone
®@ Has a molecular weight of 24000 Daltons
® Consists of 199 amino acids
@ Structure is similar to
ieGhi
ii. Placental lactogen
Gene located on chromosome 6
@ Cycle is
i. Diurnal
ii. Ovulatory
® Functions
i, Lactogenesis
ii. Promotes breast development
@ ls also responsible for decreasing serum levels of
i, Oestrogen
ii, Testosterone
@ Also produced by
i. Decidua
ii, Breast
iii. Brain
iv. Immune system
® Factors affecting prolactin secretion (Table 6.1)

Most of GH effects are mediated by IGF

Gene located on chromosome 17
Consists of 191 amino acids
Functions are
i. Mainly anabolic
@ Increases protein synthesis
= Decreases protein catabolism
ii, Lipolysis
iii. Anti-insulin actions
e Factors affecting GH secretion (Table 6.2)

6. ACTH
@ Released in response to CRH from hypothalamus
@ Can be produced by cells of the immune system
i, T-cell
ii, B-cell
iii. Macrophage
@ Stimulates production of steroids from the adrenals
ee 208 Chapter 6 Endocrinology

Table 6.1 Factors affecting prolactin secretion

ee ee ee eee eee Se eS SS
Hyperprolactinaemia
Lele paler mee aaTea aa i SLAs fot ey Sh re
Physiological Pharmacological Pathological
Ee a a a PLL hy hk A a a
Pregnancy TRH Pituitary tumour

Lactation Oestrogen Chest wall lesions

Exercise Dopamine antagonists Spinal cord lesions

Stress MAO! Hypothyroidism

Sleep Cimetidine Chronic renal failure

Hypoglycaemia Verapamil Liver failure

Stalk syndrome

Hypoprolactinaemia

Pharmacological Pathological

Dopamine agonists Sheehan's syndrome

Hypopituitarism
Bulimia

Table 6.2 Factors affecting GH secretion

Raised serum GH

Physiological Pharmacological Pathological

Sleep GHRH Chronic renal failure

Stress Oestrogen Anorexia nervosa

Exercise Adrenergic agonist

Hypoglycaemia Dopamine agonist

Decreased serum GH é

Physiological Pharmacological Pathological

Hyperglycaemia Somatostatin Obesity

Elevated free fatty acids Progesterone

Glucocorticoids

® Released in circadian rhythm — highest in the morning

® Derived from pro-opiomelanocortin (POMC)
® By-products are
i, melanocyte-stimulating hormone (MSH)
ii, Endorphins

7, Oxytocin
@ Is ananopeptide (consists of 9 amino acids)
 Thyroid gland hormones 209

@ Produced in supra-optic and paraventricular nucleus of hypothalamus

Stored in posterior pituitary
® Involved in smooth muscle contraction of
i. Uterine muscle
ii. Myoepithelial cells surrounding breast alveoli (letdown reflex)
® Oxytocin receptor
i. ls a G-protein-coupled receptor which requires Mg’* and cholesterol
ii, Also found in brain and spinal cord

8. ADH
Is a nanopeptide
Also known as vasopressin
Is derived from pre-pro-hormone precursors synthesized in the hypothalamus
Released when body fluid volume decreases
Functions
i. Vasoconstrictor
ii. Increases urine osmolarity
iii. Increases reabsorption of H,O at DCT and collecting duct
iv. Na* reabsorption in ascending loop of Henle
y. Implicated in memory formation

Thyroid gland hormones

1. Action of thyroid hormone

© Increases activity of Na*-K* ATPase (in all tissue except brain, spleen, and testis) causing
i. Increased O, consumption
ii, Heat production
®@ Decreases superoxide dismutase levels
@ Increases B-adrenergic receptors in
i, Myocardium (leading to positive ionotropic and chronotropic effects)
ii, Skeletal muscles
iii. Adipose tissue
iv. Lymphocytes
@ Blood
i. Increases EPO
ii, Increases erythropoiesis
iii. Increases DPG content of erythrocyte
@ Bone
i. Increases bone turnover
ii, Increases bone resorption, leading to osteopenia
@ Metabolism
i, Increases hepatic gluconeogenesis
ii, Increases glycogenolysis
iii. Increases lipolysis

2. Thyroid hormone production

® |, absorbed from bloodstream via iodide trapping
® Thyroglobulin synthesis
® lodination (I, binds to tyrosine contained in thyroglobulin)
i. |, + tyrosine = monoiodotyrosine (MIT)
ii, I, + MIT = diiodotyrosine (DIT)
oe 210 Chapter6 Endocrinology ;

® Coupling of iodinated residues

hh IMIBE Se ID We
eile Dil.
®@ Stored in colloid of the follicular cells

3. Thyroid hormones
® Bound to
i. Thyroid-binding globulin (TBG) = 70%
ii, Albumin = 15%
iii. Pre-albumin (transthyretin) = 15%
eT,
i, Amount is approximately 20 times more than T,
ii. Half-life = 7 days
O ais
i, The active component
ii, Half-life = 1 day
@ rT3
i. Is inactive
ii, Half life = 4h

4. Changes in pregnancy (Fig. 6.3)

ey i ihe ftrenal
4 d 13/74 clearance

+t

t TBG
Changes in deiodination
pregnancy of T3/T4 by
placenta

Figure 6.3 Thyroid changes in pregnancy

Adrenal hormones

1. Adrenal hormones are derived from the

® Adrenal cortex and
® Adrenal medulla

Adrenal cortex
1. Mediates the stress response via the production of
® Mineralocorticoids
® Glucocorticoids
2. Consists of 3 layers
@ Zona glomerulosa (produces mineralocorticoids)
 Adrenal hormones 211

® Zona fasciculata (produces glucocorticoids)

® Zona reticularis (produces weak androgens)

3, All adrenocortical hormones are synthesized from cholesterol

4. Glucocorticoids include
® Cortisol
® Corticosterone

5. Glucocorticoid actions
@ Protein catabolism
i. Inhibit DNA synthesis
ii. Inhibit RNA and protein synthesis (except in the liver)
® Formation of ATP
@ Metabolism
i. Increases gluconeogenesis
ii. Inhibits peripheral glucose usage
ili. Increases lipolysis
® Connective tissue and bone
i. Inhibits fibroblasts
ii. Loss of collagen
iii. Increases bone resorption
® Renal
i. Increases excretion of Na* and water
ii, Increases GFR
Increases secretion of stomach acid
Blood
i. Increases neutrophil count
ii. Decreases lymphocyte count

6. Aldosterone
@ \samineralocorticoid
® Has 21 carbon atoms
@ |s part of the renin—angiotensin system
® Functions
i. Reabsorption of Na* from DCT and collecting ducts
ii. Excretion of H* and K* via kidneys
iii. Acts on posterior pituitary to release ADH
@ Secretion is regulated by
i. Renin—angiotensin system
ii, Sympathetic nerves
iii, Juxtaglomerular apparatus
iv. Carotid artery baroreceptors
v. Plasma concentration of K*
vi. Plasma concentration of Na*
7. During adrenarche
@ Adrenal androgen production starts at
i. Males = 7-9 years old
ii, Females = 6-7 years old
@ The adrenal cortex secretes weak androgens
i. DHEA
ii. Dehydroepiandrosterone sulphate (DHEAS)
iii, Androstenedione
He 212 Chapter 6 Endocrinology

Adrenal medulla
le ls composed mainly of chromaffin cells

Di Adrenal medulla cells are modified neural crest cells which did not complete their
development to postganglionic neurones, but retain the same functions

Synthesizes
Adrenaline
Noradrenaline
Dopamine

Adrenaline
Synthesis: Tyrosine - L-DOPA — dopamine — noradrenaline — adrenaline
Actions
i. Lipolysis
ii. Glycogenolysis
iii. Salt and water balance
iv. Vasoconstriction
v. GIT — relaxes smooth muscle
vi. Increases plasma levels of
= Insulin
& Renin—angiotensin system
Adrenaline acts on a and B receptors
Noradrenaline acts only on a receptors
The dominant fetal catecholamine is -DOPA
Metabolized by
i. MAO
ii, COMT

Renin-angiotensin system

1. Juxtaglomerular apparatus in kidney

Composed of
i, Juxtaglomerular cells of afferent arterioles
ii. Macula densa (cells on ascending loop of Henle)
Regulates renin secretion

2. Renin
Also known as angiotensinogenase
Secreted by juxtaglomerular cells in response to
i, Decreased arterial blood pressure
ii, Decrease Na’ levels in plasma
Renin cleaves angiotensinogen to form angiotensin 1
Renin inhibitors are used to treat hypertension
Synthesis (Fig. 6.4)

Figure 6.4 Renin synthesis

3. Angiotensinogen
Secreted by liver
 Pancreatic hormones 213

® Production is increased by
i, Oestrogen
ii, Glucocorticoids

4. Angiotensin
® Synthesis
i, Angiotensinogen — angiotensin 1 (catalyst = renin)
ii, Angiotensin 1 — angiotensin 2 (catalyst = ACE)
® Function
i, Vasoconstriction
ii, Stimulates aldosterone secretion

5. ACE
@ Found in
i, Endothelial cells of the pulmonary capillaries
ii, Brain
iii. Glomeruli
@ Also catalyses
i. Bradykinin breakdown
ii, Enkephalin breakdown
iii. Substance P breakdown

Pancreatic hormones

1. Insulin actions
@ Anabolic effects
i, Glycogen synthesis
ii. TAG synthesis
® Inhibits catabolism
i. Inhibits glycogenolysis
ii. Inhibits ketogenesis
iii. Inhibits gluconeogenesis
® Stimulates glucose uptake into
i. Muscle
ii, Adipose tissue

2. Insulin antagonists
® Glucagon
Cortisol
Growth hormone
Adrenaline
Oestrogen
Thyroid hormone
Prolactin
Human placental lactogen (responsible for the insulin resistance of pregnancy)

3. Glucagon
@ Main target tissue = liver
e@ Actions
i. Glycogenolysis
ii. Inhibits glycogen synthesis
iii. Gluconeogenesis
 214 Chapter 6 Endocrinology :

iv. Lipolysis
V. lonotropic
vi. Causes release of
= Insulin
® Catecholamines

a ened

Endocrine diseases

1. Syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH)

® Clinical features
Hyponatraemia
Hypo-osmolality of plasma (<280 mOsm/kg)
iii, Excessive renal excretion of Na” (>20 mEq/L)
. Hypervolaemia
Absence of oedema
i. Normal renal function
ii, Normal adrenal function
Aetiology
Tumour — oat cell carcinoma
CNS disease
iii. Respiratory disease
. Myxoedema
Porphyria
. Drugs
= Vinblastine
B SSRIs
= Thiazide
@ Carbamazepine
Vil, Trauma
viii. Infection
ix, Surgery
Treatment
Fluid restriction (1 L/day)
Diuretics
iii. Demeclocycline (is a tetracycline which induces nephrogenic diabetes insipidus)
iv. Conivaptan (is an ADH inhibitor)
Hyponatraemia can be corrected by using hypertonic saline 5% (rapid rise in sodium
levels may cause central pontine myelinolysis; aim for maximum increase of 12 mEq/L/day
of Na‘)
2. Diabetes insipidus (Dl)
Is a disorder resulting from deficient ADH action
Treatment = desmopressin
Classification of DI (Box 6.4)
Also associated with pregnancy-related diseases such as
Pre-eclampsia
HELLP syndrome
Acute fatty liver of pregnancy (due to activation of hepatic vasopressinase)

3. Hypothyroidism
® Can result in congenital hypothyroidism in the fetus, known as cretinism
® Aetiology (Box 6.5)
 Endocrine diseases 215

Box 6.4 Classification of diabetes insipidus

® Idiopathic ® Chronic renal disease © Vasopressinase is produced

® Familial ® Hypokalaemia in the placenta, which breaks
® Syphilis © Hypercalcaemia down ADH
© Tuberculosis (TB) ® Sickle cell disease
® Tumour ® Sjogren’s syndrome
© Autoimmune © Lithium

Box 6.5 Aetiology of hypothyroidism

® Hashimoto's ® Hypopituitarism ® Hypothalamic dysfunction

® latrogenic
® lodide deficiency

@ Associated with
i. Pernicious anaemia
ii. Sjogren’s syndrome
iii. Rheumatoid arthritis
iv. Systemic lupus erythematosus (SLE)
v. Diabetes
® Clinical features
i. Cardiomegaly
ii. Decreased intestinal peristalsis
iii. Renal
® Decreased GFR
= Myxoedematous facies
iv. Anaemia
y. Amenorrhoea/menorrhagia
vi. Overweight
vii. Hands
Dry
Cool
Rough
Inelastic skin
Non-pitting oedema
Carpal tunnel syndrome
viii. Face
® Thin, dry and brittle hair
= Loss of outer 1/3 of eyebrow
® Yellowish complexion
ix. Reflex — slow relaxing reflex
® Complication = myxoedema coma
@ Tested for by Guthrie’s test

4. Hyperthyroidism
@ Aetiology (Fig. 6.5)
® Treatment
i. Carbimazole and propylthiouracil (PTU)
oS 216 Chapter6 Endocrinology yes

Toxie multinodular
Solitary adenoma
goitre

Others
1) Pituitary adenoma
2) Hydatidiform mole
Graves’ idivenns (95%) . 3) Choriocarcinoma
4) Teratoma
5) latrogenic
Hyperthyroidism

Figure 6.5 Aetiology of hyperthyroidism

ii, Surgery
iii. Radioactive iodine
® Clinical features
i. Hands
B® Pulse suggestive of atrial fibrillation
B® Excessive sweating
® Tremor
ii. Weight loss
iii, Muscular weakness
iv. Heat intolerance
v. Insomnia
vi. Eyelid retraction
vii. Lid-lag
viii. Exophthalmos
ix. Thyroid acropachy
® Complication = thyroid crisis

5. Exophthalmos
@ ls due to
i. Cross-reaction of autoimmune antibodies to intraorbital muscle
ii. Increased retro-orbital fat
iii, Intraorbital muscle infiltrated with lymphocytes
® Complications of exophthalmos include
i. Chemosis
ii, Ophthalmoplegia
iii, Diplopia

6. Addison’s disease
® |s due to decreased levels of cortisol
® ls primary adrenocortical insufficiency
® Clinical features
i. Hypotension
ii. Hyponatraemia
iii, Hypoglycaemia
iv. Hyperkalaemia
v. Hyperpigmentation (due to increased ACTH)
 Endocrine diseases 217

® Aetiology
i. CAH
ii. Infection
= TB
a CMV
iii. Autoimmune
iv. Adrenal haemorrhage
v. Infiltrative disorder
= Amyloidosis
= Haemochromatosis
vi. Rapid removal of exogenous hormone
vii. Drugs
® Ketoconazole
® Etomidate

7. Cushing’s syndrome
@ |s chronic glucocorticoid excess
®@ Aetiology (Box 6.6)

Box 6.6 Causes of Cushing’s syndrome

~ ACTH independent
© Pituitary adenoma (Cushing’s disease) ® latrogenic
© Ectopic ACTH ® Adrenal neoplasm

© Clinical features
i. Hypertension
ii, Hyperglycaemia
iii. Hyperlipidaemia
iv. Hypokalaemia
v. Amenorrhoea
vi. Osteoporosis
vii. Obesity
@ Tumours causing ectopic ACTH secretion
i. Small cell carcinoma of lung
ii, Pancreatic cancer
iii. Carcinoid
iv. Medullary carcinoma of thyroid
v. Phaeochromocytoma

8. Conn’s disease
® \s primary hyperaldosteronism
® Aetiology = adrenal adenoma
@ Shows low renin : aldosterone ratio
® Clinical features
i. Hypokalaemia
ii, Hypernatraemia
iii. Hypertension
® Treatment = spironolactone

9. Phaeochromocytoma
@ Are tumours arising from chromaffin cells
® Secretes:
| 218 Chapter 6 Endocrinology

i. Adrenaline
ii, Noradrenaline
iii. Dopamine
Associated with
i. MEN type 2 syndrome
ii. Neurofibromatosis
Can be caused by RET proto-oncogene mutations
Clinical features
i. Hypertension
ii. Hyperglycaemia
iii, Headache
iv. Sweating
Diagnosis is achieved by measuring urinary levels of vanillylmandelic acid (YMA) and
metanephrine
Untreated phaeochromocytoma leads to inhibition of renin—angiotensin system
Treatment
i. Surgery
ii, Preoperative salt loading
iii. Intraoperative o-blocker (e.g. phenoxybenzamine)
iv. Avoid pure B-blockers (e.g. atenolol)

10. Prolactinoma
@ sa benign tumour of the pituitary gland
@ Results in hyperprolactinaemia
® Classification
i. Macroprolactinoma (i.e. tumour size >10 mm)
ii. Microprolactinoma (i.e. tumour size <10 mm)
® Features
i. Headache
ii. Bitemporal hemianopia (due to pressure on optic chiasm)
iii, Galactorrhoea
iv. Hypogonadism (resulting in amenorrhoea)
v. Erectile dysfunction
@ Treatment
i, Dopamine agonist (shrinks tumour in 80% of patients)
ii, Trans-sphenoidal surgery
iii, Radiotherapy ;
® May result in osteoporosis due to reduced oestrogen and testosterone

Puberty

1. Sex determination
Default phenotype in utero = female
Male phenotype determined by
ib Spy
ii. Testosterone (promotes Wolffian ducts)
iii. Mullerian inhibiting substance (MIS) — secreted by Sertoli cells

2, Physical changes in puberty

Stages of development described by Tanner (5 stages in total) (Fig. 6.6)
Figure 6.6 Tanner’s stages for male (circled numbers represent testicular volume in ml, numbers
next to arrows represent testicular length in cm) and female
Reproduced from the Oxford Handbook of Reproductive Medicine and Family Planning, by McVeigh, Homburg and
Guillebaud, © Oxford University Press (2008). Original data from Marshall WA and Tanner JM. Archives of Disease in
Childhood 1969; 44:291-303.

@ Male development
i, Chronologically: testes + scrotum — penis > pubic hair
ii. Seminiferous tubule is solid until the age of 5
@ Female development
i. Chronologically: increased growth velocity — breast (thelarche) — pubic hair
(adrenarche) — axillary hair — menarche
ii, Breast development is determined by ovarian oestrogen
iii. Pubic hair development is determined by adrenal and ovarian androgens
iv. Average age of menarche is 12.3 years in African girls and 12.8 in Western Caucasians

3. Growth spurt in puberty

@ ls under endocrine control
th (in.
ii, IGF
® Oestrogen is important for epiphyseal fusion
® Begins in males 2 years later than females
®@ Bone mineralization peak
i, Girls at the age of 14-16 years old
ii, Boys at the age of 17.5 years old

4. GnRH and gonadotropin changes up to puberty

® GnRH
i. Is secreted in a pulsatile manner (every 90-120 min)
ii. Increased GnRH pulse frequency increases LH : FSH ratio
iii, Continuous GnRH secretion causes suppression of gonadotrophins
iv. Increased LH : FSH ratio is characteristic of midcycle dynamics
@ Fetal life
i. Fetal LH and FSH peak at mid-gestation then decline until term
ii, Fetal GnRH increases until mid-gestation
ee 220 Chapter 6 Endocrinology

@ Age 2-9
Gonadotrophin level is low (juvenile pause)
@ Peripubertal
i. Gonadotrophin release is circadian
ii, GnRH secretions increase in frequency and amplitude during early sleep
® Early puberty
i. The peak of LH and FSH occurs during the day
e Late puberty
i. The peak of LH and FSH occurs all the time
ii, Gonadotrophin diurnal rhythm is eliminated

Endocrine changes in pregnancy

1. Maternal hormonal changes in pregnancy include (Fig. 6.7)

@ LH and FSH levels are minimal
® Cortisol and corticosteroids — increase in 2nd trimester
@ 73 and T,4— peak at 10-15 weeks gestation
@ Relaxin — highest in the first trimester

2. Proteins associated with pregnancy (Box 6.7)

Placental hormones

1. Placenta produces 9 hormones during pregnancy (Fig. 6.8)

oh, ANGLE
Is a peptide hormone (glycoprotein)
Is composed of 244 amino acids
Is secreted by the syncytiotrophoblast
Functions
i, Prevents degradation of corpus luteum
ii. Induces ovulation
iii, Stimulates Leydig cells to produce testosterone
@ ls heterodimeric
® Structure has 2 subunits '
i, @—identical to LH/FSH/TSH
ii, B—unique to hCG
® Peaks at 9-12 weeks to 290000mlU/mL
® Secreted by some types of tumour
i. Choriocarcinoma
ii, Germ cell tumour
ili. Hydatidiform mole

30 nr
Consists of 190 amino acids linked by disulphide bonds
Is an anti-insulin (i.e. is diabetogenic)
Is secreted by the syncytiotrophoblast
Gene located on chromosome 17
Belongs to the same family as
i, (GH
ii. Prolactin
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Box 6.7 Proteins associated with pregnancy

Fetal compartment Placental compartment Maternal compartment

© a-fetoprotein GnRH ® Prorenin
CRH © Decidual proteins, which include
TRH © Prolactin
Somatostatin ¢ Progesterone-associated
GHRH endometrial protein
hCG ¢ |nterleukin-1
hPL © Colony-stimulating factor-1
hGH
hCT
ACTH
Oxytocin
IGF-1 and IGF-2
Epidermal growth factor
Platelet-derived growth factor
Fibroblast growth factor
Transforming growth factor
Inhibin
Activin
Follistatin
Cytokines
Opiates
Pregnancy-associated plasma
protein A

‘Progesterone i

Oestrogen Relaxin

hPL ACTH

Placental
hCG TSH
hormones

Figure 6.8 Placental hormones

® Peaks at 35 weeks gestation (5-7 mg/mL)

Half-life = 15 min
® Functions
i. Induces lipolysis — raises maternal free fatty acids (FFAs)
ii, Decreases maternal insulin sensitivity
 Labour 223

Labour

. Initiation of labour involves 2 endocrine systems

Fetal
Maternal

. Labour is characterized by
Uterine contractions
Cervical effacement and dilatation

. Cervical ripening (obvious in the last 5 weeks of pregnancy) has much in common with an
inflammatory process involving
Prostaglandin E,
Cytokines (especially interleukin (IL)-8)
Recruitment of neutrophils
Synthesis of metalloproteinases (including collagenases and elastase)
Increased cervical tissue water content
Reduction in cervical tissue collagen concentration, and rearrangement and realignment of
collagen

. The fetus is thought to trigger parturition

Fetal pituitary releases corticotrophin, which acts on the fetal adrenals
Fetal adrenals release
i. Cortisol
ii. DHEAS

. Hormonal changes leading to labour

Fetal adrenal cortisol rises towards the end of term causing
i. Increased oestrogen production
ii. Formation of oxytocin receptors
Fetal adrenal DHEAS is metabolized in the placenta leading to increased oestrogen levels,
which provoke the release of prostaglandin F,,, from the decidua, causing myometrial
contractions
Rise in placental CRH, causing augmentation of levels of
i. Oxytocin
ii. Prostaglandin Fy,

. Other factors initiating labour

NO withdrawal
Progesterone
i. Withdrawal
ii. Switch from type 1 to type 2 progesterone receptors
Increased placental release of
ih Ne
ii, Oestrogen
Upregulation of oxytocin receptors
Increased prostaglandin synthesis in
i. Uterus
ii. Fetal membranes
Increased IL
leew
ii, IL-8
se 224 Chapter 6 Endocrinology

® Fetal release of
i. Cortisol
ii. Platelet-activating factor
® Catecholamines
i. B,-adrenergic receptor agonists inhibit labour
ii. Q»-adrenergic receptor agonists cause uterine contractions
@ Fetal posterior pituitary (umbilical artery oxytocin > umbilical vein oxytocin)
® Increased myometrial gap junctions during labour

7. Ferguson reflex
@ lsaneuronal reflex triggered by pressure application to the
i. Cervix
ii. Vagina
® Causes spurts of oxytocin release
@ Occurs during the following labour phases
i. Active
ii. Expulsive

Puerperium and lactation

Puerperium
1. Most hormone levels drop dramatically except for the rise in
® Prolactin (only in breast-feeding women)
® Oxytocin

2. The following hormone levels decline in the puerperium

® Oestrogen
® Progesterone
® Thyroid
© Most hormones takes 6 weeks to return to normal

3. Menses returns in
© Breastfeeding women at 28 weeks post partum
® Non-breast feeding women at 9 weeks post partum

4. Prolactin levels drop 2 weeks post partum in non-breast feeding women, resulting in
cessation of lactation

Breastfeeding
1. Lactation
@ Maternal breast changes occur from 7 weeks gestation onwards
® Influenced by
i, Oestrogen
i Intel
iii. Prolactin
iv. Decreased serum progesterone levels
v. Oxytocin
Visual
vii. FSH
 Puerperium and lactation 225

2. Lactational amenorrhoea is a reliable form of contraception (98% effective according to the

World Health Organization (WHO)) if the following criteria are met
@ The baby is exclusively breastfed (intervals between breastfeeding are no longer than 5 h)
@ Amenorrhoea (less than 6 months postpartum)
3. Breast milk
® Composition (Box 6.8)

Box 6.8 Composition of breast milk

© Lactose ® Polyunsaturated fatty ® Casein

® Oligosaccharides acid ® Lactoferrin we
®
® Palmitic acid © |mmunoglobulin eB
® Oleic acid (A, G, M, and D) aC
® Vaccenic acid @ Lysozymes
© Conjugated linoleic ® Albumin
acid

® Macrophage
® Lymphocyte

®@ Also contains
i, 2-arachidonoyl glycerol (a type of endocannabinoid)
ii. Growth factors (e.g. epidermal growth factor (EGF), IGF)
iii, Digestive enzymes (e.g. bile acid-stimulating lipase, amylase)
iv. Hormones (e.g. feedback inhibitor of lactation (FIL), prolactin, insulin,
ACTH)
®@ Benefits (Box 6.9)

Box 6.9 Benefits of breastfeeding

ca:
ee oes
© Weight loss (breastfeeding uses 500 kcal/day) Decreases sudden infant death syndrome (SIDS)
® Strengthens maternal bonding Protects against diabetes mellitus
® Helps uterus contract post delivery and reduces risk Reduce risk of obesity
of postpartum bleeding Reduces atopy
® Reduces risk of breast cancer Reduces risk of necrotizing enterocolitis (NEC)
® Reduces risk of ovarian cancer Confers passive immunity
@ Reduces risk of endometrial cancer Lower the risk of infection (e.g. otitis media, upper
respiratory tract infection, urinary tract infection)
® Acts asa mild laxative
 226 Chapter 6 Endocrinology

Typical breast milk volume at day 5 post partum is 500 mL/day

Colostrum
i. Secreted for the first 3-5 days after delivery
ii. Typical volume = 100 mL/day
iii. Rich in the following (compared with mature breast milk)
= Vitamin A
™ Lactoferrin
HB igA
= Sodium

Fetal and neonatal endocrine system

1. Fetal endocrine system is largely functional by term

2. Surfactant production is controlled by

Cortisol
Oestrogen
Adrenaline
Thyroid hormone

3. Development of gonads and adrenals in the 1st trimester is directed by hCG

4, Fetal endocrine development (Box 6.10)

Box 6.10 Fetal endocrine development

® Hormone synthesis ® Hormone synthesized ® Cortex identifiable at © Testes seen at

begins at 12 weeks in 1st trimester 4 weeks 6 weeks
© T4 is predominant © Fetal PTH levels are ® Steroidogenesis starts ® Ovaries seen at
low at 7 weeks 7-8 weeks
® Fetal calcitonin is ® Fetal zone involution @ Testosterone
elevated complete 1 month production starts at
© Fetus is post delivery 10 weeks
hypercalcaemic ® Oestrogen production
starts at 20 weeks

© Oxytocin and
Vasopressin present at
12 weeks
© Anterior pituitary
hormone levels are
significant in fetal
circulation at
20 weeks
 CHAPTER 7

eh

_ Pathology
L

CONTENTS Coagulation 244

Inflammation 227 Sepsis 251
Cellular adaptation 231 Shock 252
Cell injury 232 Disorders of the genital tract 255
Wound healing 237 Disorders in pregnancy 265
Neoplasia 239 Pathology — specific blood tests 268

Inflammation

1. The inflammatory response consists of 2 main components

® Vascular response
® Cellular response
2. Vascular response
® Chronology of vascular response (Fig. 7.1)

ae Transient ;

Margination of : Increased blood

Blood stasis pcs
viscosity
leucocytes

Figure 7.1 Chronology of vascular response

@ Vasodilation
i. Is the earliest manifestation of acute inflammation
ii. Involves arterioles first
iii. Is induced by the action of
® Histamine
=# NO
iv. Results in increased blood flow
v. Results in increased hydrostatic pressure
 228 Chapter 7 Pathology

Exudation results in
i. Reduced intravascular osmotic pressure
ii. Increased interstitial osmotic pressure
iii, Oedema
Exudate is an inflammatory extravascular fluid that has a high protein concentration and a
specific gravity >1.02
Increased vascular permeability occurs in distinct phases
i. Phase 1 — immediate transient response
= Is mediated by histamine, leukotrienes, neuropeptide substance P, and bradykinin in
venules
@ |s short lived (less than 30 minutes)
@ ls reversible
ii, Phase 2 — delayed response
= |s mediated by kinin and complement products
= Is long lived
= Involves venules and capillaries
= Onset is delayed for 2-12h
iii. Phase 3 — prolonged response after direct endothelial injury, which affects all levels of
microcirculation

3. Cellular response
@ Involves 2 events
i. Leucocyte extravasation
ii. Phagocytosis
@ Extravasation is the sequence of events in the movement of leucocytes from the vessel
lumen to the interstitial tissue (Fig. 7.2)

Margination Leucocyte
adhesion Ereecyre
diapedesis Chemotaxis

Figure 7.2 Extravasation sequence

Leucocyte adhesion to the endothelium is regulated via endothelial binding receptors that
belong to 4 main groups
i. Selectins .
ii. Immunoglobulin super-family
iii. Integrins
iv. Mucin-like glycoproteins
Diapedesis
i. Is the process of transmigration across the endothelium
ii. Occurs predominantly in the venules
Chemotaxis is elicited by
i. Exogenous agents (e.g. bacterial products)
ii, Endogenous agents
= Components of the complement system
Chpt 8 ® Leukotriene
= Cytokines
Microbicidal substances
i. Are released into the extracellular space and phagolysosomes during phagocytosis by
leucocytes
 Inflammation 229

ii, Include
= Lysosomal enzymes
™ Reactive oxygen intermediates (e.g. H,O,)
™ Products of arachidonic acid metabolism (e.g. leukotrienes and prostaglandins)
iii, Are capable of causing endothelial and tissue damage (leucocyte-induced injury)
including
= Acute respiratory distress syndrome
= Acute transplant rejection
= Asthma
= Reperfusion injury

4. Chemical mediators of inflammation include

Hageman factor activation
i. Source = liver and plasma
ii. Also known as factor 12
iii, Functions
® Activates kinin system
= Activates clotting system
= Activates fibrinolytic system
= Activates complement system
Complement system
i. Source = liver and plasma
Cytokines and NO
i. Source = endothelium and macrophage
Platelet-activating factor
i. Source = endothelium and leucocytes
Serotonin
i. Source = platelets and mast cells
ii, Increases vascular permeability
Histamine
i. Source = platelets and mast cells
ii, Associated with IgE
Bradykinin
i. The kinin system is triggered by the activation of the Hageman factor
ii. Functions
™ Increased vascular permeability
= Vasodilation
® Smooth muscle contraction
= Chemotaxis
=™ Activates Hageman factor
iii. Is formed by the action of kallikrein (converts kininogen — bradykinin)
iv. Is inactivated in the lungs by ACE
v. ACE inhibitor (ACEi) prevents inactivation of kinin in the lungs
Prostaglandins
Leukotrienes
Platelet-activating factor
Lysosomal enzymes

5. Signs of inflammation
Raised ESR (due to RBC clumping)
Leucocytosis — increased number of immature neutrophils
4 cardinal signs
ce 230 Chapter 7 Pathology

i Rubor (redness)
ii.Tumour (swelling)
iii.
Calor (heat)
iv. Dolor (pain)
® Virchow sign (loss of function)

6. Systemic acute phase response is predominantly induced by

® I|nterleukin-1
@ TNF
7. There are 2 patterns of inflammation
® Acute
®@ Chronic

Acute inflammation
1. Characteristics
® Rapid onset
® Short duration

2. Vascular and cellular changes

@ Alteration in vascular calibre
i, Initial vasoconstriction followed by vasodilation
ii. Slowing of circulation (stasis)
iii. Margination of leucocytes
iv. Central sludging of RBCs
® Increased vascular permeability
® Exudation of fluid
™ Serous
@ Fibrinous
® Purulent
®@ Emigration of leucocytes (predominantly neutrophils)

3. Outcomes
® Complete resolution
® Fibrosis
® Abscess formation
® Chronic inflammation

4. Morphological patterns of acute inflammation

Serous inflammation
@ Fibrinous inflammation
® Suppurative inflammation
@ Ulcers

Chronic inflammation
1. Chronic inflammation is caused by
® Persistent infection (e.g. Mycobacterium)
® Prolonged exposure to foreign agents (e.g. silica)
@ Immune reaction to own tissue (e.g. autoimmune disease)

2. Can start de novo without acute inflammation

3. Features
® Long duration
 Cellular adaptation 231

® Associated histologically with the presence of

i. Lymphocytes
ii, Macrophages

4. Characterized by
@ Infiltration by mononuclear cells (macrophages) — predominant by 48h
@ Tissue destruction
® Attempted repair by proliferation of new blood vessels
@ Fibrosis

5. Granulomatous inflammation
© sa distinctive pattern of chronic inflammation characterized by
i. Granulomas (focal area)
ii, Epithelioid cells (activated macrophages)
@ Epithelioid cells are surrounded by mononuclear leucocytes
@ Eg.
ae}
= Caseating granuloma
= Langhans giant cell
= Mantoux test can be positive/negative
ii. Cat-scratch disease
= Stellate granuloma
= Contains neutrophils
iii. Schistosomiasis (contains eosinophils)
iv. Sarcoidosis
™ Non-caseating granuloma
® Schaumann’s body
® Raised ACE levels
= Kveim’s test can be positive/negative
v. Temporal arteritis
@ Any granulomatous lesion can contain giant cells

Cellular adaptation

1. Cellular adaptation
® Cellular changes that occur in response to a persistent physiological or pathological stress
@ There are 5 major forms of adaptation (Box 7.1)

2. Causes of atrophy
Decreased workload
Loss of innervation
Diminished blood supply
Inadequate nutrition
Loss of endocrine stimulation (e.g. loss of oestrogen during menopause)
Senile atrophy
Pressure

3. Hyperplasia
@ |saresult of increased cell mitosis
® Can be divided into
i. Physiological
ii, Pathological
 232 Chapter 7 Pathology j

Box 7.1 Forms of adaptation

® Decrease in cell size

ee
® \ncrease in cell size
oo
© |ncrease in number ® Occurs when a cell is
of cells replaced by another
cell type
® Reversible
® If stimuli persist can
induce cancer

® Abnormal changes in
cellular shape and size
® Also known as atypical
hyperplasia

® Physiological hyperplasia is further divided into

i. Hormonal
Tin ii, Compensatory
Gn ® Endometriosis is a form of pathological hyperplasia
Chpt 13.2

Cell injury

1. Cell injury
® Occurs when limits of adaptive responses are exceeded
® \t may be reversible or irreversible
® Hallmarks include
i. Decreased oxidative phosphorylation
ii, Depleted ATP
iii, Cellular swelling
® Cellular swelling is also known as
i, Hydropic degeneration
ii, Vacuolar degeneration

2. Cell death
® Results from irreversible cell injury
® Hallmarks include
i. Mitochondrial damage
ii, Loss of membrane permeability
® Characterized by
i. Pyknosis (condensation of chromatin)
ii, Karyorrhexis (fragmentation of nuclear material)
iii. Karyolysis (dissolution of nucleus)
® There are 3 types
i. Necrosis (traumatic cell death)
ii. Apoptosis (programmed cell death, follows a characteristic pattern)
iii. Autolysis (non-traumatic cell death occurring through the action of its own enzymes)
 Cell injury 233

3. Mechanisms of cell injury

Depletion of ATP
Influx of Ca’*
Oxygen-derived free radicals

4. Depletion of ATP leads to

Anaerobic glycolysis — leading to
i. Decreased pH
ii, Clumping of nuclear chromatin
Decreased protein synthesis — leading to lipid deposition
Failure of membrane Na*-K* pump - leading to
i. Influx of Ca?*
ii, Influx of Na*
iii, Loss of K*
iv. ER swelling
v. Cellular swelling
vi. Loss of microvilli
vii. Bleb formation

> Influx of Ca”* leads to

Increased cytosol Ca**
Activation of
i. Endonuclease + DNA damage
ii, ATPase — decreased ATP
iii. Phospholipase — decreased phospholipids membrane damage
iv. Protease — disruption of cell membrane

6. Oxygen-derived free radicals

Cause
i. DNA lesions
ii, Protein fragmentation
iii. Membrane lipid peroxidation
Can be neutralized by antioxidants, which include
i. Vitamin A, C, and E
ii, Glutathione
iii. Superoxidase dismutase (SOD)
iv. Iron and copper transport proteins (ferritin/transferritin/ lactoferritin/ ceruloplasmin)

7. Apoptosis
Programmed cell death
Characterized by
i. Intact cell membrane
ii, Degradation of nuclear DNA
Can be physiological or pathological (Box 7.2)

Box 7.2 Causes of apoptosis

‘Physiological 2 Pacbolngical
® During embryogenesis ® Cell death in tumours
® Hormone-dependent involution ® Atrophy after obstruction
@ Elimination of harmful self-reactive lymphocytes ® Cytotoxic drugs and radiation
® Cell death induced by cytotoxic T-cells ® Cell injury in viral disease
eee) 234 Chapter 7 Pathology

Does not release proinflammatory markers

® Morphology
i. Cell shrinkage
ii. Chromatin condensation
iii, Formation of
® Cytoplasmic blebs
= Apoptotic bodies
iv. Phagocytosis
@ There are 2 pathways
i. Extrinsic (death-receptor initiated)
=& TNF receptor
@ Fas
ii. Intrinsic (mitochondrial) — involves release of pro-apoptotic molecules into the
cytoplasm through the loss of the action of the Bcl-2 anti-apoptotic gene

8. B-cell lymphoma 2 (Bcl-2) gene family is

e A family of oncogenes
® Can be both anti-apoptotic (e.g. Bcl-2 proper gene) and pro-apoptotic (e.g. BAD gene) in
function
® Reside in mitochondria

9. Necrosis
® Cell death in living tissues by enzymatic degradation
® Characterised by
i. Loss of membrane integrity
ii. Enzymatic digestion of cells
iii, Host reaction
@ Occurs within 4-12h of insult
® Types of necrosis (Box 7.3)
® Gangrene is a term used to describe black necrotic tissue
i. Wet gangrene — tissues undergo colliquative necrosis
ii, Dry gangrene — tissues undergo coagulative necrosis
iii, Gas gangrene — tissues accumulate gas (evident as crepitation) due to exotoxin-
producing clostridial species (usually Clostridium perfringens)
® Patterns of necrosis are also determined by the blood supply to the organ
Necrosis of striated muscle is called rhabdomyolysis

10. Cell injury can be mediated via intracellular accumulation of metabolites or pigments, e.g.
® Lipids
i, TAG causing steatosis (‘fatty changes’). Observed in
@ Heart
@ Liver
m™ Kidney
ii, Cholesterol leading to
= Arthrosclerosis
=m Xanthoma
™ Foamy macrophages
= Niemann-Pick disease
= Cholesterolosis (in the gall bladder)
@ Protein
® Hyaline changes (giving rise to Russell bodies)
® Glycogen
 Cellinjury 235

Box 7.3 Types of necrosis

Colliquative necrosis c oe = SSeS

:
(liquefaction) gulative n necrosis
oagulative Caseous necrosisi oe
Fibrinoid necrosis;

© Due to action of tissue ® Occurs in hypoxic cell ® Features between © Due to immune-
digestive enzymes injury colliquative and mediated vascular
®@ Seen mainly in CNS, ® Due to protein coagulative necrosis injury causing fibrin-
kidney, and pancreas denaturation © Tissues become semi- like protein deposits
® Caused by focal ® Intracellular organelles solid/liquid in arterial walls
bacterial/fungal are disrupted but the
infections shape of tissues is
maintained because
the proteins stick
together

© Due to action of lipase

® Tissues aquire a chalky
appearance
© Seen in breast,
pancreas, omentum,
and skin

@ Pigments such as
i. Lipofuscin
® tis the end product of free radical injury
= Brown in colour
ii, Melanin (derived from tyrosine)
iii. Haemosiderin

11. Cellular ageing process

® Replicative senescence
i. Is the concept that cells have a limited capability for replication
ii, After a fixed number of divisions all cells become arrested in a terminally non-dividing
state
iii. Caused by telomere (short repeated sequences of DNA present at the ends of
chromosome) shortening
® Telomerase
i. ls a specialized enzyme composed of both RNA and protein that uses RNA as a
template for adding nucleotides to the end of chromosomes
ii, Maintains length of telomere
iii, Prevents replicative senescence
iv. Its activity is
B High in germ cells
= Lowin stem cells
= Absent in somatic cells
= Reactivated in cancer cells
oo 236 Chapter7 Pathology

Free radical oxidative damage

Genetic influence

Response to cell injury

1, Physiological response to injury
Immobility/rest
Loss of appetite
Catabolism

2. Metabolic and systemic response to injury

Is graded into
i. Minor — Increased HR/RR/temperature/WBC count
ii. Major — SIRS/hypermetabolism/catabolism/multiorgan dysfunction syndrome (MODS)
Divided into ebb and flow phases (the ‘ebb and flow model’)
Ebb phase (shock phase)
i. Begins at the time of injury
ii, Lasts for 24-48h
iii, Characterized by hypovolaemia; reduced CO; decreased basal metabolic rate;
hypothermia; lactic acidosis
iv. Predominant hormones are catecholamines; cortisol; aldosterone
v. It functions to conserve circulating volume and energy stores
Flow phase
i. It is a predominantly hypermetabolic phase
ii. Corresponds to SIRS
iii. Divided in an initial catabolic phase (lasting 3-4 days) aimed at mobilizing energy stores
and a later anabolic phase (lasting for weeks)
iv. Characterized by tissue oedema (vasodilation); increased CO; hypermetabolism;
increased temperature; leucocytosis; increased oxygen consumption; increased
gluconeogenesis
In the catabolic phase there is
i, Weight loss (muscle wasting approximately 500 g/day)
ii. Increased urinary nitrogen excretion (up to 20 g/day)
iii. Once the body protein mass loss has reached 30-40% of the total, survival is unlikely
Consists of
i, An immunological response
ii. A neuroendocrine response t

3. The immunological response in injury evolves from a proinflammatory to a compensatory

anti-inflammatory response (CARS)
The proinflammatory response is mediated by the innate immune system
The innate immune system interacts with the adaptive immune system (T- and B-cells)
Proinflammatory cytokines (IL-1, TNF; IL-6; IL-8)
i, Produced in first 24h
ii. Act directly on hypothalamus causing pyrexia (IL-6 mediated)
iii, Act directly on skeletal muscles to induce proteolysis
iv. Induce acute phase proteins production in liver (IL-6 mediated)
v. Cause peripheral insulin resistance (can last for 2 weeks)
Proinflammatory response is followed rapidly by an increase in levels of cytokine antagonists
(IL-1 receptor antagonist; TNF-soluble receptors | and Il), leading to CARS

4. Neuroendocrine response to injury

Is biphasic
 Wound healing 237

i, Acute phase — active secretion of pituitary and counter-regulatory hormones (glucagon;

cortisol; adrenaline)
ii. Chronic phase — hypothalamic suppression and low serum levels of respective target
organ hormones. Contributes to chronic wasting.
® Hormonal flow
i, Increased CRH from hypothalamus causes increased secretion of ACTH from anterior
pituitary
ii. ACTH causes release of cortisol from adrenal glands
® Counter-regulatory hormones function to
i. Reduce insulin levels
ii, Increase metabolism
iii. Promote hepatic gluconeogenesis
iv. Promote adipocyte lipolysis
v. Promote skeletal muscle protein catabolism
vi. Inactivate peripheral thyroid hormone (T3)
vii. Reduce testosterone levels
viii. Increase prolactin and GH in response to low levels of circulating IGF

5. Energy expenditure is increased in trauma by 25% due to

® Central thermo-dysregulation
® Increased sympathetic activity
@ Abnormalities in wound circulation
i, Ischaemic areas produce lactate that is metabolized in Cori’s cycle
ii, Hyperaemic areas cause increased CO
@ Increased protein turnover

6. Skeletal muscle protein metabolism in response to injury

® Protein degradation occurs in peripheral tissues (skin, skeletal muscle, adipose tissue)
@ Major site of protein loss is peripheral skeletal muscle, respiratory muscle, and GIT
@ Muscle catabolism cannot be inhibited fully
@ Muscle protein turnover rate = 1-2%/day

7. Hepatic protein metabolism in injury

@ Liver protein turnover rate = 20%/day
® Hepatic protein synthesis is divided roughly 50 : 50 between renewal of structural protein
and synthesis of export protein (albumin)
@ During inflammation
i. Hepatic synthesis of positive acute phase protein (fibrinogen and C-reactive protein
(CRP)) is increased
ii. Serum albumin levels are decreased due to transcapillary escape

Wound healing

1. Wound healing has 3 phases

® Inflammatory
i. Starts immediately
ii, Last 2-3 days
iii. Local vasoconstriction
iv. Thrombus formation and fibrin mesh
v. Platelets line the damaged endothelium and release ADP/platelet-derived growth factor
(PDGF)/cytokines/histamine/serotonin/prostaglandins
 238 Chapter 7 Pathology me

vi. ADP causes thrombus aggregation

vii. Cytokines attract lymphocytes and macrophages
viii. Histamine causes increased capillary permeability
® Proliferative
i. Lasts from day 3 to week 3
ii. Increased fibroblast activity producing collagen type 3 and ground substance (requires
vitamin C)
iii. Angiogenesis
iv. Re-epithelialization of wound surface
v. Formation of granulation tissue
® Remodelling
i, Maturation of collagen (type 1 replaces type 3)
ii. Decrease in wound vascularity
iii. Wound contraction

2. Classification of wound closure

® Primary intention
® Secondary intention
® Tertiary intention (also known as delayed primary intention)

3. Primary intention healing

® |s not an acute inflammatory reaction
@ Process
i. A fibrin-rich haematoma develops first
ii, Neutrophils appear at the margin of the wound within 24h and move towards the fibrin
clot
iii, Movement of epithelial cells from the wound edge deposit a basement membrane in
24-48h
iv. Macrophages replace the neutrophils at day 3
v. Granulation tissue invasion takes place
vi. Neovascularization occurs and is maximal at day 5
vii. Fibroblast proliferation at week 2
viii, Scar is devoid of inflammatory cells by week 4
4. Secondary intention healing
® Heals by granulation, contraction, and epithelialization
@ |s marked by wound contraction (S-10% reduction in size)
® Requires action of myofibroblast

5. Wound strength (skin)

® At week 1 strength is at 10% that of un-wounded skin
® At3 months it is 80% that of un-wounded skin

6. Growth factors involved in healing

EGF
TGF
VEGF (vascular endothelial growth factor)
PDGF
FGF (fibroblast growth factor)
IGF

7. Wound healing is
® Promoted by
i. Good blood supply
ii, Vitamin C
 Neoplasia 239

iii. Zine
iv. Protein
v. Insulin
vi. UV light
@ Inhibited by
i. Glucocorticoids
ii, Infection
iii. Extreme temperatures

8. Scar
® Matures over 2 years
® |mmature scar is
i. Pink
ii, Hard
iii. Raised
iv. Itchy
®@ Types of mature scar
i. Atrophic
ii, Hypertrophic (defined as excessive scar tissue that does not extend beyond the
boundaries of the original wound) — due to the excessive production of granulation tissue
ili, Keloid (defined as excessive scar tissue that extends beyond the boundaries of the
original wound) due to the persistence of type 3 collagen
Treatment of keloid/hypertrophic scar is by
i. Excision of scar
ii, Laser
iii. Intralesion steroid injection
iv. Pressure
v. Silicone gel sheeting
vi. Postoperative radiation
vii. Vitamin E
Surgical scarring can be reduced by
i, Use of monofilament sutures
ii. Removal of sutures at day 3-5
iii. Tensionless suturing
iv. Use of fine sutures and using Steri-Strips to strengthen the wound
yv. Subcuticular suturing technique

Neoplasia

1. Neoplasia
Means ‘new growth’
Characterized by
i. Abnormal growth
ii, Uncontrolled growth
iii. Uncoordinated growth
Growth persists after cessation of stimuli

Malignant neoplasia characterized by

Invasion
Rapid growth
Metastases
Poor differentiation
240 Chapter 7 Pathology

. Definitions
Carcinoma is malignancy of epithelial origin
Sarcoma is malignancy of mesenchymal origin
Teratoma is a neoplasm containing more than one germ cell layer
i, Ovarian teratoma is benign
ii. Testicular teratoma is malignant
Choristoma is a non-malignant mass of normal tissue in an ectopic location
Hamartoma is a non-malignant mass of disorganized but mature tissue indigenous to the site

. Growth ofa tumour

ls gompertzian (i.e. in early stages growth is exponential but as the tumour grows the
growth rate slows)
Majority occurs before it is clinically detectable
A radiologically detectable tumour is
i. 10mm in size
ii. Has 10° cells
2° describes the number of cells produced after ‘n’ generations of division
i, Eg. 10° = 2° since after the 30th division there will be 10° cells
Tumour size that is usually fatal = 2** (i.e. after 45 generations)
i. However, there is also concurrent tumour loss, which reduces the number of tumour cells

. Features of malignant transformation

Establishment of an autonomous lineage
i. Resisting signals that inhibit growth
ii. Acquisition of independence from signal-stimulating growth
iii, Oncogenes are a key factor in this process
Obtaining immortality
i. Normal cells undergo a finite number of division (i.e. between 40 and 60)
ii, This limitation is imposed by the progressive shortening of the end of the chromosomes
(the telomere)
iii, Cancer cells do not undergo telomeric shortening
Evasion of apoptosis (p53 is responsible for apoptosis)
Acquisition of angiogenic competence
Acquisition of ability to invade (invasion)
Acquisition of ability to disseminate and implant
Evading detection and elimination
Genomic instability '

. Differentiation
@ ltrefers to the extent to which neoplastic cells resemble normal cells
@ Benign tumours are well differentiated (i.e. morphologically and functionally similar to
mature normal cells)
® Anaplasia is lack of differentiation
e@ A high-grade tumour is one that is poorly differentiated

. Metastasis
® All cancers can metastasize except for basal cell carcinoma and gliomas
° Occurs via (Box 7.4)

. Inherited genetic predisposition to cancer includes

Inherited cancer syndromes (are autosomal dominant)
i. Retinoblastoma
ii, Adenomatous polyposis coli
iii, MEN
 Neoplasia 241

Box 7.4 Routes of metastasis

© Typical of carcinoma Typical of Typical of

© Sarcoma ® Ovarian cancer
® Renal cell carcinoma @ Breast cancer
® Osteosarcoma © Pseudomyxoma peritonei
® Choriocarcinoma

iv. Neurofibromatosis 1 and 2

v. von Hippel—Lindau syndrome
® Inherited autosomal recessive syndromes of defective DNA repair
i. Xeroderma pigmentosum
ii, Ataxia-telangiectasia
iii. Bloom’s syndrome
iv. Fanconi’s anaemia
®@ Familial cancers
i. Breast cancer
ii, Ovarian cancer
iii. Hereditary non-polyposis colonic cancer (HNPCC)

9. Cancer genes include

@ BRCA genes
HNPCC
RB gene (retinoblastoma)
p16 (melanoma)

10. BRCA genes

© BRCA-1 gene
i. Located on the long arm of chromosome 17
ii. Predisposes to
@ Breast cancer
™ Ovarian cancer
® BRCA-2 gene
i. Located on the long arm of chromosome 13
ii. Predisposes to
@ Breast cancer
Male breast cancer
Ovarian
Prostate cancer
Pancreatic cancer
® 85% lifetime risk of developing breast cancer
® Lifetime risk of ovarian cancer is
i. 55% with BRCA-1
ii, 25% with BRCA-2

11. HNPCC
Also known as Lynch’s syndrome
Has an autosomal dominant inheritance
Has 5 genes
Has 80% lifetime risk of colonic cancer
Has 30-50% lifetime risk of endometrial cancer
Has 10% lifetime risk of ovarian cancer
ce 242 Chapter7 Pathology %

12. Non-genetic predisposing factors to cancer include

® Chronic inflammation
i. Crohn's disease
ii. Ulcerative colitis
@ Pre-cancerous conditions
i, Leukoplakia
ii. Solar keratosis
iii, Pernicious anaemia
iv. Cervical dysplasia
® Carcinogenic agents (Table 7.1)

Table 7.1 Carcinogenic agents

Carcinogen Neoplasm

Wood dust Adenocarcinoma of nose and nasal sinuses

Aflatoxin B1 Hepatocellular carcinoma

Asbestos Mesothelioma
GIT cancers
Bronchogenic carcinoma

Vinyl chloride Haemangiosarcoma of liver

Chromium and nickel Lung cancer

Arsenic Skin cancer

Diethylstilbestrol Vaginal clear cell carcinoma

High fat/low fibre Colonic carcinoma

Alkylating agents Lymphoma
Leukaemia

Aniline dye Bladder cancer

B-naphthylamine
Polycyclic aromatic hydrocarbon Lung cancer

Anabolic steroids Hepatocellular carcinoma

Human papillomavirus (HPV) 16 and 18 Cervical cancer *

Epstein—Barr virus Burkitt's lymphoma
Nasopharyngeal carcinoma
Hepatitis B virus Hepatocellular carcinoma
Human T-cell lymphotrophic virus (HTLY)-1 T-cell leukaemia
Lymphoma

13. Tumour markers (Table 7.2)

14. Paraneoplastic syndromes (Table 7.3)

® Are symptom complexes in cancer patients
® Are not due to the spread of cancer but due to their endocrine function or immunological
response
15. p53
@ sa transcription factor that regulates cell cycle
 Neoplasia 243

Table 7.2, Tumour markers

Marker Neoplasm

hCG Trophoblastic tumour (choriocarcinoma)

Non-seminomatous germ cell tumour

Calcitonin Medullary carcinoma of thyroid

Catecholamines Phaeochromocytoma

AFP Hepatocellular carcinoma

Non-seminomatous germ cell tumour (YST)
Carcinoembryonic antigen (CEA) Colonic carcinoma
Pancreatic carcinoma
Gastric carcinoma
Lung cancer

PSA/PAP Prostatic neoplasm

Immunoglobulins Multiple myeloma

CA 125 Ovarian carcinoma

Primary peritoneal carcinoma

CA 19-9 Colonic carcinoma

Pancreatic carcinoma

CA 15-3 Breast carcinoma

Table 7.3 Paraneoplastic syndromes

Paraneoplastic syndrome Neoplasm

Cushing’s syndrome Small cell lung cancer

Pancreatic carcinoma

SIADH Small cell lung cancer

Intracranial neoplasm

Carcinoid syndrome Bronchial adenoma

Pancreatic carcinoma
Gastric carcinoma

Polycythaemia Renal cell carcinoma

Cerebellar haemangioma
Hepatocellular carcinoma
Fibroid (leiomyoma)
Myasthenia Bronchogenic carcinoma

Acanthosis nigrans Lung carcinoma

Uterine carcinoma

Dermatomyositis Bronchogenic carcinoma

Breast carcinoma

Venous thrombosis Bronchogenic carcinoma

Trousseau’s phenomenon Pancreatic carcinoma
 Chapter 7 Pathology

® |s a tumour suppressor
® Gene located on chromosome 17
® Functions
i. Activates DNA repair
ii, Initiates apoptosis
® Li-Fraumeni syndrome
i. ls.an autosomal dominant disorder
ii. Linked to mutation of p53 gene
iii. Has a 25-fold greater chance of developing malignancy by the age of 50 compared to the
general population

Coagulation

Coagulation system
1. The endothelium has both anti-thrombotic and pro-thrombotic properties (Fig. 7.3)
® Anti-thrombotic agents (Box 7.5)
® Pro-thrombotic agents (Box 7.6)

Anti- Pro-
thrombotic thrombotic

coagulant

ar ; Anti-
Piocinalyte fibrinolytic

Figure 7.3 Anti-thrombotic and pro-thrombotic properties of endothelium

'

Box 7.5 Types of anti-thrombotic agents

Anti platelet Anti coagulant Fibrinolytic

® Prostacyclin ® Thrombomodulin ® Tissue-type plasminogen
® NO © Anti-thrombin III activator (t-PA)
© ADPase © Tissue factor pathway inhibitor

Box 7.6 Types of pro-thrombotic agents

® yon Willebrand Factor (VWF) ® Thromboplastin © Plasminogen activator inhibitor

2. Tissue factor pathway inhibitor — inhibits activated factor Vila and Xa

 Coagulation 245

3. Platelets
® Contain
i. Fibrinogen
ii. Fibronectin
iii. PDGF
iv. Histamine
y. Serotonin
vi. Factor V and VIII
@ Platelet aggregation induced by
i. VWF
ii, ADP
iii. Thromboxane A)
® Form part of the haemostatic plug formation process (Box 7.7)

Box 7.7 Haemostatic plug formation process

Primary haemostatic plug ~ Secondary haemostatic plug : :: Fibrinbinds to plug]

® Platelet aggregation © Thrombin binds to platelets © ADP mediated activation of
® Reversible ® Irreversible platelets causes changes to
the platelet surface Gp2b-3a
receptor for fibrinogen, causing
fibrin to form and bind to the
plug

4. Coagulation cascade
® Intrinsic pathway (Fig. 7.4)
® Extrinsic pathway (Fig. 7.5)
® Both the extrinsic and intrinsic pathways act on the common pathway via activation of factor
IX (Fig. 7.6)
® Common pathway (Fig. 7.7)
® Final pathway (Fig. 7.8)

Figure 7.4 Coagulation cascade (Step 1)

Thromboplastin XI — Xila

Figure 7.5 Coagulation cascade (Step 2)

Figure 7.6 Coagulation cascade (Step 3)

 246 Chapter7 Pathology

Figure 7.7 Coagulation cascade (Step 4)

@ muhrombin)

Figure 7.8 Coagulation cascade (Step 5)

5. Protein C
® |sa physiological anticoagulant
@ Degrades factor Va and Villa
®@ Activated by thrombin

6. Protein S '
® Cofactor with activated protein C for the degradation of factor Va and Villa
@ san anticoagulant
® Binds to complement factors

7. Factor V Leiden
® \|savariant of factor V that cannot be inactivated by protein C
® Causes a hypercoagulant state
®@ An autosomal dominant condition
® Prevalence in Caucasians is 5%
® Is present in 30% of patients with deep vein thrombosis (DVT) and pulmonary
embolism (PE)

8. Fibrinolytic cascade
® Accomplished by generation of plasmin
@ Plasminogen conversion to plasmin is via
i, Hageman dependent pathway
 Coagulation 247

ii, Plasminogen activators (PA)

@ Urokinase-like PA
, & Tissue-type PA (t-PA)

f 9. Changes in pregnancy
6.2 @ Physiological drop of platelet levels (due to haemodilution despite increased platelet
production)
© Hypercoagulant state — caused by increased levels of coagulant factors (all except factors XI
and XIll)
Increased fibrinogen levels
® Increased ESR
® Fibrinolytic system
i, Placenta secretes PAI-2, which inhibits fibrinolytic system
ii. Increased anti-thrombin III levels
iii, Increased FDPs
iv. Activity remains low in labour
v. Returns to normal 1h after delivery of placenta

Coagulation abnormalities
1. Thrombosis
®@ Pathogenesis is based on Virchow’s triad
i. Endothelial injury
ii, Stasis
iii. Hypercoagulability
@ Hypercoagulability states are due to
i. Primary (genetic) disorders
® Protein C deficiency
= Protein S deficiency
= Anti-thrombin III deficiency
® Factor V Leiden
ii. Secondary (acquired)
Pregnancy
Combined contraceptive pill
Antiphospholipid antibodies
Nephrotic syndrome
Trousseau’s syndrome
Heparin-induced thrombocytopenia syndrome
@ Fate of thrombus
i, Propagation
ii. Embolization
iii. Dissolution
iv. Organization and recanalization
@ Types of thrombosis
i. Venous
ii. Arterial
iii. Cardiac

2. Antiphospholipid syndrome (APS)

27 @ Also known as Hughes’ syndrome
® |s characterized by a triad of
i. Thrombosis (arterial and venous)
ii, Recurrent miscarriage
 248 Chapter7 Pathology

iii. Presence of antiphospholipid antibody

Is an autoimmune disease
Clinical features
i, Recurrent venous or arterial thrombi
ii. Recurrent miscarriages (i.e. >3 consecutive miscarriages <10 weeks gestation)
iii. Pre-eclampsia
iv. Preterm deliveries
v. Fetal death
vi. Thrombocytopenia
vii. Cardiac valvular vegetations
viii. Livido reticularis
Types
i. Primary (when not associated with any other autoimmune conditions)
ii. Secondary (associated with other autoimmune conditions, e.g. SLE)
Fetal loss in women with APS is due to
i, Pro-coagulant state caused by antiphospholipid antibody
ii. Decreased levels of annexin-V (an anticoagulant on normal placental villi)
Treatment is
i. Aspirin
ii. Anticoagulants (low molecular weight heparin (LMWH))

3. Antiphospholipid antibodies
Are a group of heterogeneous antibodies directed against anionic phospholipids or their
binding proteins which include
i. Prothrombin
ii. Factor V
iii, Protein C and S
iv. Annexin-V
Consist of
i. Lupus anticoagulant
ii. Anticardiolipin antibodies
Prevalence in
i. Normal obstetric population = 2-5 %
ii. Patients with recurrent miscarriage = 15%
iii, SLE women = 30%

4. Trousseau’s syndrome '

Is also known as migratory thrombophlebitis
Associated with underlying malignancy

5. Heparin-induced thrombocytopenia syndrome

Is caused by the formation of antibodies that bind to the heparin-platelet complex
Activates platelets
Clinical features
i, Low platelet count
ii, Thrombosis
Treatment is with lepirudin

6. Disseminated intravascular coagulation (DIC)

Is also known as consumptive coagulopathy
Aetiology
i. Cancer
ii. Massive tissue injury
 Coagulation 249

iii. Massive haemorrhage

iv. Infection
v. Liver disease
vi. Placental abruption
vii. Pre-eclampsia
viii. Amniotic fluid embolism
® Clinical features and lab findings
i. Prolonged clotting time (increased prothrombin time (PT) and activated partial
thromboplastin time (APTT))
ii, High levels of FDPs
iii, Increased soluble fibrin complex
iv. Decreased levels of fibrinogen
v. High levels of D-dimers
vi. Thrombocytopenia
vii. Fragmented RBCs (schistocytes) on blood film

7. Embolism
@ Types include
i, Pulmonary thromboembolism
ii. Systemic thromboembolism
iii, Fat embolism
iv. Air embolism (symptoms seen only in an embolus
>100 mL of air)
y. Amniotic fluid embolism
@ PE
i. 60% are silent
ii. Results in cor pulmonale
® Clinical features of fat embolism
i. Neurological symptoms
ii, Pulmonary insufficiency
iii, Anaemia
iv. Thrombocytopenia
@ Decompression sickness
i. ls a form of air embolism
ii. Is also known as Bends’ or Caisson’s disease
@ Amniotic fluid embolism
i. Incidence is 1 ; 8000-80
000 deliveries
ii. Mortality rate of up to 60%

j 8. Thrombocytopenia
1
Aetiology (Fig. 7.9)
Is prevalent in 5-10% of pregnancies at term
Gestational thrombocytopenia
i. Is. abenign condition
ii. Does not require treatment
iii. Maternal platelets return to normal post delivery
TTP/HUS
i. Characterized by thrombocytopenia, microangiopathic haemolytic anaemia, and renal
impairment
ii. TTP is also associated with CNS involvement
ii. Is a platelet consumption disorder leading to thrombocytopenia
iv. Treatment = plasma exchange (platelet transfusion is contraindicated)
 250 Chapter7 Pathology

Platelet count
i. >80 = regional anaesthesia is safe
ii, >50 = LMWH thromboprophylaxis is safe

_ Bone marrow
suppression

Thrombotic SLEand —
thrombocytopenic m antiphospholipid
purpura (ITP) syndrome

Haemolytic
uraemic
syndrome (HUS)

Immune
Causes of
thrombocytopenic
thrombocytopenia
purpura (ITP)

Figure 7.9 Causes of thrombocytopenia

hy Vbithie
Is due to autoantibodies against platelet surface glycoproteins
Incidence = 1-2 : 10000 pregnancies
Antiplatelet |gG
i. Can cross placenta
ii, Can cause fetal thrombocytopenia (risk is 5-10%)
Treatment of ITP
i. Corticosteroids (first-line therapy)
ii. Immunoglobulins (in resistant cases)
iii, Splenectomy
iv. Azathioprine
v. Platelet transfusion

10. Infarction
@ Is an area of ischaemic necrosis caused by occlusion of either the arterial supply or venous
drainage to a tissue
© Aetiology
i. Thrombosis
ii. Embolism
ili, Vasospasm
iv. Expansion of atheroma
v. Extrinsic compression of vessel
Classification of infarcts (based on the colour; reflecting the amount of
haemorrhage)
i, Red (haemorrhagic) — due to venous obstruction
ii, White (anaemic) — due to arterial obstruction
 Sepsis 251

Sepsis

1. Protective mechanisms against infection

® Mechanical
® Chemical — low pH
® Humoral — antibodies/complement
® Cellular — natural killer (NK) cells/macrophages

2. Septic ladder
@ SIRS is defined as 2 of the following
i. Temp <36°C or >38°C
ii. Tachycardia >90 bpm
ili. Tachypnoea >20/ min
iv. WBC <4 or >12
Sepsis is defined as SIRS if it is a result of infection
Severe sepsis is sepsis with evidence of failure of more than 1 organ system
MODS leads to multiple organ system failure (MOSF)
MODS
i. Is defined as 2 or more failed organ systems
ii. Carries a 60% mortality rate

3. Abscess
® |sacollection of pus surrounded by an acute inflammatory response and a pyogenic
membrane
Contains hyperosmolar material that draws fluid in and increases the pressure causing pain
® Clinical features
i. Calor
ii, Rubor
iii. Dolor
iv. Tumour
@ Pus is composed of dead and dying WBCs
Most abscesses relating to surgical wounds take 7-10 days to form
®@ Outcomes
i. Resolution via incision and drainage
ii. Antibioma — if treated with antibiotics
iii. Chronic abscess (contains plasma cells/lymphocytes)
iv. Fistula
v. Sinus

4, Determinants of wound infection

® Host response
Virulence and inoculums of infective agent
Vascularity and tissue health
Presence of foreign body
Presence of antibiotics during the decisive period (decisive period.is the 4h taken to
mobilize host defences)

5. Categories of surgery according to infection risk

® Clean (infection rate with antibiotic prophylaxis is 2%)
® Clean-contaminated (infection rate with antibiotic prophylaxis is 10%)
®@ Contaminated (infection rate with antibiotic prophylaxis is 20%)
@ Dirty (infection rate with antibiotic prophylaxis is <40%)
 252 Chapter7 Pathology

Shock ar ats |
cellular
1. Shock is a systemic state of low tissue perfusion, which is inadequate for normal
respiration

2. Shock pathogenesis
@ Lack of oxygen leads to metabolic acidosis (Fig. 7.10) me
@ Consumption of cellular glucose stores leads to cessation of anaerobic respiration causing
cell lysis (Fig. 7.11)
® Microvascular — hypoxia and acidosis activate the immune and coagulation systems, leading
to increased capillary permeability (Fig. 7.12)

~ Anaerobic respiration

Figure 7.10 Shock pathogenesis 1

Cell lysis Hyperkalaemia

Figure 7.11 Shock pathogenesis 2

et Free °, radicals, and Capillary endothelial t Capillary

hee. eytokines <2. cell damage permeability

Figure 7.12 Shock pathogenesis 3

® Cardiovascular
i. Decreased pre-load and after-load cause reflex tachycardia and vasoconstriction
ii, Reduced perfusion leads to reduced heat generation (causing hypothermia)
® Respiration
i. Metabolic acidosis causes an increased respiratory rate and minute ventilation (in an
attempt to excrete CO,)
ii, A compensatory respiratory alkalosis results
®@ Renal
i, Decreased filtration at glomeruli
ii, Oliguria
ili, Activation of renin-angiotensin system, leading to vasoconstriction
® Hormonal — release of
i. ADH
ii, Cortisol
® Acidosis leads to coagulopathy
3, Ischaemia-reperfusion syndrome
© Metabolites (H* and K*) that build up during tissue hypoperfusion are flushed back into the
systemic circulation
® This leads to
i, Acute lung injury
ii, Acute renal injury
iii, MODS
4. Classification of causes of shock (Box 7.8)

Box 7.8 Causes of shock

® Haemorrhagic ® Myocardial infarction ® Tamponade © Septic

® Non-haemorrhagic ® Arrhythmias without Oc PE ® Anaphylactic
© 3rd spacing output ® Pneumothorax ® Neurogenic

Endocrine 2

® Adrenal insufficiency
® Hypothyroidism
® Hyperthyroidism

a Characteristics of different types of shock

® Mixed venous saturation — only high in distributive shock
Venous pressure — high in obstructive and cardiogenic shock
CO — only high in distributive shock
Vascular resistance — only low in distributive shock
Base deficit — high in all types of shock

6. Occult hypoperfusion
® lsastate characterized by normal vital signs but where there is continued tissue
hypoperfusion
®@ Manifests only by
i. Low mixed venous oxygen saturation
ii. Persistent lactic acidosis

7. Dynamic fluid response

® Patients can be divided into 3 groups based on their response to a 250-500 mL of
intravenous fluid challenge over 10 min
i. Responders — show a sustained improvement (no active bleeding or fluid loss)
ii. Transient responders — improve but revert back to their previous state over 20 min
(have moderate ongoing fluid losses)
iii, Non-responders — show no improvement (persistent uncontrolled haemorrhage or fluid
loss)

8. Central venous pressure (CVP)

® Normal CVP value = 5-15 cmH,O
@ After an intravenous fluid challenge of 250-500 mL over 10 min
i. The normal CVP response is a rise of 2-5 cmH,O which gradually drifts back to the
original level over 20 min
ii, No CVP change indicates an underfilled patient
iii. Large sustained CVP change indicates an overfilled patient
 254 Chapter7 Pathology ;

9. Markers of global hypoperfusion

Base deficit
Lactate (when >6mmol/L patients have higher morbidity and mortality rates than those with
no metabolic acidosis)

10. Mixed venous oxygen saturation

Is obtained from the right atrium
ls a measure of O, delivery and extraction by tissues
Normal value = 50-70%
Levels < 50% indicate
i, Inadequate oxygen delivery
ii. Increased oxygen extraction
Levels >70% is seen in sepsis due to decreased utilization of O, at the cellular level

11. Haemorrhage
Leads to
i. Acidosis
ii. Hypothermia
iii. Coagulopathy
Degree of haemorrhage
i, <15% is within the limits of compensatory mechanisms (compensation is at the expense
of GIT, muscle, and skin)
ii, 15-30% (decompensation starts)
iii. 30-40% (fall in BP detected)
iv. >40%
3 types of haemorrhage (Box 7.9)

Box 7.9 Types of haemorrhage

® Occurs immediately ® Delayed haemorrhage within ® Occurs within 7-14 days of

24 h of primary event primary event
® Can be due to dislodgement of ® Caused by sloughing of vessel
clot/vasodilation/normalization wall
of BP

12. Blood transfusion

Packed red cells
i, Each unit has 330mL red blood cells (RBC)
ii, Each unit has 250mg iron
ili, Stored at 2-6 °C
iv. Shelf life is 5 weeks
Fresh frozen plasma (FFP)
i. Stored at -40°C
ii, Shelf-life is 2 years
Cryoprecipitate (is rich in factor VIII and fibrinogen)
Platelets
i, Each pool contains 250 x 10” cells/L
ii, Stored at 20-24°C
iii. Shelf-life is 5 days
 Disorders of the genital tract 255

13. Complications of transfusion can be divided into 2 groups

® Single transfusion
i. Haemolytic transfusion reaction (due to ABO incompatibility)
ii, Febrile transfusion reaction (non-haemolytic and due to graft versus host response from
residual leucocytes in blood)
iii, Allergic reaction
iv. Infections
vy. Air embolism
vi. Thrombophlebitis
vii. Transfusion-related acute lung injury (from FFP)
® Massive transfusion
i. Coagulopathy
ii. Hypocalcaemia
iii. Hyperkalaemia
iv. Hypokalaemia
v. Hypothermia
vi. lron overload

14. Management of transfusion induced coagulopathy

@ FFP if PT >1.5 x normal
Cryoprecipitate if fibrinogen <0.8 g/L
Platelets if platelets <50 x 10’/mL
Tranexamic acid
Aprotinin
Recombinant factor Vila (NovoSeven®)

15. Blood substitutes

®@ Biomimetics
i. Mimic the standard oxygen-carrying capacity of blood
ii. Haemoglobin based
@ Abiotics
i. Synthetic oxygen carriers
ii. Perfluorocarbon based

Disorders of the genital tract

Tin
Obs

Cervical pathology
-154 4. Cervical screening in the UK
®@ Routine age range of 20-64 (25-60 in England)
@ Every
i. 3 years in 25-49 year olds
ii, 5 years in 50-65 year olds
® Statistics
i. Screening false negative is 10%
ii, Pap-smear false negative is 50%
@ Incidence of
i. Borderline and mild dyskaryosis is 10%
ii. Moderate and severe dyskaryosis is 1-2%
iii. Inadequate smears is 10%
 256 Chapter 7 Pathology

2. Cervical intraepithelial neoplasia (CIN)

@ Isa
i. Form of cervical dysplasia
ii, A premalignant condition
® Major aetiology is HPV 16 and 18
® Most CINs spontaneously regress (50% of CIN 2 will regress within 2 years without
treatment)
® Progression to cancer takes about 15 years
® Cytological characteristics include
i. Nuclear enlargement
ii. Increased nuclear ; cytoplasmic ratio
iii. Nuclear pleomorphism
iv. Hypochromasia
y. Increased mitotic activity
® Evolution over 5 years
fee ClINes
m@ 32% regress
m 55% remains persistent
& 12% progress to invasive cancer
ii, CIN 2
mB 43% regress
@ 35% remain persistent
= 5% progress to invasive cancer

3. Cervical glandular intraepithelial neoplasia (CGIN)

e@ Usually coexists with squamous disease
® |s multifocal in 15%
® Incidence of smears showing CGIN is 1 : 2000
®@ Ratio of CGIN:; CIN is 1:50
® Risk of recurrence following treatment is 15%

4. Cervical cancer
® Incidence is 9; 100000
® Is the commonest gynaecological cancer worldwide
® Mean age of presentation = 52 years old
® Distribution is bimodal with peaks at
i. 35-39 years old '
ii, 60-64 years old
® Lifetime risk in
i, Europe = 1%
ii, Asia/Africa = 5%
® 99.7% of cervical cancers are due to all types of HPV
® 70% of cervical cancers are due to HPV 16 and HPV 18
® Types
i, Squamous cell carcinoma (80%)
ii, Adenocarcinoma (15%)
iii, Adenosquamous carcinoma
iv. Rare (< 1%)
= Small cell carcinoma (is a type of neuroendocrine tumour that carries a poor
prognosis due to early lymphatic and systemic spread; may present with carcinoid
syndrome)
= Clear cell carcinoma
 Disorders of the genital tract 257

= Glassy cell carcinoma

™ Sarcoma Botryoides (i.e. a type of embryonal rhabdomyosarcoma)
® Staging (Table 7.4)

Table 7.4 FIGO 2010 classification of cervical cancer

FIGO classification of cervical cancer Treatment

Stage 0 Carcinoma in situ

Stage 1 Limited to cervix: micro-invasive lesion Hysterectomy or

1A; Depth <3 mm Large loop excision of the

Length <7 mm transformation zone (LLETZ) or

1A Depth 3-5 mm trachelectomy

Length <7 mm

Limited to cervix: visible lesion Radical hysterectomy

1B, Lesion <4 cm and

lymphadenectomy
1B, Lesion >4 cm

Stage 2 Invades beyond uterus but not to pelvic wall or lower Radiation therapy and cisplatin-
1/3 of vagina based chemotherapy and

2A Without parametrial invasion nysteregia ay

2B With parametrial invasion

Stage 3. Extends to pelvic side wall or lower 1/3 of vagina or Radiation therapy and cisplatin-
hydronephrosis based chemotherapy

3A No pelvic side wall involvement

3B Pelvic side wall involvement or

hydronephrosis

Stage 4 Extends beyond true pelvis Radiation therapy and cisplatin-

based ch h
4A Invades mucosa of bladder and rectum aaeciqugie eres

4B Distant metastasis

@ Risk of lymph node involvement

i. In stage 1A, is 1 in 3000
ii. In stage 1A) is 5%
iii. In stage 2A is 25%
iv, In stage 3 is 45%
v. In stage 4a is 55%

Uterine pathology
Uterine fibroids (also known as uterine leiomyomas)
Affects 20-40% of women in the reproductive age
Oestrogen-dependent benign tumours
Arise from uterine smooth muscle
Well circumscribed
There is no conclusive evidence that benign fibroids can become malignant
The risk of malignant transformation to leiomyosarcoma in rapidly growing fibroids is 0.25%
Intravenous leiomyomatosis
i. Is a variant fibroid
oo 258 Chapter 7 Pathology

ii. Can metastasize via haematological spread

oe iii, Can occur in any organ
Obs :
Gy 2. Endometriosis
Chpt 13.2 ® Disease characterized by the occurrence of ectopic endometrium
® Frequent sites
i. Pouch of Douglas
ii, Ovaries
Occurs in women of fertile age
Prevalence is 1-2%
Aetiology is unknown
Theories
i. Oestrogen dependent
ii, Genetic
iii. Transplantation
iv. Retrograde implantation of endometrium from menstruation
v. Coelomic epithelium metaplasia
® Endometriotic tissue consists of
i. Endometrial stroma
ii, Glands
® Can be associated with cancers (clear cell carcinoma)
® Symptoms include
i. Dysmenorrhoea
ii, Dyspareunia
iii, Dyschezia
iv. Dysuria
v. Chronic pelvic pain
vi. Infertility in 40% of patients with endometriosis
® CA-125 is elevated in endometriosis
Staging is based on the revised classification of the American Society of Reproductive
Medicine
i. Stage 1 — superficial lesions and filmy adhesions
ii. Stage 2 — deep lesions at cul-de-sac
iii. Stage 3 — all the above and endometriomas on ovaries
iv. Stage 4 —all the above and extensive adhesions

3. Adenomyosis '
® |s defined as presence of endometrial glands in the myometrium
®@ Prevalence is 20%

4. Endometrial hyperplasia
® ls related to prolonged oestrogen stimulation of the endometrium
® Consists of 3 groups
i. Simple hyperplasia
ii, Complex hyperplasia
iii. Atypical hyperplasia
© Atypical hyperplasia has the highest rate of progression to malignancy (25%-50%)
® Treatment is
i, Progestogens (for simple and complex hyperplasia)
ii, Total abdominal hysterectomy and bilateral salpingo-oophorectomy (for atypical
ieis hyperplasia)

St
Chpts 15.5
5 Endometrial
5 naometriat cancer
c
& 15.6 ® Risk factors (Fig. 7.13)
 Disorders of the genital tract

@ Types (Fig. 7.14)

i. Uterine adenocarcinoma
ii, Uterine carcinosarcoma
® Non-endometrioid carcinoma
i. Is a poorly differentiated carcinoma

Endometrial
hyperplasia

Hypertension

Ovarian
Early
cancer
menarche
Breast cancer

Late
menopause

Figure 7.13 Endometrial cancer risk factors

Endometrial
Cancer

Sarcoma

Carcinosarcoma
Non- (mixed
Endometrioid Adenosarcoma Stromal tumours
endometrioid mullerian
tumour)

Papillary serous Clear cell

carcinoma carcinoma

Figure 7.14 Endometrial cancer subtypes

oe 260 Chapter 7 Pathology

ii, Resembles serous ovarian carcinoma

iii. Has a poorer prognosis
iv. Is managed the same as a grade 3 endometrial carcinomas
Staging (Table 7.5)
Carcinosarcomas have a 5-year survival of 25-30 %

Table 7.5 FIGO 2010 classification of uterine cancer

SS SSS

FIGO classification of uterine cancer 5-year survival

——— __

Stage 1 Limited to uterus 85-90%

1A Invasion <1/2 of myometrium

1B Invasion >1/2 of myometrium

Stage 2 Cervical stromal invasion 65%

Stage 3 Extension beyond uterus but confined to pelvis 45-60%

3A Invasion of uterine serosa, adnexa and peritoneal fluid

3B Vaginal invasion
He Nodal involvement (C1 = pelvic and C2 = para-aortic)

Stage 4 Distant metastasis 15%

4A Invasion of mucosa of rectum and bladder

4B Distant metastases including abdominal metastases and/
or inguinal lymph nodes

T.in PCOS
Obs
Gyn
1. PCOS
Chpt 12.11 ® Prevalence is 5%
® Also known as Stein—Leventhal syndrome
® Diagnosis based on Rotterdam criteria (2 out of 3 to be met)
i, Oligo-ovulation
ii, Excess androgen activity
ili, Polycystic ovaries on imaging (i.e. >12 follicles in each ovary measuring 2-9 mm in
diameter or an ovarian volume >10 mL)
® High androgen levels are possibly due to
i, Increased luteinizing hormone levels (cause increased thecal cell production of
androgens)
ii. Decreased SHBG levels
iii. Increased insulin levels
iv. Extra-ovarian production of androgens (e.g. Cushing’s syndrome, congenital adrenal
hyperplasia)
® Women with PCOS are at risk of
i, Endometrial hyperplasia/neoplasia
ii. Insulin resistance
iii. Dyslipidaemia

Ovarian tumours
Ale Primary ovarian cancer types are divided into 3 groups (Box 7.10)
 Disorders of the genital tract 261

Box 7.10 Types of primary ovarian cancer

® Serous (75%) ® Sertoli-Leydig (testosterone- ® Germinoma

® Mucinous secreting) ® Endodermal sinus tumour
@ Brenner's ®@ Thecofibroma (secretes AFP and a-antitrypsin)
® Clear cell ® Granulosa (oestrogen-secreting) ® Choriocarcinoma
® Differentiated (secretes hCG)
© Endometrioid ® Teratoma
© Fibroma © Embryonal (secretes LDH)

2. Secondary ovarian cancer arise from

® Primary peritoneal cancer
® Breast cancer
@ GIT cancer

3. Germ cell tumour accounts for 70% of ovarian tumours in the under 20 age group

4. Krukenberg cancer
® ls secondary ovarian cancer from a gastrointestinal primary cancer
® Characterized by appearance of mucin-secreting signet-ring cells
@ Usually affects both ovaries

5. Teratomas
@ Include
i. Dermoid cysts (derived from all 3 germ cell layers)
ii. Mature teratomas
iii. Struma ovarii (contains mostly thyroid tissue) — only 5% are malignant
iv. Carcinoid component
® Benign teratomas
i. Are the commonest ovarian tumour (accounts for 40% of all ovarian tumours)
ii. Are bilateral in 10-15%
iii, 1% undergo malignant transformation
® Struma ovarii may cause hyperthyroidism

6. 5-year survival rate for all stages of ovarian cancer is 45.5%

7. 30% of ovarian adenocarcinomas express HER2 oncogenes

8. Ovarian endometrioid carcinoma

® 15% coexist with endometriosis
@ 15-30% are associated with uterine endometrial carcinoma

9. Brenner’s tumour
® ls composed of transitional cells
® Secretes oestrogen
@ Mostly benign
@ 15% are bilateral

10, Dysgerminomas
e@ Are the commonest malignant germ cell tumours
@ Are female equivalent to a seminoma
® Bilateral in 20%
@ Are extremely radiosensitive
 262 Chapter7 Pathology

11, Fibroma-thecomas
® Pure thecomas are rare
e@ Associated with
i. Meigs’ syndrome (ovarian tumour, hydrothorax (more common on the right side), and
ascites)
ii, Basal cell nevus syndrome

12. Granulosa-theca cell tumour

® Secretes oestrogen
@ May produce
i. Endometrial hyperplasia
ii, Precocious sexual development
® Risk of endometrial carcinoma in 10-15% of patients

13. Leydig cell tumour

@ Also known as hilus cell tumour
®@ Derived from theca cells
@ Reinke crystalloids are present in the cytoplasm of the Leydig cell
® Are unilateral
®@ Associated with elevated levels of 17-ketosteroid
® Almost always benign

14. Tumour markers

®@ Biochemical
i. CA 125 (elevated in 50% with early disease & 80% in late disease)
ii. CA 119 (elevated in mucinous epithelial ovarian cancer)
ii, CEA
iv. AFP
v. B-HCG
vi. Lactate dehydrogenase (LDH)
® Cytokeratins
i. CK7 positive
ii, CK 20 negative
® Risk of malignancy index (RMI) = CA 125 x menopausal status x ultrasound features
i, Premenopausal score = 1
ii, Postmenopausal score = 3
iii. >1 ultrasound feature seen = 3
iv. RMI >200 is highly indicative of malignancy

Ou 14. Staging (Table 7.6)

yn

nae re Vulval and vaginal pathology

15.12 1, Lichen sclerosis
® Also known as chronic atrophic vulvitis
© Affects women of all ages
® Common after menopause
® Clinical features
i. Narrowed introitus
ii, Labial atrophy
® Cardinal histological features
i. Epidermal atrophy
ii, Hydropic degeneration of the basal layer
iii. Dermal inflammation
 Disorders of the genital tract 263

iv. Sclerotic stroma

@ May be associated with squamous vulval carcinoma in 5%

Table 7.6 FIGO 2010 classification of ovarian carcinoma

FIGO classification of ovarian carcinoma

Stage 1 Limited to 1 or both ovaries

1A Involves 1 ovary
Peritoneal washing’s negative
1B Involves both ovaries
Peritoneal washing’s negative
ike Capsule ruptures
Peritoneal washing’s positive
Stage 2 Pelvic extensions

2A Implants on uterus

2B Implants on pelvic structure

KE Peritoneal washing’s positive

Stage 3 Peritoneal implants beyond pelvis or with extension to small bowel/omentum

3A Microscopic implants

3B Macroscopic implants <2 cm

Ae Macroscopic implants >2 cm

Stage 4 Distant metastasis

2. Lichen simplex chronicus

@ Also known as hyperplastic dystrophy
@ |s secondary to pruritus
® Clinical features
i. Acanthosis of vulval squamous epithelium
ii. Hyperkeratosis
®@ Histological features
i. Thickened epithelium
ii, Increased mitotic activity in basal and prickle cell layer

3. Vulval intraepithelial neoplasia (VIN)

® Characterized by
i. Epithelial nuclear atypia
ii. Increased mitosis
iii. Lack of surface differentiation
® 90% of VIN is associated with HPV
® 10-30% is associated with another primary squamous neoplasm in the vagina or cervix

4. Extramammary Paget’s disease

® |sanon-invasive intraepithelial adenocarcinoma
® Not usually associated with underlying invasive malignancy
® Can be associated with adenocarcinoma arising from
i, Urethra
 264 Chapter 7 Pathology

ii, Rectum
iii. Bartholin’s gland
Clinical features of the lesion
i. Sharp demarcation
ii. Erythematous
ii. Pruritic

5. Vulval cancer
Incidence in UK = 3 : 100 000 women
Accounts for 4% of all gynaecological cancers
Median age of presentation = 74
Commonest symptom = itching (75%)
10% of vulval cancer patients are under 40 years old
Types
i. Squamous cell carcinoma (85%)
ii. Melanoma (5%)
iii. Basal cell carcinoma (1%)
iv. Adenocarcinoma
v. Sarcoma

6. Vulval cancer staging (Table 7.7)

Table 7.7 FIGO 2010 classification of vulval carcinoma

FIGO classification of vulval carcinoma

Stage 1 Confined to vulva

1A Lesions <2 cm in size with stromal invasion <1 mm
1B Lesions >2 cm in size with stromal invasion >1 mm

Stage 2 Extension to adjacent perineal 1/3 lower vagina

structures 1/3 lower urethra
Anus

Stage 3 Positive inguino-femoral nodes

3A <2 lymph node metastases
3B >2 lymph node metastases
JE With extracapsular spread
Stage 4 Extension to upper urethra and
vagina
4A Upper vagina
Upper urethra
Bladder
Rectum
4B Distant metastases including pelvic lymph nodes
O_O

7. Vaginal cancer
Accounts for 1% of gynaecological malignancies
Primary carcinoma of the vagina is uncommon
Associated with HPV
Types
i. Squamous cell carcinoma (90%)
ii, Adenocarcinoma (clear cell)
iii, Germ cell tumours
iv. Sarcoma Botryoides
 Disorders in pregnancy 265

q Disorders in pregnancy

1, Pre-eclampsia
rts
1-8.13 ® Definition is blood pressure >140/90 with proteinuria after 20 weeks gestation (Fig. 7.15)

> 20 weeks | P ey
gestation _ roteinuria

Figure 7.15 Triad of pre-eclampsia

Prevalence of
i. Hypertension is 10-15% of pregnancies
ii, Pre-eclampsia is 2-3%
iii, Eclampsia is 0.05% in the UK
iv. Eclampsia in pre-eclamptic women is 2%
Aetiology is unknown
Pathophysiology is thought to be due to poor placentation causing
i. Utero-placental resistance
ii. Abnormal placental function
Pre-eclampsia is a
i. Vasoconstricted state
ii, Plasma contracted state
Associated with intravascular coagulation
Associated with endothelial dysfunction
i. Increased capillary permeability
ii. Increased vascular tone
iii, Increased fibronectin
iv. Platelet thrombosis
Biochemical changes
i, Decreased nitric oxide by increasing ADMA
ii, Increased thromboxane Aj, angiotensin, and endothelin
iii. Decreased prostacyclin
Classification (Box 7.11)

Box 7.11 Classification of pre-eclampsia

® BP > 140/90 ® BP > 160/110

© Proteinuria 300 mg/24 h ® Proteinuria > 5 g/24h

Clinical features
i. Symptoms
& Headache
m Visual disturbance
= Epigastric/right upper quadrant pain
a 266 Chapter7 Pathology

= Vomiting
® Ankle swelling
= Seizures
ii. Signs
= Hyper-reflexia
® Clonus
= Oliguria
Investigations can show
® Deranged liver enzymes
Low platelets
Abnormal renal function
Deranged clotting
Elevated urinary protein
® Risk factors
i. Age >40 years old (doubles the risk of pre-eclampsia)
ii. Body mass index (BMI) >30
iii. Family history of pre-eclampsia (4 fold increase in pre-eclampsia risk)
iv. Primiparity
v. Multiple pregnancy
vi, Previous pre-eclampsia (7 fold increase in pre-eclampsia risk)
vii. Hydatidiform mole
viii. Triploidy
ix. Pre-existing hypertension
x. Renal disease
xi. Diabetes
xii, Antiphospholipid syndrome
© Complications
i. Haemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome
ii. Placental abruption
iii, FGR
iv. Eclampsia
v. Pulmonary oedema
vi. DIC
vii. Commonest causes of death in pre-eclampsia are
= Cerebral haemorrhage
= ARDS
2. Obstetric cholestasis
® Prevalence varies geographically. It is higher in
i Scandinavia
ii. Chile
iii. Bolivia
iv. China
® Clinical features
i, Pruritus of limbs and trunk (mainly palms and soles)
ii, No rash
iii. Abnormal liver function tests
iv. Jaundice is rare
@ Pathogenesis is multifactorial (genetic, environmental, endocrine) and is not well understood
® Complications
i, Vitamin K deficiency
ii, Postpartum haemorrhage
 Disorders in pregnancy 267

iii, Pre-term delivery

iv. Intrapartum fetal distress in 22%
v. Meconium-stained amniotic fluid in 25-45%
vi. Intrauterine fetal death (is 14% but with active management is comparable to the
general population)
vii. Fetal intracranial haemorrhage
Risk of recurrence is 90% in future pregnancies
4 @ Affects 0.7% of pregnancies
EFin
“Obs
Sy 3. Acute fatty liver of pregnancy
pt 8.14 ® Prevalence is 1: 9000-13000 pregnancies
e Usually presents after 30 week gestation
e Risk factors
i. Primigravida
ii. Obesity
ili. Male fetus (ratio 3 : 1)
iv. Multiple pregnancy
Maternal mortality is 10-20%
Perinatal mortality is 20-30%
Clinical features
i. Vomiting
ii. Abdominal pain
iii, Jaundice
iv. Abnormal liver function
v. Profound hypoglycaemia
vi. Marked hyperuricaemia
vii. Coagulopathy
Complications are
i. Fulminant hepatic failure
ii, Encephalopathy
iT. in
Obs
Gn 4. HELLP syndrome
pt 8.14 ® Incidence is 20% in women with severe pre-eclampsia
e Pathogenesis involves
i. Endothelial cell injury
ii. Microangiopathic platelet activation and consumption
Effects on pregnancy
i. Abruption
ii. Acute renal failure
ili. Hepatic necrosis
iv. Liver rupture
y. Subcapsular liver haematoma
vi. Perinatal mortality = 10-60%
vii. Maternal mortality = 1%
Risk of recurrence in future pregnancies is 3-5%
Risk of pre-eclampsia in future pregnancies is 75%

5. Peripartum cardiomyopathy
Is a form of dilated cardiomyopathy
Occurs between 8 months gestation to 5 months post partum
Associated with
i. Congestive heart failure
ii, Decreased left ventricular ejection fraction
 Chapter 7 Pathology

iii. Cardiac arrhythmias

iv. Thromboembolism
v. Sudden death
The cause is unknown
It is a diagnosis of exclusion
Maternal mortality = 25-50%
Management
i. Diuretics
ii, B-blockers
iii, ACEI
iv. Anticoagulation
v, In refractory cases
® Left ventricular assist device
® Heart transplant

Pathology — specific blood tests

1. Coombs’ test
2 types
i. Direct
ii. Indirect
Is positive if agglutination occurs
Indirect Coombs’ test
i. Detects antibodies against RBCs present in patient’s serum
ii, Used for antibody screening (both for cross-matching and for antenatal screening)
Direct Coombs’ test (Box 7.12)

Box 7.12 Diseases that give a positive direct Coombs test

ae : Drug-induced immune-mediated
: : Alloimmune haemolysis Autoimmune haemolysis F
haemolysis

© Haemolytic disease of newborn @ SEE ®@ Methyldopa

® Idiopathic (primary cold ® Penicillin
haemagglutinin syndrome) ® Quinidine
® Secondary due to a
lymphoproliferative disease or °
an infection such as infective
mononucleosis (secondary cold
haemagglutinin syndrome)

i. Detects antibodies bound to RBC surface antigens

ii, Indicates immune-mediated attack on RBCs

2. Kleihauer’s test
Is used to measure the fetal RBCs in the maternal circulation
Normally fetal maternal haemorrhage is <4mL at delivery
Anti-D immunoglobulin
i. 500IU neutralizes 4mL of Rhesus positive RBC
ii, Should be given within 72 h of sensitisation in non-sensitised Rhesus negative women
iil. Provides protection for 6 weeks
 CHAPTER 8

; | Immunology
Se

CONTENTS
General immunology 269
Immunology — pregnancy 280

General immunology

1. The immune system is divided into 2 functional units

Innate
Adaptive

2. Innate immune system

Is the first line of defence
Also known as the non-specific immune system (i.e. its response is non-specific and antigen
independent)
Is unchanged over time (i.e. has no memory)
Is fast to develop (within hours)
Consists of soluble and cellular mediators (Box 8.1)
Also includes anatomical barriers (e.g. skin and epithelial layers)

Box 8.1 Mediators of the innate immune system

Soluble mediators
Complement system components ® Monocyte
Coagulation system components © Dendritic cells
Lactoferrin and transferrin ® Neutrophil
Interferon ® Eosinophil
Cytokines and chemokines (e.g. interleukins) © Mast cells
Acute phase proteins (e.g. CRP) © Basophil
@ Natural killer (NK) cells

3. Adaptive immune system

Is responsible for specific lymphocytic activity
Is slow to development (within days)
Has memory
Augments with time
Has immune tolerance to self (i.e. no immune response to self-antigens)
 270 Chapter 8 Immunology

Has diversity
Has 2 arms
i. Humoral immunity (antibody production)
ii. Cellular immunity
Consists of soluble and cellular mediators (Box 8.2)

Box 8.2 Mediators of the adaptive immune system

SMa e Soluble mediators Cellular mediators

® Complement system components @ T-cell

@ Antibodies © B-cell
® Cytokines © Antigen-pesenting cells

4. Immune tolerance
Is the process through which immune response to self-antigens is prevented
There are 3 forms
i. Central tolerance
ii. Peripheral tolerance
iii. Acquired tolerance
Prevents the development of autoimmunity
Central tolerance
i. Occurs in the thymus and bone marrow
ii. Begins in fetal life
Acquired tolerance includes the immune tolerance that occurs in pregnancy

5. Hypersensitivity — there are 4 types (Box 8.3)

Box 8.3 Types of hypersensitivity

Type 3
‘Type 4 Type 2 asa Type 4
Mast cell mediated Complement mediated scysed <— T-cell mediated
complex mediated

© Mast cell ® Antibody dependent © Immune complex ® Cell-mediated

degranulation ® Activation of deposition reaction
® Associated with IgE complement via ®@ Develops in = 10 days ® Delayed reaction
® Eg. classical pathway by ® Eg. (takes
= 48 hrs to
¢ Hay fever IgM and IgG * Rheumatoid develop)
¢ Allergy E.g. arthritis ® Involves T-cells
¢ Haemolytic disease ¢ SLE ® Eg.
of newborn ¢ Glomerulonephritis ¢ Graft rejection
¢ Pernicious anaemia Serum sickness ¢ Contact sensitivity
e Transfusion ¢ Symptom of TB
e Graves’ disease e Symptom of
e Myasthenia gravis leprosy
¢ Autoimmune
disease
¢ Food allergies

6. Transplantation
® Graft classifications
i. Autograft = from the same person
ii, Allograft = from a different individual of the same species
iii, Xenograft = from a different species
 General immunology 271

Types of rejection
i. Hyperacute rejection = a severe immunological response to the graft that occurs within
minutes to hours of transplantation (due to pre-formed host antibodies)
ii, Acute rejection = a primary immune response to the graft that occurs within days to
weeks (due to the presence of donor leucocytes)
iii. Chronic rejection (occurs months to years after transplantation)

7. There are 3 types of vaccine

Attenuated (MMRBOYY), which are live organisms
i. Mumps
ii, Measles
iii, Rubella
iv. Bacille Calmette Guérin (BCG)
v. Polio (Sabin, which is oral)
vi. Yellow fever
vii. Varicella zoster
Killed
i. Cholera
ii. Polio (Salk, which is i.m.)
iii. Rabies
iv. HepatitisA
Acellular — toxoid
i. Tetanus
ii. Diphtheria
Acellular — organism subunits
i. Pertussis (whooping cough)
ii. Hepatitis B
iii. Influenza
iv. Neisseria meningitidis

Soluble mediators
fs Complement system
Consists of approximately 30 proteins
Are a part of both the innate and adaptive immune systems
Synthesized in the liver
Present in inactive form in plasma
Constitutes 10% of total body protein
Activity is analogous to the coagulation cascade
Complement activation has 3 pathways
i. Classical
= Requires antibody as a trigger
= Fixation of C1 to IgG/M
ii, Alternative
™ Requires antigen as a trigger (e.g. lipopolysaccharides (LPS)/endotoxin)
iii. Mannose-binding lectin pathway
iv. All 3 pathways
@ Produce protease C3 convertase
B Cleave C3 to C3a and C3b
Complement system functions
i. Opsonization (via C3b)
ji. Leucocyte adhesion, chemotaxis, and activation (via C5a)
oe 8 272 ~~Chapter 8 Immunology :

iii. Cell lysis via membrane attack complex (MAC)

iV. Inflammatory mediator (via activation of lipoxygenase pathway of arachidonic acid
metabolism by C5a)
Vv. Increase in vascular permeability (via C3a and CS5a)
© Specific complement component functions
C3b — opsonization
C3a and C5a
=@ Have anaphylatoxin activity
B Stimulate histamine release
li, (Coe
= Chemotaxis
E Activates lipoxygenase pathway
iv. C5b and Cé6-9 — cell lysis via MAC

2. Interferons (IFN)
@ Are glycoproteins
® Area class of cytokines
® Functions
Antiviral — inhibit viral replication within cells
. Anti-oncogenic
iii. Activate
= NK cells
= Macrophages
. Upregulation of major histocompatibility complex (MHC) class 1
Increased p53 activity (p53 promotes apoptosis)
® Bodictan of IFNs is induced by
Microorganisms (via infected host cells)
Cytokines
® 3 major classes of IFN
IFN-1 ()
IFN-2 (B and )
IFN-3
3. CRP
® san acute phase serum protein
® Coats pathogens to promote opsonization
® |s produced by the liver ;
® Gene is located on chromosome 1

4, ESR (Box 8.4)

®@ ls anon-specific measure of inflammation
® Basal ESR is higher in females
@ ESR (mm/H) = (Age (years) + 10 (if female))/2

Box 8.4 Causes of altered ESR level

ESR decreased in ‘ie ; : ESR increased in

@ Sickle cell ® Inflammation
® Polycythaemia
@ Heart failure
 General immunology 273 Ce

5. Cytokines
@ Are group of proteins responsible for cellular signalling
Are produced by leucocytes and other body cells
Are water soluble
Are glycoproteins
Bind to cell surface receptors
Classification of cytokines
i. Promoters of Th-1 helper cells
m IFN-y
ms |L-2
ii, Promoters of Th-2 helper cells
@ |L-4/5/6
= TGF-B
iii. Non-immunological cytokines
# EPO
& Thrombopoietin
iv. Chemokines
y. Colony-stimulating factor

6. IL-1 and TNF

@ Are 2 major cytokines that mediate inflammation
@ They act on
i. Endothelium
ii, Leucocytes
iii. Fibroblasts
@ They induce systemic acute phase reactions, which include
i. Fever
ii, Increased sleep
iii. Decreased appetite
iv. Increased acute phase proteins
v. Neutrophilia
vi. Shock
@ Effects on endothelium include
i. Increased leucocyte adherence
ii, Increased prostacyclin synthesis
iii. Increased procoagulant activity
iv. Increased anticoagulant activity
v. Increased levels of
= |L-1, 6, and 8
= PDGF
vi. Induce synthesis of nitric oxide
@ Effects on fibroblasts include
i, Increased proliferation
ii Increased collagen synthesis
iii. Increased collagenase secretion
iv. Increased protease secretion
v. Increased prostaglandin E synthesis

7. EPO
® |saglycoprotein
® Produced by the kidney
®@ Regulates RBC production
 274 Chapter 8 Immunology ; !

8. Thrombopoietin
Is a glycoprotein
Produced by
i. Kidney
ii, Liver
iii. Striated muscle
iv. Stromal cells in bone marrow
Regulates production of platelets (megakaryocytes)

Cellular mediators
1. Cellular mediators
Originate from the bone marrow
Include
i, Myeloid cells (e.g. leucocytes)
ii, Lymphoid cells (e.g, B-cells, T-cells, and NK cells)
Myeloid progenitor cells give rise to
i. Erythrocytes
ii, Platelets
iii, Leucocytes
iv. Dendritic cells

2. Leucocytes
Are divided into 2 groups (Box 8.5)

Box 8.5 Groups of leukocytes

. Granulocytes Agranulocytes
® Neutrophil (65%) ® Monocyte (half-life = 1 day)
® Eosinophil ® Macrophage = Monocyte outside blood vessels
© Basophil (half-life = months)
® Lymphocyte (25%)

® Granules
i, Store antibiotic compounds and enzymes
ii, Utilized in the digestion of endocytosed particles
Neutrophils are incapable of replication
Eosinophils
i. Combat parasitic infections
ii, Associated with atopy and allergy
ili, Stain pink with eosin which is a red dye (acid-loving)
iv. Induce mast cell degranulation
vy. Contain
= Histamine
= Plasminogen
= Lipase
= Major basic protein
Only macrophages can form giant cells
© Hofbauer cells are phagocytic cells present in the placenta

3. Lymphocytes consist of 3 cell types

T-cells (80%)
B-cells (15%)
 General immunology 275 Le

® NK cells (10%)
i. Specific for MHC class 1 and have CD16 receptors
ii. Decidual NK cells (present in pregnancy) stain positive for CD56 but are negative for
CD16
4. T-cells
© Are part (principal mediators) of the adaptive immune system
® Are divided into
i. T-cells expressing the surface protein CD4 (i.e. Th-1 and -2 cells)
= MHC class 2 restricted
= Express a or B T-cell receptors
ii. T-cells expressing the surface protein CD8 (i.e. T cytotoxic and suppressor)
@ Specific for MHC class 1
= Express o or B T-cell receptors
iii. T-cells expressing both surface proteins CD4 and CD8
® Are MHC-unrestricted
= Express y or 6 T-cell receptors
e@ T-cell development
i. Originates in the bone marrow
ii, Cells mature in the thymus
iii. Undergo clonal deletion (i.e. a process by which T- and B-cells expressing receptors for
self-antigens are deactivated)
Do not recognize free antigens
Recognize antigens bound to MHC molecules (MHC dependent)
Th-1 cells
i. Mediate cellular response
ii. Interact with monocytes, macrophages, and CD8-positive T-cells
iii. Produce IFN-y and IL-2
© Th-2 cells
i. Mediate humoral response
ii, Interact with B cells
iii, Produce IL-4 and -5

5. B-cells
® Development
i. Originate in the bone marrow
ii. Differentiation induced by
= Th cells
= Antigens
® Differentiate into
i. Plasma cells — secrete antibodies
ii, Memory cells
® Contain on their surface
i. Fe receptors
ii, Complement receptors
iii. MHC class 2
® Produce immunoglobulins (Ig G, A, M, E, and D)

6. Lymph nodes
® Are divided anatomically into
cortex
ii, Medulla
Sy 276 Chapter 8 Immunology

® Cortex is divided into 2 regions

i. Outer (nodular) — contains B-cells
ii. Inner (juxtamedullary) — contains T-cells
@ Medulla has 2 parts
i. Medullary cord — contains plasma and T-cells
ii. Medullary sinuses — contains histiocytes (immobile macrophages) and reticular cells

7. MHC
® Encodes for cell-surface antigen-presenting proteins
® Gene is located on short arm of chromosome 6
® There are 2 classes
i. MHC class 1
= Expressed on all nucleated cells
= Has 3 major sub-loci genes (A, B, and C)
® Has 3 minor sub-loci genes (E, F, and G)
= Presents intracellular antigens
ii. MHC class 2
® Has 3 major sub-loci genes (DP, DQ, and DR)
@ Has 2 minor sub-loci genes (DM and DO)
& Expressed on antigen-presenting cells
™ Presents extracellular antigens to T-lymphocytes

8. Antigen-presenting cells include

® B-cells
® Dendritic cells
© Macrophages

9. Immunoglobulins
® Structure (Fig. 8.1)
i. 2 heavy chains
ii, 2 light chains
iii. Bound by disulfide bonds
iv. There is a variable region
= Forms the antigen-binding site

Antigen-binding site
Variable
Sac ” region

Light chain 4
Constant
region

: r———» Fe region
Heavy chain ————_»

Figure 8.1 Immunoglobulin structure

 General immunology 277

® Also known as Fab (fragment antigen binding) region

= Consists of portions of a light and a heavy chain
v. There is a constant region
= Fe (fragment crystallizable region) receptor binding site
= Made up of 2 heavy chains only
® Consist of5 classes (Ig G, A, M, E, and D) (Box 8.6)

Box 8.6 Classes of immunoglobulin

© 75% of total Ig pool ® 20% of total Ig pool © 5% of total Ig pool ® Binds to basophil and
® Monomer © Dimer ® ‘1st lg produced in mast cells
® Has 4 subtypes (lgG1, ® Has 2 isoforms infection ® Monomer
IgG2, lgG3, IgG4) ® Found in mucosal © Pentamer ® Involed in allergy and
epithelium (GIT; ® Confined to parasitic infections
respiratory tract; intravascular pool
urogenital tract)

© <1% oftotal lg pool

® Monomer

Immunohistochemistry (IHC)
1. IHC is the process of identifying antigens in cells by using antibodies

2. Widely used in diagnosis of abnormal cells

3. 2 methods used in IHC detection of antigens

@ Direct (where only one antibody is used)
® Indirect (where two antibodies are used)

4. Diagnostic IHC markers (Table 8.1)

in
dbs Immunological disorders
3yn
if Sue
s 7.24
@ Prevalence
i. 1: 1000 women
ii, Women are affected more than men with a ratio of 9: 1
@ Clinical features
i, Joint involvement — arthritis
ii, Skin involvement
@ Malar rash
= Photosensitivity
= Raynaud’s phenomenon
iii. Haematological manifestations
® Haemolytic anaemia
= Thrombocytopenia
@ Leucopenia
oo 278 Chapter 8 Immunology

Table 8.1 Diagnostic IHC markers

ee en ee eee —eEee————— EE

Marker Positive in Negative in

CK7 Lung adenocarcinoma Squamous cell carcinoma

Breast adenocarcinoma Colonic carcinoma
Ovarian adenocarcinoma (serous Mucinous adenocarcinoma of ovary
and endometrioid) Hepatocellular carcinoma
Cervical adenocarcinoma Prostatic adenocarcinoma
Bladder adenocarcinoma Renal epithelial tumour

CK 20 Gastrointestinal epithelium
Urothelium
Colorectal carcinoma
Rectal carcinoma
Pancreatic duct adenocarcinoma
Mucinous ovarian adenocarcinoma

CA 19.9 GIT carcinomas

Pancreaticobiliary carcinomas
Mucinous ovarian tumour

CA 125 Ovary adenocarcinoma

Cervical adenocarcinoma
Endometrial adenocarcinoma
GIT adenocarcinoma
Breast adenocarcinoma
Thyroid adenocarcinoma

CA 15.3 Recurrent breast carcinoma

Calretinin Ovarian sex cord stromal tumour

CEA (is an oncofetal GIT adenocarcinoma

glycoprotein) Lung adenocarcinoma
Medullary carcinoma of thyroid

Epithelial membrane Mesotheliomas

antigen (found in
human milk fat globule
membranes)

Inhibin Ovarian sex cord stromal tumour

iv. Renal involvement

v. Neurological involvement
® SLE autoantibodies include
i Antinuclear antibodies (ANA)
ii. Antibodies to double-stranded DNA
iii, Extractable nuclear antigens (ENA)
m Anti-Ro antibodies
= Anti-La antibodies
iv. Anticardiolipin antibodies
@ Pregnancy increases the risk of SLE relapses
® Complications of SLE during pregnancy include
i. Miscarriage
ii. Pre-eclampsia
 : General immunology 279 ee

iii, FGR
iv. Fetal death
v. Pre-term delivery
vi. Congenital heart block
vii. Cutaneous neonatal lupus
® Complications during pregnancy are decreased if
i, SLE in remission around the time of conception
ii, There is no of renal disease
® Cutaneous neonatal lupus
i, Is transient
ii, Occurs in 5% of infants born to anti-Ro/La positive mothers
® Congenital heart block
i, Is permanent
ii, Occurs in 2% of infants born to anti-Ro/La positive mothers
iii, Perinatal mortality rate is 19%
iv. Fetal heart rate responses during labour unreliable

2. Multiple sclerosis (MS)

@ san autoimmune disorder of the CNS due to auto antibodies directed against myelin-
producing oligodendrocytes
®@ Destruction of myelin is due to cell-mediated immunity by Th-1 cells
® Diagnosis is based on 2 demyelinating lesions in the brain or spinal cord disseminated in
time and space
@ There are 2 forms of MS
i, Relapsing-remitting (85% of patients)
ii, Primary progressive MS
@ Prevalence in UK is 0.1%
® Lifetime risk of developing MS if
i, One parent affected = 2%
ii One sibling affected = 3%
iii. Two parent affected = 20%
iv. Dizygotic twin affected = 7%
v. Monozygotic twin affected = 30%
@ Relapse rate
i. Decreases in pregnancy due to decreased cell-mediated immunity and increase in
humoral immunity associated with pregnancy
ii, Increases by 50% during the first 3 months after delivery
®@ Investigations include
i. Magnetic resonance imaging (MRI)
ii. CSF — raised IgG in 70% of patients and oligoclonal bands on CSF electrophoresis
iii, Visual evoked potential
@ Treatments include
i. Corticosteroid
ii. IFN beta
iii. Plasma exchange
iv. Glatiramer acetate

3. Myasthenia gravis
@ Prevalence is between 1: 10000 and 1 : 50000
@ |s due to IgG antibodies against the nicotinic acetylcholine receptor on the motor endplate
® Only affects skeletal muscles
@ Diagnosis is via the Tensilon test
oe 280 Chapter 8 Immunology

Complications in pregnancy
i. Arthrogryposis multiplex congenital (development of fetal contractures due to lack of
movement caused by transplacental passage of myasthenic antibodies) in 20%
ii, Pre-term delivery
iii. Intrauterine FGR
In pregnancy
i. 40% have exacerbation
ii, 30% have remission
iii. 30% have no change in disease progress

Immunology — pregnancy

1. The fetus
@ lsasemi-allograft
® |s antigenically competent
i. Produces IgM at 11 weeks
ii, T-cell development is slow
iii. NK cell activity is 50% that of adults
iv. Cytotoxic T cell function is 1/3 that of adults
® Maternal lg transfer to the fetus
i. Only IgG can cross the placenta
i, Starts at 12 weeks
iii. Peaks at 32 weeks (although significant protection is provided 236 weeks)
iv. Is passive

2. Uterine immune system cells

Lymphocytes
i. B-cells (virtually none)
ii, T-cells (10%)
ili. NK cells (70%)
Uterine large granulolymphocytes (ULGLs)
Macrophages (20%)
Dendritic cells (2%)
Ratio of T-cells ; B-cells = 1:1
CD 8° T-cells >CD 4* T-cells
t

3. Maternal immunology
Humoral and cellular response remain about the same with mild discrepancies
i. Humoral immunity tends to dominate (Th-2 cell mediated) hence SLE (Th-2 dependent)
worsens in pregnancy
ii, Progesterone suppresses Th-1 cell hence rheumatoid arthritis (Th-1 dependent)
improves in pregnancy
Increased complement activation
Increased acute phase protein levels
Decreased NK cell activity
Increased endothelial cell activation mediated via
eVEGR
ii, PAI-1
Decreased immunoglobulin levels of
eee
i, IgA
iii, IgM
 Immunology
— pregnancy 281 Co

4. Fetal cells
® Syncytiotrophoblast
i. Is in direct contact with maternal cells
ii, Does not express class 1 and 2 MHC antigens
iii. Does not stimulate cytotoxic activity
iv. Inhibits NK cell activity
@ There are 2 immunological interfaces in human pregnancy
i. Extra-villous cytotrophoblast/decidua (early pregnancy)
ii. Syncytiotrophoblast/maternal blood (late pregnancy)
@ Extra-villous trophoblast
i. Expresses class 1 MHC antigens (e.g. HLA-C, HLA-E, HLA-G)
ii, Does not express class 2 MHC antigens
® Blastocyst develops MHC class 1 and 2 at 4 weeks

5. Immuno-contraception
@ ls a birth control method using the body’s immune response to avert pregnancy
@ Not used in humans but utilized in animals (e.g. for controlling the numbers of some species
of wild deer)
e Antibodies can act on 3 potential antigen sites
i. Sperm surface
ii. Zona pellucida
iii. Implantation-associated antigens (e.g. hCG)
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CHAPTER 9

Microbiology

CONTENTS
Bacteria 283
Fungi 293
Protozoa 294
Viruses 296

Bacteria

1. Bacteria
®@ Are prokaryotic (i.e. have no membrane-bound organelles)
® Can be classified into 3 main groups (Box 9.1)

Box 9.1 Bacterial groups

| | | Acidefast | Unusual
® Gram positive ® Cell wall has high lipid ® Have no peptidoglycans
© Gram negative content - hence difficult to (e.g. Chlamydia, Mycoplasma)
© Gram variable (Gardenella stain (e.g, Mycobacteria,
vaginalis, Mobiluncus) Norcardia)

®@ Are visible by light microscopy (average diameter =~ 1 Um)

@ Have a cell wall which is made up of
i. N-acetyl glucosamine/muramic acid
ii, Peptidoglycans
B Have penicillin-binding sites
= Are the target for B-lactams
iii. Polypeptides
iv. Polysaccharides

2. Taxonomy
@ By shape
i. Bacilli (rods)
ii. Cocci (grains)
@ By O, requirement
i. Aerobes
ii, Anaerobes
 284 Chapter 9 Microbiology

@ By spore forming
@ By staining

3. Anaerobe organisms can be classified into 2 types

® Facultative anaerobes, which are capable of aerobic respiration if O2 is present
® Obligate anaerobes, which die in the presence of O,

4. Gram stain
® Process involves
i, Staining with crystal violet
ii. Then staining with Gram’s lodine
iii, _Decolourizing with acetone
iv. Counter-stain with methyl red
® Gram-positive bacteria
i. Stain blue — retain crystal violet stain
ii, Stain due to peptidoglycan — a thick polysaccharide coat that loses stain very slowly once
taken up
iii. Include (Box 9.2)

Box 9.2 Examples of gram positive bacteria

© Staphylococcus (form chains) Clostridium

® Streptococcus (form grape-like clusters) Corynebacterium
Listeria
Bacillus
Actinomycetes

© Gram-negative bacteria (Fig. 9.1)

i, Stain pink because the cell wall is thinner and does not retain the crystal violet dye, so it
takes up the methyl red stain
ii. Cell wall consists of
®™ Outer layer of LPS
= Periplasmic layer containing B-lactamase

negative

Bacilli Spirochaetes Vibrio

Neisseria Leptospira
gonorhoeae (weil’s) Cholera

Neisseria Borellia
meningitidis (lyme)

Moraxella Treponema
catarrhalis (syphillis)

Figure 9.1 Gram-negative bacteria nomenclature

 Bacteria 285

@ Inner peptidoglycan layer

iii. Gram-negative bacilli include
Haemophilus influenzae
Klebsiella pneumonia
Legionella
Pseudomonas aeruginosa
Escherichia coli
Proteus mirabilis
Helicobacter pylori
Salmonella typhi
= Campylobacter
iv. Can also be divided based on lactose fermentation (Box 9.3)

Box 9.3 Gram negative bacteria classification according to lactose fermentation

Lactose fermenters (orange on McConkey agar) Lactose non-fermenters (pink on McConkey agar)
@ Klebsiella ® Pseudomonas
® Escherichia coli ® Salmonella
® Enterobacter ® Shigella
® Citrobacter © Yersinia
® Salmonella
© Helicobacter pylori
© Proteus

5. Bacterial toxins consist of 2 types

e@ Exotoxins
i, Secreted by organisms
ii, A feature of Gram-positive and Gram-negative bacteria
iii, Form toxoids
@ Endotoxin
i. Released on cell death and lysis
ii, A feature of Gram-negative bacteria
iii. The main forms is lipid A from LPS

6. Bacterial antimicrobial resistance occurs via

® Bacterial mechanisms of antimicrobial resistance
i. Drug inactivation (e.g. production of B-lactamases)
ii, Alteration of drug target site (e.g. alteration of penicillin-binding sites)
iii, Bacterium metabolic pathway alteration
iv. Fibronectin coat
v. IgA cleaving protease
® Mechanisms of transfer of antimicrobial resistance
i. Horizontal gene transfer
ii. Vertical gene transfer
®@ Mechanisms of horizontal gene transfer
i. Plasmid DNA transfer
ii. Chromosomal mediated resistance
iii, Bacterial conjugation

7. Vaginal flora is influenced by oestrogen levels contributing to

@ Increased vaginal glycogen concentration
@ pH 3.5-4.5 due to conversion of glycogen to lactic acid by lactobacilli
 286 Chapter 9 Microbiology S

8. Clinical isolation of bacteria

Use of specific microbiological swabs
Storage at 4°C
Preliminary laboratory report takes 18h
Identification is via detection of
i. Antigens
ii, Antibodies
iii. Nucleic acids

Examples of Gram-positive organisms

1. Streptococcus — general facts
Many are facultative anaerobes
They can be
i. Catalase negative
ii. Oxidase negative
Form chains
Divided into 3 groups based on levels of haemolysis when cultured on horse blood agar
(Box 9.4)

Box 9.4 Streptococci classification according to haemolysis when cultured on horse blood agar

Nonshaemolytic = = = Partial haemolytic (0) Complete haemolytic (8)

© E. faecalis © S. viridans ® Group A, C, and G
® Enterococcus © GroupB
© Pneumococcus @ GroupF

2. B-haemolytic streptococci are subdivided by Lancefield grouping (A-O)

Groups A, C, and G are associated with
i. Toxic shock syndrome
ii, Necrotizing fasciitis
ili. Vaginitis
Group B is associated with
i. Chorioamnionitis
ii, Neonatal sepsis
iii. Endometritis
Group F — can cause abscesses

3. Group A streptococcus
Also known as Streptococcus pyogenes
Virulence factor is determined by the presence of
i. M protein
ii, Hyaluronidase
ili. Streptokinase
iv. DNAse
v. Superantigens
M-protein is
i A fimbrial protein
ii, Involved in capsule formation
ili, Is anti-phagocytic
iv. Involved in destroying C3 convertase and preventing opsonization by C3b
v. Responsible for organism adhesion and invasion
 Bacteria 287

® Causes
i. Scarlet fever
ii. Toxic shock
iii. Rheumatic fever
iv. Glomerulonephritis
| y. Necrotizing fasciitis

_ 4. Group B streptococcus (GBS)

6.6 ® A\so known as Streptococcus agalactia
® Maternal carriage
i. 20-35% carry GBS
ii, Intermittent carriage
® Fetal
i. Maternal to fetal colonization rate = 80%
ii. Invasive neonatal disease occurs in 0.5 : 1000 births
iii. Neonatal mortality from early-onset GBS disease in UK is 6%
@ Indications for antibiotic prophylaxis during labour (following a risk-based
approach)
i. Early-onset GBS disease in a previous baby
ii. GBS found in vagina/urine during index pregnancy
iii. Prolonged rupture of membranes at term (>18h)
iv. Preterm labour <37 completed weeks of gestation
v, Preterm rupture of membranes with known GBS
vi. Intrapartum pyrexia
@ Antibiotic regimens
i. Benzylpenicillin
B® 3gi.v. loading dose followed by
= Benzylpenicillin 1.5g i.v. 4 hourly until delivery
ii, Clindamycin 900 mg i.v. 8 hourly until delivery
iii. Erythromycin 500 mg 6 hourly until delivery
iv. Vancomycin as a very last resort

5. Streptococcus pneumoniae
® |sadiplococcus (forms pairs)
Forms draughtsman-shaped colonies
Is optochin sensitive
Is bile soluble
Causes
i. Meningitis
ii, Pneumonia
iii. Primary bacterial peritonitis (in prepubertal girls)

6. Enterococcus genus
® Consists of 2 species
i, Enterococcus faecalis
ii. Enterococcus faecium
@ Are gastrointestinal commensal organisms
e Are resistant to many antimicrobials
Causes
i. Endocarditis
ii. Proctitis
® Can be haemolytic or non-haemolytic — used to be classified as group D
oo 288 Chapter 9 Microbiology

7. Listeria monocytogenes
@ Affects 1: 10000 pregnant women
@ Some strains are B-haemolytic
® Produces flagella at room temperature but not at 37°C
® Causes — listeriosis
i. Meningitis
ii. Hepatosplenomegaly
iii, Bradycardia
® Transmitted
i, In contaminated food
ii, To the fetus via
® Transplacental spread
B® Ascending infection
® In the placenta causes
i. Miliary granuloma
ii. Focal necrosis
® Fetal mortality rate from listeriosis is 50%
Treatment
i. Amoxicillin or gentamicin
ii. Duration 3 weeks

8. Staphylococcus
®@ ls a genus of facultative anaerobes
®@ Forms grape-like bunches
® Classified on ability to form coagulase
® Cause
i. Scalded skin syndrome
ii, Toxic shock
iii, Slime in iv. cannulae
@ Meticillin-resistant Staphylococcus aureus (MRSA) is
i, Coagulase positive
ii. DNAse positive
iii, Catalase positive

9. Actinomycetes israelii
® |s
i. An anaerobe
ii, A bacillus
® Shows branching
Is slow growing
® Occurs in
i, Mouth
ii. Intrauterine contraceptive devices (|UCDs)
® Causes chronic granulomatous disease
® Produces sulphur granules in tissues
Treatment
i. Penicillin
ii. Requires 6-12 months antibiotic therapy

tm Examples of Gram-negative/variable organisms

Obs
Sn 1, Neisseria family
Chpt 3.3 @ Are diplococci
 Bacteria 289

Cause
i. Meningitis (N. meningitidis)
ii. Gonorrhoea (N. gonorrhoeae)
Are capnophilic (i.e. thrive in the presence of high CO,)
Treatment = cephalexin
Multidrug resistance is growing

2. Gonorrhoea
Infects mucous membranes of
i. Urethra
ii. Endocervix
iii. Rectum
iv. Pharynx
v. Conjunctiva
Can infect Bartholin’s gland
Treatment
i. IM ceftriaxone 250mg stat
ii, Oral cefixime 400 mg
iii. IM spectinomycin 2g
A test of cure should be done 3 days after treatment
40% will also have concurrent Chlamydia
Complications
i. Gonococcal ophthalmia neonatorum
ii. Neonatal vaginitis, proctitis, and urethritis
iii. Disseminated gonococcal infection

3. Gardnerella vaginalis
Is a facultative anaerobe
Is Gram variable
Is a bacillus
Is anormal commensal organism of the vagina
Is B-haemolytic
4. Bacterial vaginosis (BV)
Polymicrobial condition of the vagina characterized by
i. Variable degrees of depletion of protective Lactobacillus species
ii. Marked increase in the population of other organisms especially anaerobes including
G. vaginalis, Mobincullus, and Atopobium vaginale
Over 60% of affected women are asymptomatic
Aetiology is unknown
Associated with mid-trimester miscarriage, preterm birth, rupture of membranes,
endometritis
More common in black women
Amsel criteria for diagnosis (require 3 out of 4)
i. Vaginal discharge
ii Clue cells
iii. pH >4.5
iv. Fishy odour with alkali (10% KOH) on a wet mount (whiff test)
Hay/Ison criteria (is based on Gram stain of vaginal discharge)
i. Grade 1 = normal flora (predominantly lactobacilli)
ii. Grade 2 = mixed flora
iii. Grade 3 = BV and absent lactobacilli
oe 290 Chapter 9 Microbiology

Clinical features
i. Fishy smelling vaginal discharge (worse after intercourse)
ii. White or grey vaginal discharge
Treatment = metronidazole 400 mg b.d. for 7 days
T.in
Obs
Syn 5. Syphilis
Chpt 3.6 Is caused by the spirochaete Treponema pallidum
Classification
i, Early — includes primary, secondary and early latent stages (i.e. < 2 years of infection)
ii, Late — includes late latent and tertiary stages (i.e. > 2 years of infection)
Stages
i. Primary — chancre appears 10-90 days after initial exposure (persist 4-6 weeks before
disappearing)
ii. Secondary — occurs 1-6 months post primary infection
= Symmetrical non-itchy rash on trunk and
® Condylomata latum
& Mucous patches around genitals or mouth
iii. Tertiary — occurs 1-10 years after initial infection
™ Characterized by the formation of gummas
® Neurosyphilis — tabes dorsalis; generalized paresis of the insane; Argyll Robertson
pupil
= de Musset’s sign
Microbiological identification
i. Cannot be cultured in lab
ii. Serology is indistinguishable from
B Yaw
@ Pinta
iii. Difficult to differentiate between active and treated past infection of syphilis
iv. Non-specific test
= Venereal Disease Research Laboratory (VDRL)
= Rapid plasma reagin (RPR)
@ Wasserman’s reaction
™ Hinton’s test
v. Specific tests
= Fluorescent treponemal antibody-absorption test (FTA-ABS)
™ Treponema pallidum particle agglutination assay (TPPA)
vi. Serology progress: IgM/FTA-ABS — IgG — TPPA — VDRL
vii. False positives in non-specific tests occur in
= Viral infections
= Lymphoma
m™ Tuberculosis
@ Malaria
™ Chagas’ disease
m™ Pregnancy
Causes endarteritis obliterans
Treatment
i, Penicillin G
ii, Doxycycline
The Jarisch-Herxheimer reaction is common post treatment

6. Mycoplasma hominis
Present in 20% of sexually active women
Can be either a primary or a co-pathogen in pelvic inflammatory disease (PID)
 Bacteria 291

® Can cause postpartum pyrexia

®@ Can be a co-pathogen in chorioamnionitis
@ Treatment
i. Doxycycline
ii. Clindamycin
: iii, Resistant to macrolides

a. 7. Chlamydia trachomatis
3.2 ® san obligate intracellular gram negative organism
® Has 3 subgroups
i. A-C (follicular conjunctivitis)
ii, D-K (genital)
iii. L1-L3 (lymphogranuloma venereum)
® Contains both DNA and RNA
® Grows on McCoy’s culture
®@ Lifecycle
i. Is 72h
ii. Elementary body — Reticular body — Inclusion body
@ Treatment
i. Azithromycin
ii. Doxycycline
iii, Erythromycin
iv. Ofloxacin
v. Rifampicin
® Test of cure is only recommended in pregnant or breastfeeding women

8. Vaginal discharge in children can be caused by

Foreign body (which is the commonest cause)
Streptococcus pyogenes
Haemophilus influenza
Shigella sonnei
Pinworms
Chlamydia
Neisseria gonorrhoeae

Wound infection
1. Typically require 10° organisms to establish

2. In the presence of a foreign body 10° organisms are required

Necrotizing fasciitis
1. Consists of 2 types

2. Type 1
® ls associated with surgery/diabetes
@ ls due to polymicrobial infection
i. Anaerobes
ii, Facultative anaerobes
iii, Obligate anaerobes

3. Type 2 — due to Group A streptococcus

4. Treatment
@ Surgical debridement
@ Antibiotic combination
 292 Chapter 9 Microbiology

i. Benzylpenicillin 1.2g iv. q.d.s.

ii, Clindamycin
iii. Ciprofloxacin
@ Surgical re-exploration of the wound
To in
o PID
Chpt 3.2 4. Clinical manifestations include
e Pelvic and/or abdominal pain
e Dyspareunia
® Post-coital bleeding
@ Discharge
e Cervical tenderness
e Fever

2. Complications
Ectopic pregnancy
Tubal infertility
i. 12% after 1st episode
ii, 20% after 2nd episode
ili, 50% after 3rd episode
Chronic pelvic pain
Fitz—Hugh—Curtis syndrome (i.e. right upper quadrant pain and perihepatitis — occurs in 15%
of women with PID)

3. Causative organisms include

Chlamydia
Neisseria
Mycoplasma
i, hominis
ii, ureaplasma
Gardnerella
Trichomonas vaginalis
GBS
4. Treatments regimens (Fig. 9.2)

Outpatient
regimens Inpatient regimens

IV cefoxitin 2g t.dis. + IV IV clindamycin 900mg t.d.s.

on ; ie ycy
doxycycline 100mg 8 b.d. + IV g gentamicin (2mg/kg
(2mg/k,
ears AOD 400mg
metronidazole nig bi b.d. followed by oral doxycycline loading dose followed by
(14 days) 100mg b.d. + oral 1.5mg/kg t.d.s.) followed by
metronidazole 400mg b.d. oral clindamycin 450mg
(14 days) q.d.s. (14 days)

IM ceftriaxone 250mg stat WV ciprofloxacin 200mg b.d. :

followed by oral doxycycline + IV doxycycline 100mg b.d. IV Saisie bagi b.d. + 1V
100mg b.d. + metronidazole +1V metronidazole 500mg metronidazole 500mg t.d.s.
400mg b.d. (14 days) t.d.s, (14 days) (14 days)

Figure 9.2 PID treatment regimens

 293

Reiter’s syndrome
1. Is areactive arthritis caused by bacterial infection

2. Causative organisms include

Salmonella
Yersinia
Shigella
Campylobacter
Chlamydia
N. gonorrhoeae

3. Clinically manifests as a triad of

@ Urethritis
@ Arthritis
e@ Uveitis

Fungi

4. Are multicellular eukaryotic organisms

2. Cell walls
® Have no peptidoglycans
® Contains ergosterol

3. Are eukaryotic (i.e. have membrane-bound organelles)

4. Contain
@ Fibrils
® Chitins
@ Mannan
@ Glucan

Are aerobic

Reproduce via both asexual and sexual methods

Secrete keratinase

4 main groups (Box 9.5)

oye
COR

Box 9.5 Fungal groups

ie Yeast tke morphic

®@ Multicellular ® Unicellular ® Example: Candida © Grows as yeast at
® Grows as branching ® Reproduces by Biiee
filament (hyphae/ budding ® Grows as mycelia at
mycelia) ® Example: Cryptococcus 20°C
® Reproduces by spores ® Example: Histoplasma
© Example: Aspergillus
fe ee 294 Chapter 9 Microbiology

Protozoa

Protozoa are unicellular, eukaryotic, free-living organisms

Consist of 2 types
® Protozoa
® Helminths

Include
@ Trichomonas vaginalis
Toxoplasma gondii
Giardia
Cryptosporidium
Plasmodium

Reproduction can either be asexual or sexual

Methods of asexual replication include

® Merogony (also known as schizogony)
® Sporogony
® Endodyogeny
® Endopolygeny

Form
Trophozoites (the protozoon proliferative stage within the host cell)
Schizonts
Sporozoites (the cell form that infects new hosts)
Merozoites (result of merogony that occurs within the host cell)
Bradyzoites
Tachyzoites
Oocysts
Ookinetes (the fertilized zygotes capable of movement)

Helminths are divided into 3 groups

® Fluke (trematode)
® Tape (cessatode)
®@ Ring (nematode)

8. T. vaginalis
® |sa flagellate protozoon
® Transmission is venereal
® Diagnosed via
i. Wet prep
ii, Polymerase chain reaction (PCR)
iii, Culture
® Symptoms include
i, Discharge
ii, Intense vulvo-vaginal itching and irritation
ili. Strawberry cervix
iv. Preterm delivery
® Treatment is with metronidazole or tinidazole
T.in
Obs
Gyn 9. T. gondii
Chpt 8.26 ® Js a zoonotic infection (predominantly via felines)
® Diagnosis
 Protozoa 295

IgM/A avidity
Serial samples taken 3 weeks apart
Affects
Muscle
Neural tissue
Placenta
Transmission in pregnancy
Is via transplacental in primary infection
Greatest risk = 26-40 weeks
Lowest risk = 10-24 weeks
iv. The earlier the infection occurs in pregnancy the more severe the disease in the
newborn
Maternal risk
Chorioretinitis
Encephalitis
Congenital infection causes
Stillbirth
Cerebral calcifications
iii, Microcephaly/hydrocephalus
Choroidoretinitis
Cerebral palsy
i. Epilepsy
ii. Hepatosplenomegaly
viii. Thrombocytopenia
lil eatment
i. Spiramycin
ii. Sulfadiazine/pyrimethamine/folinic acid
Toxoplasma IgM persist for 3 years after eradication

10. Malaria
@ Is amosquito-borne (female Anopheles mosquito) infectious disease
Infects red blood cells
Caused by Plasmodium
falciparum
vivax
iii. ovale
. malariae
knowlesi
Severe malaria is defined as parasitaemia of more than 2%
Maternal clinical features include
Fever
Respiratory distress and pulmonary oedema
iii. Arthralgia
iv. Retinal damage
Splenomegaly
. Hepatomegaly
i. Haemoglobinuria and renal failure
Vili . Biochemical abnormalities
@ Hypoglycaemia
= Anaemia
& Thrombocytopaenia
 t
oe 296 Chapter 9 Microbiology

Box 9.6 Management of malaria

® \nsecticides (DDT, permethrin) @ Mefloquine ® Quinine

® Mosquito nets ® Doxycycline © Chloroquinine
© Skin repellents (50% DEET) ® Malarone e@ Artemisinin
® Quinine

= Acidosis
= Hyperlactataemia
ix. Coma
x. Convulsions
xi, Mortality (20% in non-pregnant women and 50% in pregnant women)
Fetal effects of malarial infection include
i. Miscarriage
ii. Stillbirth
iii. Premature labour
iv. Low birth weight
vy. Placental parasitaemia
Diagnosis is made via thin and thick blood fiims
Management (Box 9.6)

Viruses

1. General facts
Viruses have no organelles
They depend on their host for
i, Energy metabolism
ii. Protein synthesis
Their genetic material is in the form of either (Box 9.7)
i. RNA
i DNA
Have a viral coat = capsid
Fetal transmission rate generally increases with gestational age
Incubation period for most viruses is approximately 21 days*

Box 9.7 Examples of viruses according to genetic material type

© Rubella Herpes
© HIV Parvovirus
® Hepatitis A, C, D, E, G HPV
Hepatitis B
EBV
CMV
VZV

2. Herpes is a virus family consisting of

®@ Cytomegalovirus (CMV)
© Herpes simplex
® Varicella
 Viruses 297

2}, ELMNY
50-80% women are seropositive
Chpt 8.24 Feto-maternal transmission rate = 40% (increases with gestational age)
Causes symptoms in 10% of infected infants
Causes congenital defects
i, Hearing loss — sensorineural
ii, Retinitis
ili. Cerebral palsy
iv. Hepatosplenomegaly
v. Hyperbilirubinaemia
vi. Intracranial calcification
vii. Thrombocytopenia
viii. Intrauterine FGR
ix, Microcephaly
CMV IgM persists for months/years
Diagnosis of maternal infection
i. Maternal IgG avidity
ii, High avidity means old infection
Excreted in neonatal urine = 30%
T.in
Obs
Syn 4. Herpes simplex
Chpt 8.25 2 types
i. Type 1-— accounts for 30% of genital infections in the UK (50% in the USA)
ii. Type 2 — accounts for 70% of genital infections in the UK (50% in the USA)
Fetal transmission
i. Is high if primary infection occurred in the last trimester with a rate 230%
ii. If there is a secondary episode during labour, the transmission rate is 1-3%
Incubation = 21 days
Affects
i. Skin
ii. Eyes
iii. Mouth
iv. CNS
High fetal mortality
Relative indication for caesarean section = presence of maternal lesions within 6 weeks of
birth in the absence of
i. Ruptured membranes
ii, Spontaneous rupture of membranes (SROM) >6 h
T.in
Obs
Syn . Varicella zoster
Chpt 8.24 Fetal transmission (congenital fetal varicella syndrome)
i. Limited to the 1st 20 weeks of gestation
ii, Overall rate = 1%
iii, Rate at 1-12 weeks = 0.4%
iv. Rate at 13-20 weeks = 2%
Fetal varicella syndrome is characterized by
i. CNS anomaly
= Microcephaly
® Cortical atrophy
ii. Limb hypoplasia
iii. Cicatricial scarring
iv. Eye defects
oo 298 Chapter9 Microbiology

@ Microphthalmia
® Cataracts
® Chorioretinitis
There is a risk of neonatal varicella if maternal infection occurs within 10 days of delivery
Maternal complications include
i. Pneumonitis (10%)
ii, Encephalitis
iii. Hepatitis
® Treatment
i. If maternal infection occurs — aciclovir
ii. If exposed to varicella — prevention of disease with VZlgG administration
iii. VZIgG is not beneficial in a patient with chicken pox
Tein
Obs
Gyn 6. Rubella
Chpt 6.6 @ |s also known as German measles
Is a togavirus
Has a single-stranded RNA genome enclosed in a capsid
Spreads via droplets
Congenital defects (congenital rubella syndrome) if acquired during pregnancy include
i. Eye manifestations
= Cataract
= Glaucoma
ii, Heart defects
= PDA
& VSD
= Pulmonary stenosis
iii. Sensorineural hearing loss
iv. Haematological manifestations
= Thrombocytopenic purpura
& Haemolytic anaemia
= Lymphadenopathy
Feto-maternal transmission rate
i. 1st trimester = 90%
i, 2nd trimester = 30%
ili, Risk of transmission is decreased after 16 weeks
Causes defects in
i, 1st trimester = 90% of infected fetuses
ii, 2nd trimester = 20% of infected fetuses
iii, >16 weeks = minimal risk of deafness only
iv. >20 weeks = no increased risk
T.in
Obs
Gyn 7. Parvovirus B19
Chpt 8.25 Also known as
i, Fifth disease
ii, Slapped cheek syndrome
ili, Erythema infectiosum
60% of women are immune to parvovirus B19
Causes
i, Miscarriage (overall risk of fetal loss = 6-12%)
ii, Hydrops fetalis (3%) — due to fetal anaemia
Does not cause congenital defects
The virus attacks P blood group antigen (globiside) on RBCs and fetal heart
 Viruses 299

® Fetal transmission
i, Mainly in 1st trimester
il. Rate = 30%
@ Treatment = intrauterine fetal blood transfusion
@ Not an indication for termination of pregnancy

8. HIV
@ Isa lentivirus (a member of the retrovirus family)
® Primarily infects
Th cells (particularly CD4)
Macrophage
Dendritic cells
® Transmission
Sexual — risk of transmission per act (in high risk countries) is
= Female to male = 0.04%
=# Male to male = 0.08%
= Receptive anal intercourse = 1.7%
(Latex condoms reduce this risk by 85%)
iii. Blood products, i.e.
® Intravenous drug users
= Blood transfusion
. Perinatal transmission
(HIV have been found in low concentration in saliva, tears, and urine — potential for
transmission from these is negligible)
® Structure
i, Spherical (120nm diameter)
ii. Composed of 2 copies of single-stranded RNA enclosed by a capsid
Capsid is
= Composed of viral protein p24
@ Surrounded by a matrix composed of viral protein p17
. Viral envelope
@ Surrounds the matrix
= Composed of phospholipids and glycoprotein (i.e. go120 and gp41)
Vv. Glycoprotein enables the virus to attach to and fuse with target cells
® Prevalence in the UK antenatal population
Average is 0.17% (highest in London — 0.32%, and lowest in the North East and South
West — 0.08%)
Approximately 1/3 of infections are due to HIV1 and 2/3 due to HIV2
® Fetal transmission rate
i, Without treatment = 15% (in European or North American countries)
ii, With treatment <1%
® Factors that increase vertical transmission rates
High maternal viral load
Low CD4 count
iii. Prolonged rupture of membranes
. Chorioamnionitis
Co-morbidity e.g. malaria, hepatitis C virus (HCV)
i. Breastfeeding
ii, Preterm birth
® Neonatal serology is of limited value as passively acquired maternal antibodies persist until
18 months of age
® AIDS occurs when CD4 count is below 200/mm? blood
ok 300 Chapter9 Microbiology

® Increases risk of
i. Miscarriage
ii. Pre-term delivery
iii, Intrauterine FGR
® Complications include
i. Kaposi’s sarcoma
ii, Pneumocystis carinii pneumonia
iii. Non-Hodgkin's lymphoma
iv. AlDS-related dementia

9. Human papillomavirus (HPV)

® Consists of 5 groups
i. O-papillomavirus
ii, B-papillomavirus
ili. y-papillomavirus
iv. Nu-papillomavirus
v. Mu-papillomavirus
® «c-papillomaviruses consist of 2 subtypes
i. Low risk — 6 and 11 (induce non-malignant changes)
ii, High risk— 16, 18, 31, 33 and 45 (induce malignant changes)
® Only infects epithelial cells
® Structure
i. Is made up of 75 capsomeres
ii, Each capsomere consist of 5molecules of L1 co-protein
iii, Contains circular DNA
® Genome is composed of
i. Early proteins (E1, E2, E3, E4, E6, E7)
ii, Late proteins (L1 and L2)
£6 and E7 are HPV proteins associated with cancer
Causes inactivation of
pos
ii, pRB
@ Incubation period is 2-8 months
@ Regresses spontaneously via cell-mediated immunity (70% regress within 1 year; 90% regress
within 2 years)
@ Treatment
i. Podophyllotoxin
ii, Imiquimod
al iil, Cryotherapy
cwisat0 1° epatitis virus
Syn 10 H e498 .

&b7 ® Types A-G

® Hepatitis A — maternal-fetal transmission is rare
@ Hepatitis B (Table 9.1)
i. Incubation = 6 weeks to 6 months
ii, Progress of antigen detection with time
m™ Surface + Core > e Antigen
iii, Antibody production chronology (IgM)
=™ Core > e Antigen — Surface
iv. Immunity is confirmed by anti-surface IgM
vy. Prevalence among pregnant women in UK = 0.5%
vi. Mother to child transmission
 Viruses 301

= Occurs via vertical transmission (includes pregnancy, labour and lactation)

= The transplacental route accounts for 5% of transmissions
vil. Feto-maternal transmission rate
= Transmission rates depend mainly on the viral load and on the antigen profile
= If mother is Hep B surface-antigen positive (HBsAg) = 20%
= If mother is Hep B e-antigen positive (HBeAg) = 90%
= Transmissions occurring during the 1st trimester = 10%
® Transmissions occurring during the 3rd trimester = 90%
viii. Treatment in pregnancy is possible with
& Interferon
& Lamivudine
ix. Prophylaxis to a neonate of a Hep B e-antigen positive mother should be given at birth
®™ Hep B vaccine
& |gG
® Hepatitis C
i. Prevalence in UK = 0.3-0.7%
ii. Increases risk of obstetric cholestasis
iii. Vertical transmission = 3-5%
® Hepatitis E
i. Risk of maternal mortality = 5%
ii. Risk of fulminant hepatic failure in pregnancy = 20%

Table 9.1 Hepatitis B serology

Stage of infection HBsAg HBeAg’ IgM anti- IgG anti- HepB Anti-
(surface (e Ag) coreAb coreAb virus HBe Ab
Ag) DNA
Acute (early) a + at + + =

Acute (resolving) * - + + = sof

Chronic (high i anf = le 10 +/—

infectivity)

Chronic (low ty = S + = fof

infectivity)

Immune (90%) = - - + = Te +/-

Post vaccination - = = = = =

11. HTLV
@ Prevalence in UK = 0.25%
®@ Feto-maternal transmission is via breast milk
® Manifestations of congenital infection occur after 10-30 years
i. T-cell leukaemia
ii, Tropical spastic paraparesis
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CHAPTER 10

Pharmacology

CONTENTS Tocolytics 320

General principles 303 Antihypertensive agents in pregnancy 322
Pharmacology in pregnancy 304 Antiepileptic drugs 323
Analgesics 306 Anticoagulants 325
Antibiotics 309 Gastrointestinal agents 327
Antifungals 314 Anti-inflammatory and immune modulators 328
Antivirals 314 Endocrine agents 331
Antimalarial drugs 317 Drugs used in gynaecology 332
Uterotonics 318 Contraceptives 334

General principles

1, Pharmacology comprises of 4 subdivisions

® Pharmacokinetics (i.e. what the body does to the drug)
i. Absorption
ii. Distribution
iii, Metabolism
iv. Excretion
@ Pharmacodynamics (i.e. what the drug does to the body)
® Pharmacotherapeutics
@ Toxicology

2. 4 phases of human drug clinical testing

®@ Phase 1 — studied in normal volunteers
®@ Phase 2
i. In target population
ii, Compared with a control drug
® Phase 3
i. Similar to phase 2, but in large groups
ii. Compared with a control drug
® Phase 4 — Post-marketing surveillance

3. Distribution of a drug depends on

® Capillary permeability
® Drug solubility (lipophilic drugs distribute across cell more easily)
@ Binding to plasma proteins
Wy 20 Chapter10 Pharmacology

4, Biotransformation
@ Makes drugs more polar (lipophilic properties of adrug hinder its elimination)
@ Involves 2 phases
i. 1—metabolism
ii, 2— conjugation
® Metabolism includes
i. Oxidation
ii. Reduction
iii. Hydrolysis
@ Conjugation occurs with
i, Glucuronate (e.g, paracetamol and morphine)
ii, Glutathione
iii, Sulphate (e.g. the contraceptive pill)
iv. Acetic acid (e.g. hydralazine and isoniazid)
® Phase 1 occurs via the action of cytochrome P450
@ Phase 2 occurs in the liver cytosol

Volume of distribution (Vd)

@ |s the ratio of the amount of drug in the body to its plasma concentration
® Large Vd
i. Lipophilic drugs
ii, Signifies that most of the drug is being sequestered in some tissue

Drug interactions
® Enzyme inductors (e.g. phenytoin)
®@ Enzyme inhibitors (e.g. sulfonamides)
® Enterohepatic circulation (reduced by ampicillin)
® GIT flora (reduced by ampicillin)

Pharmacology in pregnancy

. In pregnancy the following factors influence drug bioavailability

® Increased circulating volume
® Increased renal blood flow (hence increased renal clearance of water-soluble
drugs)
Increased 3rd space
Increased fat content
Decreased albumin and binding proteins (hence free drug levels may not be low)
Increased gastric emptying time
Increased liver metabolism (hence increased clearance of drugs dependent on liver
metabolism)
® Liver blood flow shows no change in pregnancy (hence no change in clearance of drugs
whose elimination is dependent on liver blood flow, e.g. propranolol)

Teratogens
® Potential teratogens include all the ‘A’ drugs
i. Anticonvulsant
ii, Antibiotics
ili, Anticoagulants
iv. Antimetabolites
v. Androgens
 Pharmacology in pregnancy

vi. Alcohol
vii. Antipsychotics
® Timing and defects (Box 10.1)

Box 10.1 Teratogenic effect of drugs according to timing of exposure

ue fe
© Limb defects @ Anencephaly © Transposition of great ® Cleft lip
vessels

® VSD © Hypospadias
® Syndactyly

3. Most drugs cross the placenta except HIT

® Heparin
®@ Insulin
® Tubocurarine

4. Drugs that cause abortion (MET)

® Misoprostol
®@ Ergotamine
@ Thrombolytics

5. The US Food and Drug Administration (FDA) pregnancy categories state the risk of a
substance to a fetus (Table 10.1)

6. The FDA requires large amounts of data on a drug for it to be classified as pregnancy
category A (thus many drugs that are category A in other countries are designated category
C by the FDA)

Table 10.1 FDA pregnancy category

A No fetal risk in pregnancy

Animal studies have failed to demonstrate a risk to fetus

No adequate studies in pregnant women

Cc Animal studies have shown adverse effect on the fetus

No adequate studies in pregnant women
Benefit of drug outweighs the potential risk

D Evidence of risk of human teratogenicity

Potential benefits outweigh potential risk
x Evidence of risk of human teratogenicity
Potential risk outweigh potential benefit of drug

Breastfeeding
1. Most drugs enter the breast

2. Drugs not excreted in breast are

@ Warfarin
@ Aminoglycosides
a 306 Chapter 10 Pharmacology

3. Dopamine agonists (FDA pregnancy category B)

Dopamine is a prolactin antagonist (increased dopamine causes a decrease in prolactin
levels)
Reduces milk production
Used in
i. Pituitary tumours
ii, Parkinson’s disease
iii. Inhibition of lactation
iv. Hyperprolactinaemia
Includes
i. Bromocriptine
ii. Cabergoline

4. Domperidone
Is a dopamine antagonist
Is used to
i. Stimulate lactation (by increasing prolactin secretion)
ii, Increase gastric motility
Also used in treatment of
i. Emesis
ii. Parkinson’s disease
Does not cross the blood-brain barrier

Analgesics

1. Morphine (FDA pregnancy category C)

Acts on u-opioid receptors in
i. Brain
ii, Substantia gelatinosa of spinal cord
iit Gly
Associated with
i. Analgesia
ii. Sedation
iii, Euphoria
iv. Dependence
v. Respiratory depression
vi. Miosis (pinpoint pupil)
vil. Constipation
vill, Sphincter of Oddi spasm
Antidote
i, Naloxone
ii, NMDA (N-methyl-b-aspartic acid) antagonists (e.g. ketamine)
Metabolized in
i. Liver
ii, Kidney
iii. Brain

2. Heroin (FDA pregnancy category X)

Is diacetylmorphine (also known as diamorphine)
Is a prodrug of morphine
More lipophilic, hence crosses blood-brain barrier easily
 Analgesics 307

More potent than morphine

Binds to y-opioid receptors
Side effects
i. Euphoria
ii. Drowsiness
iii. CNS depression
Fetal effects (if taken antenatally) are non-teratogenic and include
i. Placental infection
ii, FGR
iii. Preterm birth
iv. Fetal death
Neonatal narcotics abstinence syndrome
i. Incidence of narcotic use in the USA = 5%
ii, Usually presents within 48h of birth
iii, Can occur up to 4 weeks after birth — this is because methadone is stored in fetal lung,
liver, and spleen
iv. Characterized by
& CNS hyperirritability
High-pitched crying
Respiratory distress
Poor feeding
Seizures

3. Fentanyl (FDA pregnancy category C)

Is a u-opioid agonist
Rapid onset
Short acting
100 times more potent than morphine
Can cross the placenta

4. Lidocaine (FDA pregnancy category B)

Blocks voltage-gated sodium channels — prevents neurone depolarization
Is an antiarrhythmic
Half-life is 2h
Metabolized by the liver
Toxicity symptoms
i. Circumoral paraesthesia
ii. Tinnitus
iii. Blurred vision
iv. Seizures
y. Loss of consciousness
vi. Cardiorespiratory compromise
vii. ECG changes (widening PR interval and widening QRS)
Risk of cardiac toxicity is greatest in patients with underlying cardiac conduction problem
(avoid giving in Wolff—Parkinson—White syndrome)
Maximum dose
i. Without adrenaline = 3-5 mg/kg
ii, With adrenaline = 7mg/kg

5. Cocaine (also known as benzoylmethylecgonine)

Is obtained from the leaves of the coca plant
Acts as a
To 308 Chapter10 Pharmacology

i. CNS stimulant
ii, Appetite suppressant
iii. Topical anaesthetic
iv. Selective serotonin reuptake inhibitor (SSRI)
y. Potent vasoconstrictor
e ls metabolized primarily in the liver
@ ts metabolite can be detected in the urine
i. Within 4h ofintake
ii. Up to 8 days post cocaine use
® Side effects
i. Tachycardia
ii. Hallucinations
iii. Bronchospasm
iv. Crack lung syndrome
v. Myocardial infarction
vi. Tooth decay (due to breakdown of tooth enamel)
vii. Bruxism (involuntary tooth grinding)
e Fetal effects (if taken antenatally) include
i. Vasoconstriction of uterine, placental, and umbilical artery leading to
# FGR
@ Fetal death
= Placental abruption
ii. Prune-belly syndrome
iii. Hydronephrosis
iv. Reduced head circumference
vy. Gastroschisis

6. Tramadol (FDA pregnancy category C)

® lsacentrally acting analgesic
® Actsasa
i, Weak p-opioid agonist
ii, Serotonin releasing agent
iii. Noradrenaline reuptake inhibitor
iv. Nicotinic acetylcholine receptor antagonist
v. M1 and M3 muscarinic acetylcholine receptor antagonist
Primary active metabolite is O-desmethyltramadol
Maximum dose is 400 mg/day

7. Ethanol (FDA pregnancy category X)

®@ |s
i. An organic compound in which the hydroxyl functional group is bound to a carbon atom
ii. A product of glucose fermentation
Chemical formula is C;H;OH
Boiling temperature = 78.4°C
Acts as a
i, CNS depressant
ii, Y-aminobutyric acid (GABA) receptor agonist
® Metabolized
i, In the liver by alcohol dehydrogenase to acetaldehyde
ii. Follows zero-order kinetics
® Blood alcohol level of
i, 0.05% (0.5 g/L) causes euphoria
 Antibiotics 309

ii, 0.08% (0.8 g/L) is the upper legal limit for driving
iii. 0.1% (1 g/L) causes CNS depression
iv. 0.4% (4g/L) can cause death
® Recommended maximum consumption quantity is
i. For males = 140-210 g/week
ii, For females = 84-140 g/week
® Complications of ethanol abuse (Box 10.2)

Box 10.2 Complications of ethanol abuse

i@ Anaemia
oI
® Cardiomyopathy
i
® Chronic gastritis
ee
® Miscarriage
® Thrombocytopenia ® Hypertension ® Pancreatitis © Aneuploidy
® Elevated triglycerides ® Stroke ® Liver cirrhosis and © Structural congenital
hepatitis anomalies
® Fatty liver disease
®@ Oropharyngeal cancer

@ Wernicke—Korsakoff
syndrome
® Polyneuropathy
© Delirium tremens
@ Fetal alcohol
syndrome
® Dependence

® Fetal alcohol syndrome

i. Isa disorder of permanent birth defect in the offspring of women who drink alcohol in
pregnancy
ii, Incidence = 0.6 per 1000 live births in Canada
iii. Features (Box 10.3)

Box 10.3 Features of fetal alcohol syndrome

CNS tural N devel tal

Growth deficiencies Craniofacial anomalies atari sh orem Sue
anomalies anomalies :

© Low birth weight © Smooth philtrum ® Microcephaly ® Epilepsy

® Short stature ® Thin vermilion © Agenesis of corpus ® \|mpaired fine motor
®@ Small palpebral callosum skills
fissures ® Cerebellar hypoplasia © Neurosensory hearing
loss
® Learning disabilities
® Cognitive deficits

Antibiotics

General facts
1. Bactericidal antibiotics
e Are antibiotics that target bacterial
i. Cell wall
Tad 310 Chapter 10 Pharmacology

ii, Cell membrane

iii, Enzymes
® Kill bacteria
® \n low doses act as bacteriostatic

2. Bacteriostatic antibiotics
® Inhibit bacterial growth and replication by inhibiting
i. Protein production
ii. DNA synthesis
iii, Cellular metabolism
® High dose of bacteriostatics become bactericidal

3. Drugs that interfere with folate metabolism

® Sulfonamides inhibits conversion of benzoic acid to folate
® Dihydrofolate reductase inhibitors (inhibits conversion of folate to tetrahydrofolate) include
i. Trimethoprim
ii. Methotrexate
iii. Pyrimethamine

Example of antibiotics
1. Penicillin
® |sagroup of antibiotics derived from Penicillium fungi
® Can be broadly divided into 5 groups
i. B-lactams
ii. B-lactamase resistant
iii, Broad-spectrum penicillins
= Amoxicillin
= Ampicillin
® Co-amoxiclav (consists of amoxicillin with the B-lactamase inhibitor clavulanic acid)
iv. Antipseudomonal penicillins
® Ticarcillin
= Piperacillin
v. Mecillinams

2. Sulfonamides
® Consist of 2 groups
i. Sulfonlyureas
ii. Thiazide diuretics
© Acts as a competitive inhibitor of dihydropteorate synthetase (an enzyme involved in folate
synthesis)
® Side effects
i, Porphyria
ii, StevensJohnson syndrome
iii, Lyell syndrome (also known as toxic epidermal necrolysis)
iv. Blood dyscrasias
= Agranulocytosis
= Haemolytic anaemia
= Thrombocytopenia

3. Nitrofurantoin (FDA pregnancy category B)

® |s bactericidal
® Is usually used to treat urinary tract infections
® ls excreted mainly by the kidneys
 (panunuos)
311
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@ Has poor tissue penetration and thus should not be used to treat
i, Pyelonephritis
ii. Renal abscess
e Side effects
i. Pulmonary fibrosis
ii, Neonatal haemolysis (if used antenatally)

Antifungals

1. General facts
® Fungal cell wall is composed of ergosterol (which is susceptible to antifungal medications)
© Human cell membrane is composed of cholesterol (which is less susceptible to antifungal
medications)
@ Side effects of antifungals include
i. Nephrotoxicity
ii. Hepatitis
iii, Anaphylaxis

Antivirals

1. Antiviral drugs do not destroy their target pathogens (they merely inhibit pathogen
development)

2. Aciclovir (FDA pregnancy category B)

® Isa guanine analogue
e |sa prodrug
® Primarily used to treat herpes virus infections
® Inhibits viral DNA polymerase

Table 10.3 Antifungals

Group Drug Mechanism of action Fetal risk

Polyene Nystatin Inhibits synthesis of ergosterol FDA pregnancy cat. B

Amphotericin B :

Imidazole Ketoconazole Inhibits synthesis of ergosterol FDA pregnancy cat. C

Miconazole
Clotrimazole
Econazole
Fluconazole

Allylamines Terbinafine Inhibits squalene epoxidase action FDA pregnancy cat. B

Amorolfine (an enzyme required for ergosterol
synthesis)

Echinocandins Caspofungin Inhibits cell wall glucan synthesis FDA pregnancy cat. C
Griseofulvin Binds to keratin and interferes with FDA pregnancy cat. C
microtubule function in mitosis

Pyrimidine Flucytosine Inhibits fungal DNA/RNA synthesis FDA pregnancy cat. C

analogue
——————n—n ee
 Antivirals 315

® ls converted into active form

i. In viral cell
ii. By viral thymidine kinase
® Pharmacokinetics
i. Poor water solubility
ii. Poor oral bioavailability (15-30%)
iii. Elimination half-life is 3h
iv. Renal excretion

3. Neuraminidase inhibitors
® |s used in the treatment and prophylaxis of influenza virus A and B
® Include
i, Zanamivir (Relenza)
ii, Oseltamivir (Tamiflu)
@ Zanamivir (FDA pregnancy category C)
i. Dosing is limited to inhaled route
ii. Pharmacokinetics
= Oral bioavailability = 2%
= Renal excretion
iii. Could cause bronchospasm in asthmatic people
® Oseltamivir (FDA pregnancy category C)
i. Is a prodrug
ii. Pharmacokinetics
= Oral bioavailability = 75%
= Metabolized in the liver to its active metabolite
® Renal excretion
iii. Side effects include
= Stevens—Johnson syndrome
= Neuropsychiatric disorders

4. Ribavirin (FDA pregnancy category X)

®@ Primarily used to treat
i. Respiratory syncytial virus infection
ii. Hepatitis C
® ls a prodrug
@ sa purine analogue
® Pharmacokinetics
i. Oral bioavailability = 45%
ii. Mean half-life = 12 days
iii. Long half-life (RBCs concentrate the drug and are unable to excrete it; this pool is
eliminated when RBCs are degraded in the spleen — a process that can take up to
6 months)
iv. Renal and faecal (10%) excretion
® Side effects
i. Haemolytic anaemia
ii, Teratogenic (in some animal species)

5. Antiretroviral therapy (ART) (Table 10.4)

@ Used for the treatment of retroviral infections (e.g. HIV)
e@ Aim is to achieve a viral load of <50 HIV RNA copies/mL plasma
® HAART (highly active antiretroviral therapy) includes combinations consisting of at least
3 drugs belonging to at least 2 classes of antiretrovirals
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 Antimalarial drugs 317

® HAART side effects include

i. Lactic acidosis
ii. Hyperglycaemia
iii. Hepatitis
iv. Pancreatitis
v, Peripheral neuropathy
® |s used in the treatment of HIV
i. When CD4 T-lymphocyte count is between 200 and 350 cells/mm? in asymptomatic
patients
ii. When viral load is greater than 10000 HIV RNA copies/mL plasma
iii. In severely symptomatic patients

6. Drugs used in preventing HIV transmission from mother to fetus

@ HAART is the treatment of choice if the woman is not on antiretroviral therapy prior to
pregnancy
i. Should commence between 20 and 28 weeks of gestation
ii, Discontinued soon after delivery
iii, Zidovudine is administered orally to the neonate for up to 6 weeks of life (within 4h of
birth)
iv. Is known as START (short-term antiretroviral) therapy
@ Alternative to HAART is zidovudine monotherapy
® Zidovudine is the only antiretroviral drug specifically indicated for use in pregnancy
(excluding the 1st trimester)
® Women who conceive on HAART should continue taking it throughout pregnancy

Antimalarial drugs

1. There are 2 main groups of drugs

@ Chemo-prophylaxis
®@ Treatment

2. Chemo-prophylaxis (Box 10.4)

®@ Is not 100% effective
© Can be either
i. Causal (i.e. directed against liver schizont stage — e.g. Malarone)
ii. Suppressive (i.e. directed against the RBC stage of the malarial parasite — e.g.
mefloquine)

Box 10.4 Safety of anti-malarial chemo-prophylaxis in pregnancy

Safe in pregnancy
© Mefloquine ® Doxycycline (causes irreversible teeth discoloration
® Malarone (is a combination of atovaquone and and fetal bone growth disruption)
proguanil) © Primaquine (causes fetal haemolysis)

3. Proguanil is a biguanide agent

4. Mefloquine (FDA pregnancy category C)

® |s the recommended chemo-prophylaxis in pregnant women (can be used in the first
trimester)
® |s the drug of choice in chloroquine-resistant falciparum malaria
oe 318 | Chapter10 Pharmacology

Trade name is Lariam

Metabolized extensively in the liver
Half-life = 2-4 weeks
Excreted via
i. Bile
ii. Faeces
Side effects include
i. Depression
ii, Insomnia
iii. Hallucinations
iv, Seizures

5. Malaria treatment choices in pregnancy include

Artesunate (not licensed for treatment in UK)
Quinine (FDA pregnancy category C)

Uterotonics

1. Oxytocin (FDA pregnancy category A)

Is synthesized in
i. Supraoptic nucleus
ii, Paraventricular nucleus
Stored and released by posterior pituitary gland
Non-neuronal sources of oxytocin include
i. Retina
ii. Thymus
iii, Adrenal medulla
iv. Pancreas
v. Leydig cells
vi. Corpus luteum
vii. Placenta
Is a nanopeptide (consists of 9 amino acids)
Half-life is 6 minutes
Excreted in
i. Bile
ii. Urine
Acts on G-protein receptors which require
i. Magnesium
ii, Cholesterol
Inactivated/destroyed in the GIT
Regulates circadian rhythm
Peripheral functions of oxytocin include
i. Letdown reflex
ii, Uterine contraction
Maternal oxytocin triggers a transient inhibitory switch in GABA signalling (from excitatory
to inhibitory) in the fetal brain during delivery
Route of administration of synthetic oxytocin
i. Intranasal
ii, Intramuscular
ili, Intravascular
Side effects (Box 10.5)
 Uterotonics 319

Box 10.5 Side effects of oxytocin

® Subarachnoid e Tachycardia ® Pelvic haematoma @ Oliguria

haemorrhage ® Hypertension ® Uterine rupture ® Natriuresis
® Seizures ® T Cardiac output ® Hyponatraemia
®@ Arrhythmia ® Water intoxication

2. Prostaglandins
@ Are 20-carbon lipid molecules (including a 5-carbon ring) derived from fatty acids
® They are produced at many sites throughout the body (produced by all nucleated cells
except for lymphocytes)
® Actas local messengers, hence are classified as paracrine hormones
® They have many functions throughout the body, including contraction and relaxation of
smooth muscle
® In obstetric practice they are used for
i. Induction of labour
ii. Termination of pregnancy
iii. Management of postpartum haemorrhage (PPH)
® Commonly used prostaglandins in obstetrics include
i. Prostaglandin E, (misoprostol is a synthetic form) — commonest use is for treatment of
PPH and for termination of pregnancy
ii, Prostaglandin E, (dinoprostone is a naturally occurring form) — commonest use is for
induction of labour by ripening the cervix
iii. Prostaglandin F,,., (dinoprost is naturally occurring, carboprost is synthetic) - commonest
use is for induction of labour, termination of pregnancy, and treatment of PPH

3. Misoprostol (FDA pregnancy category X)

® ls asynthetic prostaglandin E, analogue
@ Half-life is 40 minutes
® Functions
i. Prevention of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers
ii. Labour induction
@ Mechanism of action in prevention of gastric ulcers
i. Inhibits secretion of gastric acid by the parietal cell via G-protein coupled receptor
mediated inhibition of adenylate cyclase (leading to decreased intracellular cAMP)
ii, Increases secretion of gastric mucus
iii. Increases gastric mucosal blood flow
® Side effects include
i, Uterine rupture
ii, Uterine hyperstimulation
iii. Amniotic fluid embolism
iv. Diarrhoea
v. Vomiting
vi. Headache

4. Dinoprostone (FDA pregnancy category C)

® |saprostaglandin E, analogue
® |s associated with transient pyrexia (may be due to its effect on hypothalamic
thermoregulation)
i. Occurs within 15-45 min of administration
os 320 Chapter 10 Pharmacology

ii. Return of temperature within 2-6h after discontinuation of therapy

5. Ergometrine (FDA pregnancy category X)

@ Belongs to the group of ergot alkaloids
® Chemically similar to lysergic acid diethylamide (LSD)
@ Works on the following receptors
iota
ii. Dopamine
iii, O&-adrenergic
® Functions
i. Vasoconstrictor
ii, Constricts intracranial extracerebral vessels
iii, Uterine contraction
iv. Relieves migraine
® Side effects
i. Ergotism or St Anthony’s fire (prolonged vasospasm resulting in gangrene, hallucinations,
abortions)
ii, GIT (diarrhoea and vomiting)
® Contraindications
i. Induction of labour
ii. 1st and 2nd stage of labour
iii, Vascular disease
iv. Severe cardiac disease
v. Severe hypertension

T. in
Obs ;
Syn Tocolytics
Chpt 8.19
1. There are 4 groups of tocolytics
® Oxytocin receptor antagonist (e.g. Atosiban)
© £,-agonists
i. Salbutamol
ii. Ritodrine
iii. Terbutaline
®@ Calcium channel blockers (e.g. nifedipine)
® NSAIDs (e.g. indometacin)

2. Atosiban
® san oxytocin receptor antagonist
® Route of administration is intravenous
® Contraindications
i, Pre-eclampsia
ii. Intrauterine death
iii, Intrauterine infection
iv. Antepartum haemorrhage
v. Premature rupture of membranes after 30 weeks
® Side effects
i. Vomiting
ii. Tachycardia
ili. Hypotension
iv. Headache
v. Hot flushes
oe Tocolytics 321

vi. Hyperglycaemia
vii. Fever

3. f,-agonists (FDA pregnancy category B)

® Side effects
i. Fluid retention secondary to decreased water clearance (pulmonary oedema)
ii. Increased myocardial workload (myocardial ischaemia)
iii. Increased heart rate
iv. Increased gluconeogenesis of liver and muscle
v. Increased glycogenolysis
vi. Hyperglycaemia
vii. Hypokalaemia
viii. Muscle cramps
ix. Headaches
® Include (Box 10.6)

Box 10.6 Examples of tocolytic B2-agonists

phe ~Salbutamol_ e ea.
Rinoddae ee Terbutaline
® Half life = 2h ® Halflife=6h ® Half life = 2h
® Route = oral ® Routes = oral, inhaled and ® Routes = oral, inhaled and iv.
subcutaneous

4. Nifedipine (FDA pregnancy category C)

@ Dihydropyridine calcium channel blocker
Is a vascular smooth muscle relaxant
Has no antiarrhythmic activity
Half-life is 2h
Excretion via
teeUrine
ii, Bile
® Unlicensed in pregnancy
@ Also used in treatment of
i. Hypertension
ii, Angina
iii, Raynaud’s phenomenon
iv. Pulmonary hypertension
® Side effects
i, Hypotension
ii, Vasodilatation
iii, Tachycardia
iv. Dependent oedema
v. Dyspnoea
@ Contraindications
i. Cardiogenic shock
ii, Aortic stenosis
iii, Acute porphyria
iv. Within 1 month of myocardial infarction
 322 Chapter 10 Pharmacology pe:

ta Antihypertensive agents in pregnancy

Gn
Chpt 8.12 1. Hydralazine (FDA pregnancy category C)
® Vasodilator — arterioles > venules
®@ Antioxidant
® Metabolized by acetylation
® Fast acting
® Side effects
ib SHE
ii. Tachyphylaxis
iii. Fluid retention
iv. Diarrhoea
v. Headaches
vi. Blood dyskariasis
® Dose = 25mg t.d.s. to 75mg q.d.s.

2. Methyldopa (FDA pregnancy category B)

® Has dual mechanism of action
i. Centrally acting o agonist
ii. Competitive inhibitor of DOPA decarboxylase (i.e. the enzyme that converts -DOPA
into dopamine)
® Prodrug
i. Active metabolite is o-methylnorephinephrine
ii, Metabolized in liver
Half-life is 100 minute
Side effects are minimized if daily doses are below 1g
Side effects (Box 10.7)
Dose = 250mg b.d. to 1g t.d.s.

Box 10.7 Side effects of methyldopa

se me suppression
® Rebound hypertension ® Dry mouth © Bell’s palsy @ Leukopenia
© Angina ® Stomatitis ® Parkinsonism ® Thrombocytopenia
® Postural hypotension © Sialadenitis ® Haemolytic anaemia
© Hepatitis .
© Pancreatitis

T Prolactin Psychological

® Gynaecomastia © SLE ® Depression

© Amenorrhoea ® Anxiety
© Sexual dysfunction

3, Labetalol (FDA pregnancy category C)

® Mixed o,f blocker
® Half-life is 8h
® Used only in 3rd trimester
®@ Associated with
 Antiepileptic drugs 323 Loe

eGR
ii, Neonatal hypoglycaemia
® Dose = 100mg b.d. to 600mg gq.d.s.

4. Calcium channel blockers

®@ Two groups
i. Non-dihydropyridine
EB Verapamil (FDA pregnancy category C)
® Diltiazem (FDA pregnancy category D)
ii, Dihydropyridines (vascular selective calcium channel blockers)
= Nimodipine (FDA pregnancy category C)
= Nifedipine
® Nimodipine
i. Preferential action on cerebral arteries
ii, Used in vasospasm post subarachnoid haemorrhage (SAH)

5. Antihypertensives to be avoided in pregnancy

® ACEis cause
i. Cardiovascular system (CVS) congenital malformations
ii, Impaired fetal renal function — oligohydramnios
iii. Skull defects
® Thiazide diuretics causes neonatal thrombocytopenia (if used in the third trimester of
pregnancy)
@ Statins (FDA pregnancy category X) results in CNS and limb defects

Tin
Sn Antiepileptic drugs
pt 7.14
1. Epilepsy increases risk of teratogenicity regardless of antiepileptic therapy
® Background risk of teratogenicity is 2-3%
@ lf the mother has epilepsy and
i. Not on medication the risk is 4%
ii. On medication the risk is 6-8%

2. In patients who are fit-free for 2 years the risk of recurrent seizures if therapy is withdrawn
is <20%
3. General points about antiepileptic drugs in pregnancy
® Increase risk of teratogenicity by 3x
®@ Associated with
i. NTDs
ii. Cleft lip/palate
iii. Cardiac defects
iv. Urogenital defects
v. Neonatal coagulopathies
Mothers should be on folic acid 5 mg/day in pregnancy
@ Vitamin K should be given at birth to neonates

4. Carbamazepine (FDA pregnancy category D)

es safest in pregnancy
® Fetal levels are approximately 50-80% of maternal serum levels
@ Also used in treatment of
i. Bipolar disorder
ii. Trigeminal neuralgia
SS 324 Chapter 10 Pharmacology

5. Valproate (FDA pregnancy category D)

© Drug of choice for primary generalized epilepsy
® Has worst teratogenic profile among the antiepileptic medications
® Fetal consequence include
i THEIR
ii. Hyperbilirubinaemia
iii, Hepatotoxicity
iv. Transient hyperglycaemia
v. NTDs
vi. Cardiac anomalies
vii. Craniofacial defects
viii. Urogenital defects (e.g. hypospadias)
ix. Limb defects

6. Phenytoin (FDA pregnancy category D)

@ Lowers serum folate
® Fetal consequence include
i. Fetal anticonvulsant syndrome
ii, Cleft lip/palate
iii. Microcephaly
iv. Cardiac abnormalities
v. Mental retardation
@ Not associated with NTDs
®@ Maternal side effects
i. Nystagmus
ii, Paraesthesia
iii, Megaloblastic anaemia
iv. Gingival hypertrophy
v. Stevens—Johnson syndrome
vi. Toxic epidermal necrolysis
® Overdose causes
i. Nystagmus
ii. Diplopia
iii. Slurred speech
iv. Ataxia
v. Hyperglycaemia

7. Newer classes of antiepileptic drugs

® Lamotrigine (FDA pregnancy category C)
i. Also used in the treatment of bipolar disorder
ii, Excreted in breast milk
iii, Crosses human placenta
Topiramate (FDA pregnancy category C)
Vigabatrin (FDA pregnancy category C)
Levetiracetam (FDA pregnancy category B)
Gabapentin (FDA pregnancy category B)

8. Magnesium sulphate (FDA pregnancy category B)

® Used in
i. Arrhythmias
ii, Asthma
iii. Eclampsia
 Anticoagulants 325

® Side effects
i. CNS depression
ii, Respiratory depression
© Antidote is 10ml 10% calcium gluconate

. Diazepam (FDA pregnancy category D)

® |s a benzodiazepine
® ls a positive allosteric modulator of GABA
® Used to treat status epilepticus
@ Also used to treat
i. Insomnia
ii, Anxiety
ili, Restless leg syndrome
iv. Alcohol withdrawal
@ When taken in the 3rd trimester causes
i. Neonatal benzodiazepine withdrawal syndrome (i.e. hypotonia, reluctance to suckle,
cyanosis, impaired metabolic response to cold stress)
ii. Floppy infant syndrome
® Antidote is flumazenil

Anticoagulants

. Maternal risks of thromboprophylaxis in pregnancy include

@ Bleeding (2%)
® Wound haematoma (2%)
® Allergic skin reaction (1.8%)
® Osteoporosis (0.04%)

. Warfarin (FDA pregnancy category X)

® |sasynthetic derivative of coumarin
® Interferes with synthesis of vitamin K-dependent clotting factors
i ill
ii, VII
iii, IX
iv. X
® Initial effects of warfarin are thrombogenic due to decrease in
i. Protein S
ii. Protein C
@ Has high protein binding
@ Antidote is
eden
ii, Vitamin K
iii, Prothrombin complex concentrate
®@ Teratogenic risk is an additional 2%
@ Maternal side effects
i. Skin necrosis — due to decreased levels of protein C
ii. Purple toe syndrome (due to fat embolus)
iii, Purpura fulminans

. Warfarin embryopathy
© Occurs in 5% of fetuses if warfarin is administered between 6 and 12 weeks gestation
See 326 Chapter10 Pharmacology

@ |s dose dependent (higher incident noted in patients taking >5 mg/day)

® Features include
i. Chondrodysplasia punctata
ii. Midface hypoplasia
iii. Pectus carinatum
iv. Stippled epiphyses (leading to short proximal limbs and phalanges)
v. Scoliosis
vi. Laryngomalacia
vii. Congenital heart defects
viii. Ventriculomegaly

4. Heparin — unfractionated (FDA pregnancy category C)

® Has the highest negative charge density
@ Weighs 8-15kDa
®@ One unit of heparin is
i. The amount equivalent to 0.002 mg of pure heparin
ii. The quantity required to keep 1mL of cat’s blood fluid for 24h at 0°C
iii. Also known as Howell unit
@ Naturally occurring anticoagulant in
i. Mast cells
ii. Basophils
® Activates antithrombin Ill, causing inactivation of
i. Thrombin
ii. Factor Xa
® Side effects
i. Heparin-induced thrombocytopenia
ii. Osteoporosis
iii. Alopecia
iv. Hyperkalaemia
®@ Antidote is protamine sulphate
® Does not cross placenta
@ Not secreted in milk

5. Heparin - LMWHs (FDA pregnancy category B)

@ Average molecular weight is 4.5kDa
® Have a smaller risk of osteoporosis compared to unfractionated heparin
@ Include '
i. Enoxaparin (Clexane)
ii. Tinzaparin (Innohep)
iii. Dalteparin (Fragmin)
Effects of LMWH are monitored via anti-factor Xa activity
No need for monitoring APTT coagulation parameter
© Doses of different types of LMWHs (Table 10.5)

Table 10.5 Doses of LMWHs

In Pregnancy Enoxaparin Dalteparin Tinzaparin

SSS EEE EE EE ee ee eee eee
Prophylactic dose 0.6 mg/kg o.d. 75 unit/kg o.d. 75 unit/kg o.d.
Therapeutic dose 1mg/kg b.d. 100 unit/kg b.d. 175 unit/kg o.d.
——$——
es
 Gastrointestinal agents 327

6. Tissue plasminogen activator (t-PA)

@ Catalyses the conversion of plasminogen to plasmin
Plasmin is a fibrinolytic enzyme
Encoded by PLAT gene on chromosome 8
Streptokinase is a form of tPA
Recombinant t-PAs include
i. Alteplase
ii. Reteplase
e Antidote is aminocaproic acid (an antifibrinolytic)

7, Anticoagulants in patients who have contraindications to heparin include

@ Danaparoid (is an inhibitor of activated factor X)
® Lepirudin (is a direct thrombin inhibitor)
® Fondaparinux (is an inhibitor of activated factor X)

Gastrointestinal agents

Gastro-oesophageal reflux disease drugs

1. H) receptor blockers (FDA pregnancy category B)
@ Are drugs that block the action of histamine on parietal cells in the stomach
@ Include
i. Cimetidine
ii. Ranitidine
@ Avoid cimetidine as it is an anti-androgen
@ Ranitidine is safest in pregnancy

2. Proton pump inhibitors (PPIs)

@ Act by irreversibly blocking H’/K*-ATPase of the gastric parietal cell
® Reduces gastric acid secretion by up to 99%
@ Include
i. Omeprazole (FDA pregnancy category C)
ii. Pantoprazole (FDA pregnancy category B)
iii, Lansoprazole (FDA pregnancy category B)
iv. Rabeprazole (FDA pregnancy category B)
® Vitamin B,. deficiency may occur with long-term use
e@ Avoid in pregnancy (reported cases of anencephaly)

3. Antacids
@ Are used to neutralize stomach acidity
@ Include
i. Magnesium hydroxide (milk of magnesia)
ii, Calcium carbonate (Rennie)
iii, Aluminium hydroxide (Gaviscon)
@ Can result in milk-alkali syndrome (also known as Burnett’s syndrome)
® Gaviscon is safest in pregnancy

Antiemetics
1. Most antiemetics are FDA pregnancy category B (prochlorperazine is FDA pregnancy
category C) (Table 10.6)
od 328 Chapter 10 Pharmacology

Table 10.6 Antiemetics

ee ee ee ee ee
Antiemetics Mechanism of action Side effect
SSR ON Peak eS ee Ue a ee ee
Cyclizine H, receptor antagonist Xerostomia
Drowsiness
Central anticholinergic action Antimuscarinic effects
Extrapyramidal effects

Metoclopramide | Dopamine D, receptor antagonist Extrapyramidal effects

5-HT3 receptor antagonist Hyperprolactinaemia
5-HT, receptor agonist Agranulocytosis
Is also a gastroprokinetic agent Supraventricular tachycardia
Neuroleptic malignant syndrome
Tardive dyskinesia
Oculogyric crisis (treated with procyclidine)

Ondansetron 5-HT3 receptor antagonist Constipation

Granisetron Reduces activity of vagus nerve Headache
Prochlorperazine Potent typical antipsychotic Tardive dyskinesia
Seizures
Neuroleptic malignant syndrome

Laxatives and antidiarrhoeals

1. Laxatives
® Can be divided into 4 main groups (Box 10.8)
® Lactulose is FDA pregnancy category B
® Senna is FDA pregnancy category C

Box 10.8 Groups of laxatives

© Bran ® Docusate ® Lactulose @ Senna

® Methylcellulose ® Sorbitol ® Bisacodyl
® Fybogel ® Glycerine ® Microlax enema
suppositories ® Castor oil
® Sodium phosphate

’
2. Loperamide (FDA pregnancy category B)
® {san antidiarrhoeal
Is a u-oploid agonist
Acts only on opioid receptors in the large intestine
Does not cross the blood-brain barrier (thus does not have opioid effects in the CNS)

Anti-inflammatory and immune modulators

1, NSAIDs
® Most NSAIDs are FDA pregnancy category D
@ Are non-selective inhibitors of cyclo-oxygenase (COX-1 and COX-2)
® Have antipyretic activity
® Include (Box 10.9)

2. Indometacin (FDA pregnancy category C)

e ls an NSAID
 Anti-inflammatory and immune modulators 329

Box 10.9 Types of NSAIDs

Acetic acid Enolic acid Fenamicacid ee Propionic acid

derivatives derivatives -_ derivatives : derivatives
® \Indometacin ® Piroxicam © Mefenamic acid © |buprofen
® Diclofenac ® Meloxicam ® Flufenamic acid ® Naproxen
® Ketorolac © Ketoprofen

Selective COX2
inhibitors
® Celecoxib
® Rofecoxib

® Inhibits synthesis of prostaglandin by inhibiting COX1 and COX2 enzymes

@ Used to treat a PDA post natally
@ Side effects if given antenatally
i. Premature closure of ductus arteriosus
ii, NEC
iii, Neonatal pulmonary hypertension
iv. Neonatal renal damage

3. Aspirin (FDA pregnancy category D)

@ Also known as acetylsalicylic acid
@ Isan
i. Antipyretic
ii, Anti-inflammatory
iii. Antiplatelet (inhibits synthesis of thromboxane A; irreversibly)
® Side effects
i. Gastritis
ii, Reye’s syndrome (under the age of 12)
iii. Metabolic acidosis (in overdose)
iv. Neonatal haemorrhage if given within 5 days of delivery (hence stopped at 36 weeks
gestation)
v. Miscarriage (if used under 12 weeks gestation; although interestingly low dose aspirin is
used in the treatment of recurrent miscarriage)

4, Steroids — glucocorticoid group (FDA pregnancy category C)

® Include
i, Prednisolone
ii, Dexamethasone
iii, Betamethasone
® Antenatal corticosteroid treatment in preterm deliveries is associated with reduction in
rates of
i. RDS
ii, Intraventricular haemorrhage
iii. Neonatal death
® Side effects include
i. Hyperglycaemia
ii, Leukocytosis
iii. Cushing’s
iv. Peptic ulcers
v. Osteoporosis
| 330 Chapter 10 Pharmacology

vi. Psychiatric disturbances

e Hydrocortisone cover is needed to prevent adrenal crisis in patients (taking prednisolone
dose >7.5mg/day for >2 weeks) undergoing
i. Surgical procedures
ii. Starvation
iii, Labour

5. 5-aminosalicyclic acid (FDA pregnancy category B)

® Includes
i. Mesalazine
ii. Sulfasalazine
e@ Used in treatment of
i. Ulcerative colitis
ii, Crohn’s disease
@ Side effects
i. Agranulocytosis
ii. Hypospermia

6. Chemo-therapeutic agents include

e Alkylating agents (FDA pregnancy category D)
i. Cisplatin
ii. Carboplatin
iii. Cyclophosphamide
iv. Chlorambucil
@ Antimetabolites (interfere with DNA production during the S-phase of the cell cycle)
i. Purine analogues (azathioprine)
ii. Pyrimidine analogues (5-fluorouracil)
iii, Antifolates (methotrexate)
® Alkaloids (block cell division by preventing microtubule function)
i. Vincristine (FDA pregnancy category D)
ii, Vinblastine (FDA pregnancy category D)
iii, Podophyllotoxin
iv. Paclitaxel
® Topoisomerase inhibitors (FDA pregnancy category D)
i. Topotecan
ii, Irinotecan
iii. Etoposide ;
® Antineoplastic (FDA pregnancy category D)
i. Doxorubicin
ii, Bleomycin

7, Azathioprine (FDA pregnancy category D)

® Interferes with purine synthesis
® sa prodrug
i. Active metabolite is 6-mercaptopurine and 6-thioionosinic acid
ii, Metabolized by xanthine oxidase
® Side effects
i. Bone marrow suppression
ii. Carcinogenic

8. Mycophenolate mofetil (FDA pregnancy category C)

@ Interferes with purine synthesis (by inhibition of inosine monophosphate dehydrogenase)
® ls a prodrug (active metabolite is mycophenolic acid)
® Less toxic that azathioprine
 Endocrine agents 331

9. Methotrexate (FDA pregnancy category X) side effects (Box 10.10)

Box 10.10 Side effects of methotrexate

Bone marrow ie —< :

®@ Anaemia ® Hepatitis © Pericarditis © DVT

© Leukopenia © Pancreatitis ® Pericardial effusion ® Retinal vein
® Thrombocytopenia ® Pharyngitis ® Pulmonary fibrosis thrombosis
® Gingivitis ® Cerebral thrombosis
® Stomatitis

Endocrine agents

Table 10.7 Endocrine agents

Drug Mechanism of action Side effects Fetal risk

Carbimazole Prodrug Bone marrow FDA pregnancy

Active form = methimazole suppression cat. D
Prevents thyroid peroxidase enzyme _—_ (agranulocytosis)
from coupling and iodinating
tyrosine residues on thyroglobulin
Reduces production of T3 and 14

Propylthiouracil Inhibits thyroperoxidase enzyme Agranulocytosis FDA pregnancy

(PTU) Inhibits peripheral conversion cat. D (preferred
of T4 to T3 by inhibiting over carbimazole
tetraiodothyronine 5’ deiodinase as has lower
enzyme placental transfer
and excretion in
breast milk)
Metformin Is a biguanide agent Hypoglycaemia FDA pregnancy
Suppresses hepatic gluconeogenesis Lactic acidosis cat. B
(via activation of AMP-activated Gastrointestinal
protein kinase) upset
Increases insulin sensitivity
Enhances peripheral glucose uptake
Increases fatty acid oxidation
Is not metabolized and excreted
unchanged in the urine
Reduces overall mortality by 30%
when compared to insulin
Reduces LDL cholesterol and
triglycerides

Glibenclamide Is a sulfonylurea class of drug Hypoglycaemia FDA pregnancy

Stimulates insulin release by Cholestasis cat. B
inhibiting ATP-sensitive K+
channels in the pancreatic B cells
Metabolized by the liver

(continued)
a 332 Chapter 10 Pharmacology

Table 10.7 Continued

Drug Mechanism of action Side effects Fetal risk

Rosiglitazone Is a thiazolidinedione agent Increased risk FDA pregnancy

Decrease insulin resistance of myocardial cat. C
and leptin levels by binding to infarction (by 43%)
peroxisome proliferator-activated Stroke
receptors (PPAR) in the fat cell Bone fractures
nucleus Macular oedema
Hepatotoxic
Repaglinide Is a meglitinide agent Hypoglycaemia FDA pregnancy
Stimulates insulin release by Weight gain cat. C
inhibiting ATP-sensitive K+
channels in the pancreatic B cells
Acarbose Reduces the rate of digestion of Flatulence FDA pregnancy
complex carbohydrates by Diarrhoea cat. B
inhibiting O&-glucosidase enzyme in
the small intestines
Inhibits pancreatic amylase
Metabolized in the GIT

Vildagliptin Is a dipeptidyl peptidase-4 (DPP-4) Pancreatitis FDA pregnancy

inhibitor cat. B

Exenatide Is an incretin Pancreatitis FDA pregnancy

Is a glucagon-like peptide agonist Possible increase in cat. C
Increases pancreatic insulin secretion thyroid cancer risk
Suppresses pancreatic release of
glucagon

Drugs used in gynaecology

1. Mifepristone (FDA pregnancy category X)

Is a competitive progesteronic receptor antagonist
Causes
i, Cervical softening and dilatation
ii. Decidual degeneration
iii, Release of endogenous prostaglandins
iv. Increased sensitivity of myometrium to prostaglandins
Is an
i. Anti-glucocorticoid
ii, Anti-androgen
Used in
i, Emergency contraception
= Delays ovulation
® Prevents implantation
ii, Medical termination (600 mg)
= Up to 9 weeks gestation
Contraindications
i. Severe asthma
ii. Chronic adrenal failure
 Drugs used in gynaecology 333 oo

iii, Ectopic pregnancy

iv. Acute porphyria
v. Hepatic impairment
vi. Renal impairment

2. Cyproterone acetate (FDA pregnancy category X)

@ san anti-androgen
i, Suppresses action of testosterone and DHT on tissues
ii, Suppresses LH
@ Used in
be
ii. Prostate cancer
iii, Priapism
iv. Hirsutism
® Has a weak progestogenic activity (can be used to treats hot flushes)
® Suppresses synthesis of
i. Cortisol
ii. Aldosterone
iii. Oestrogen
@ Side effects
i. Hepatotoxicity
ii. Low cortisol
iii. Low aldosterone
= Loss of sodium
& Hyperkalaemia
iv. Gynaecomastia
vy. Galactorrhoea
vi. Osteoporosis
vii. Thrombosis (only if given with oestrogen)

Hormone therapy
1. Tibolone
® Also known as Livial
® ls aselective tissue oestrogenic activity regulator (STEAR)
® Used as
(oly
ii, Osteoporotic prevention
@ Has oestrogenic, progestogenic, and androgenic properties
®@ Functions
i. Relives climacteric symptoms
ii, Prevents osteoporosis
iii, No endometrial stimulation
iv. Non-oestrogenic effects on breast tissue

2. SERMs
@ Include
i. Raloxifene
ii. Tamoxifen
iii, Clomifene (acts via blocking oestrogen leading to an increase in FSH)
® Have both oestrogen and anti-oestrogen activity
® Excreted via faeces
 ~—
co 334 Chapter 10 Pharmacology

e@ Used for
i. Prevention of osteoporosis
ii. Decreasing risk of breast cancer
® Side effects
i. Thrombosis
ii. Endometrial carcinoma (tamoxifen)
iii. Hot flushes

3. Danazol
@ |s derived from a synthetic ethisterone, which is a modified testosterone
@ Has a weak androgenic activity
® sa gonadotrophin antagonist
®@ Acts on the pituitary gland and inhibits LH and FSH causing inhibition of ovarian
steroidogenesis, resulting in decreased secretion of oestradiol
Does not affect pituitary hormones
® Used to treat
i. Endometriosis
ii. Uterine fibroids
iii. Menorrhagia (induces amenorrhoea)
® Does not cause osteoporosis
Can masculinize a female fetus
@ Side effects
i. Fluid retention
ii. Weight gain
iii. Masculinizing side effects

4. Buserelin
® |sa GnRH agonist
® Acts on the pituitary
i, Initially causes increase of LH and FSH levels
ii, Eventually after 21 days
B® Receptor downregulation occurs
™ LH and FSH levels decrease
@ Used to treat
i. Prostate and breast cancer
ii. Endomeitriosis
iii. Uterine fibroids
Maximum duration of treatment is 6 months
® Side effects
i. Menopausal symptoms
ii, Osteoporosis

Tein
Ob: .
Gin Contraceptives
Chpt 4

General facts about contraceptives

1. Pregnancies in the UK
® Unplanned = 30%
® Unplanned pregnancies due to contraceptive method failure = 10%
@ Termination rate = 2%

2. Methods of contraception include

® Combined oral contraceptive pill (COCP)
 Contraceptives 335 a

® Progesterone only
i, Progesterone only pill (POP)
ii. Injection (Depo-Provera)
iii. Implant (Implanon)
® Intrauterine coils
i. Devices (IUCD; copper based)
® ji. Systems (IUS; progesterone based)
® Barrier plus spermicide
i. Condom
ii, Femidom
iii, Diaphragm
iv. Sponge
Coitus interruptus (withdrawal method)
Sterilization
Thermo-regulation (Billings’ method)
Lactational amenorrhoea method

3. The pearl index is the number of unwanted pregnancies per 100 women using the method
of contraception for 1 year (Table 10.8)

Table 10.8 Pearl indexes for different contraceptive methods

Contraceptive methods Pearl Index

Oral G@ GCP 0.1-1.5

POP 1.5-3

Intra-uterine IUS 0.1

IUCD <3

Implanon <0.1

Depo-Provera Oat

Barriers Condom 4-10

Diaphragm 8-20

Sterilization <0.5

Withdrawal 10-20

Thermo-regulation 20-30

COCP
1. Mechanism of action
® Inhibits ovulation (by suppressing FSH and LH)
® Increases viscosity of cervical mucus

2. Contraindications
@ Pregnancy
@ Post partum
i. Breastfeeding <6 weeks post partum
ii, Non-breastfeeding <3 weeks post partum
@ Smoking >15/day above the age of 35
© BMI >35
i 336 Chapter10 Pharmacology

@ Arterial disease
i, >2 risk factors for cardiovascular disease
ii. Ischaemic heart disease
iii, Stroke
® Hypertension
i. Systolic BP >160 mmHg
ii. Diastolic BP >95 mmHg
@ Valvular heart disease with
i. Pulmonary hypertension
ii. Subacute bacterial endocarditis
Venous thromboembolism
Migraine with aura
Cancer
i. Breast
ii, Malignant hepatoma
® Cirrhosis
Raynaud’s disease
® SLE

3. COCPs can be used in the following cancers

® Cervical
®@ Endometrial
® Ovarian
® Gestational trophoblastic disease

4. Generations of COCPs
@ First (contain high dose of oestrogen 50 yg)
i. Ovran
ii. Norinyl
® Second (contains standard dose of oestrogen 30-35 yg)
i, Gilest
ii, Loestrin
iii. Logynon
iv. Microgynon
v. Microgynon ED
vi. Norimin
@ Third (contains new forms of progesterone)
i. Femodene
ii. Femodene ED
iii, Marvelon
iv. Mercilon

5. Oestrogen content in COCPs

® Low = 20ug
® Standard = 30-35 pg
® High = 50yg

6. Progesterone content in COCPs

® First and second generation
i, Levonorgestrel
ii, Norethisterone
® Third generation
i. Desogestrel
 Contraceptives 337

ii. Gestodene
ili. Norgestimate

7. Third generation progesterones

® Increase risk of venous thrombosis
® Reduce the incidence of
i. Acne
ii Headache
ili, Weight gain
iv. Breast symptoms
v. Breakthrough bleeding

8. Missed pill rule

® If missed <3 pills (2 if taking a low oestrogen content COCP)
i. Take missed pill
ii. No need extra precaution
® If missed >3 pills (2 if taking a low oestrogen content COCP)
i. Take missed pill
ii, Extra precaution for 7 days
iii. If in third week omit pill-free interval
iv. If in first week use emergency contraception

9. Risk of venous thromboembolism

@ Background risk is 5 in 100000
® On COCcP
i. Second generation is 15 in 100000
ii. Third generation is 25 in 100000
®@ In pregnancy is 60 in 100000

10. Decreased risk of

® Ovarian cancer by 40-80% in user >10 years
® Endometrial cancer
i. By 50%
ii, Benefit last for 20 years after discontinuing COCP

11. Increased risk of

@ Breast cancer
i. Risk falls to normal after 10 years of discontinuing COCP
ii. No increased risk with oestrogen alone
® Cervical cancer (unclear at the moment)

Progesterone-only contraception
1. Mechanism of action
@ |nhibits ovulation
i. Low-dose progesterones inconsistently inhibit ovulation in 50% of cycles
ii, Intermediate-dose progesterones (Cerazette and Implanon) inhibit ovulation in 97-99%
of cycles
iii. High-dose progesterones (Depo-Provera) completely inhibit ovulation and follicular
development
® Increases viscosity of cervical mucus

2. Side effects
® Irregular bleeding
® Weight gain
 =
ce 338 Chapter10 Pharmacology

® Breast discomfort
® Depression
@ Acne
ns
3. Can be used within 3 weeks of delivery without any extra precautio

4. Oral progesterone-only contraception

e Includes
i. Etynodiol diacetate (Femulen)
ii. Norethisterone (Micronor)
iii, Levonorgestrel (Norgeston)
iv. Desogestrel (Cerazette)
® Contraindications
i. Pregnancy
ii, Undiagnosed vaginal bleeding
iii. Liver tumour
iv. Acute porphyria
v. History of breast cancer (can be used after 5 years of disease remission)
® Safety window is 3h except for Cerazette where it is 12h

5. Missed pill rule

@ POP has a short time frame (3h) except for Cerazette (12h)
@ After a missed pill
i. Take the missed or late pill
ii. Extra precaution should be used for 48h

6. Bleeding patterns on POP

@ Amenorrhoea in 20%
® Regular bleeding in 40%
® Erratic bleeding in 40%

7. Parental progesterone-only contraception

@ Includes
i. Medroxyprogesterone acetate i.m. injection (Depo-Provera)
ii. Norethisterone enantate i.m. injection — lasts 8 weeks
iii. Etonogestrel-releasing implant (Implanon) — effective up to 3 years
® Reliably inhibits ovulation

8. Medroxyprogesterone acetate (Depo-Provera)

® Is given i.m.
® Lasts for 12 weeks
® Timing of injections
i, Given 5 days post partum in non-breastfeeding women
ii. If given <6 weeks post partum, risk of menorrhagia increases
® Side effects
i. Weight gain (2kg/year) in 70%
li, Osteoporosis (hence avoid use for more than 2 years)
iii, Delay in return to fertility by 6-18 months
® Bleeding patterns with Depo-Provera
i, Irregular bleeding
ii, Amenorrhoea in 55% at 12 months
iii. Amenorrhoea in 68% at 24 months
® 60% conceive within 12 months of discontinuation
84% conceive within 24 months of discontinuation
 Contraceptives 339

© Decreases serum oestrogen level due to its complete inhibition effect on ovulation
@ Associated with reduction in bone density within the first 2 years of use
® Reduces risk of endometrial cancer by 80%
9. Implanon
® Contains etonogestrel 68mg
® Lasts for 3 years
® Serum levels of progesterone
i. Reach ovulation-inhibiting levels within 24h of insertion
ii, Reach peak levels within 1-13 days
iii, Decline within 1 week of implant removal
® 90% start to ovulate within 3 weeks of removal
@ Bleeding patterns on Implanon
i. Amenorrhoea in 20%
ii. Prolonged bleeding in 20%
iii, Infrequent bleeding in 5%

Intrauterine coils
1. Two types
®@ Devices (copper based)
® System (progesterone based)

2. Insertion
®@ |mmediately after first or second trimester abortion
@ From 4 weeks post partum
@ Atany time in the menstrual cycle
® Extra precaution is not needed for
i. Copper coil (is effective immediately)
ii. Mirena if inserted on day 1 of cycle (otherwise will need 7 days precaution)

3. Complications
@ Risk of expulsion is
i, 5%
ii, Common in the first year (especially within the first 3 month)
® Risk of uterine perforation is 1 in 1000
@ Risk of pelvic infection is greatest in the 20 days post insertion

4. Intra-uterine coil device

® Contains copper
®@ Mode of action
i. Copper is toxic to ovum and sperm
ii. Inhibits fertilization
iii. Inhibits implantation
@ Irregular or heavy bleeding is common in the first 3-6 months
Licensed for 7-10 years’ use depending on brand

5. Intrauterine coil system (Mirena)

® Contains a compartment which gradually releases levonorgestrel
® Mode of action
i. Mediated via progestogenic effect on endometrium
ii. Endometrial atrophy occurs within 1 month of insertion
iii. Increase in endometrial phagocytic cells
iv. Increase cervical mucus viscosity
v. 75% still continue to ovulate
 340 Chapter10 Pharmacology =

Lasts for 5 years

Bleeding patterns
i. Irregular bleeding is common in the first 6 months
ii, Amenorrhoea in 65% at 12 months

Emergency contraception
as Emergency contraception methods include
Levonorgestrel 1500 yg (within 72h of unprotected sexual intercourse)
Yuzpe’s regimen
Copper intrauterine device (within 5 days of unprotected sexual intercourse or within 5
days of ovulation)
EllaQne

Levonorgestrel 1500 yg
Efficacy of use
i. Within 24h = 95% effective
ii, 24-48h = 85% effective
ili, 49-72 h = 58% effective
Inhibits ovulation for 5-7 days if taken prior to ovulation
Women taking liver enzyme inducers should take 3000 yg of levonorgestrel within 72h
Side effects
i. Nausea in 14%
ii. Bleeding within 7 days of taking levonorgestrel in 16%
Timing of next menses
i. Within the expected date = 80%
ii, Within 7 days after the expected date = 95%

. EllaOne
Contains ulipristal acetate 30mg
Is a selective progesterone receptor modulator (SPRM)
Can be used up to 120h after unprotected sexual intercourse
Mode of action
i, Inhibits ovulation
ii, Suppresses growth of follicles
ili. Delays endometrial maturation
 CHAPTER 11

Intrapartum science

CONTENTS
Labour 341
Electronic fetal monitoring 343

Labour
oi
bs
Gy, General facts
Chet ?.1 4, Labour is also known as parturition
2. Is diagnosed retrospectively by detection of
® Cervical dilatation
® Cervical effacement

3. Labour is divided into 3 stages

@ Stage 1 (effacement and dilatation of the cervix up to full dilatation — 10 cm) — divided in to
i. Latent phase (dilatation up to 4cm)
ii, Active phase (dilatation from 4cm onwards)
® Stage 2 (from full cervical dilatation to delivery of the fetus) — divided into
i. Propulsive phase
ii, Expulsive phase (delay is defined if the expulsive phase last > 2 h in nulliparous and > 1h
in multiparous women)
® Stage 3 (delivery of placenta)

4. The angulation of the birth canal is known as the curve of Carus

5. Mechanism of labour
@ Engagement
i, The transverse or oblique diameter of the fetal head enters the pelvic brim
ii Asynclitism occurs prior to engagement
Descent of fetal head to below the ischial spines and flexion
Fetal head rotation to the occipito-anterior position, shoulders enter pelvis
Extension and delivery of fetal head
Restitution
Delivery of shoulders and rest of body

=oan Disorders of labour

Obs
©, 1. Labour dystocia
shpt 9.4 ® 3 patterns have been described
 ra
342. Chapter 11 Intrapartum science

i. Prolonged latent phase

ii. Primary dysfunctional labour
iii, Secondary arrest
@ Prolonged latent phase
i. Incidence = 3.5% in nulliparous women
ii, Relates to delayed cervical ripening
iii, Augmentation with oxytocin is not beneficial
e Primary dysfunctional labour
i. _Is cervical dilatation slower than 1cm/h during the active phase of stage 1 of labour
ii, Incidence = 26% in nulliparous women and 8% in multiparous women
@ Secondary arrest ;
i. Incidence = 6% in nulliparous women and 2% in multiparous women
os ii, Usually linked with fetal malposition
Sm :
Cpe 827 2. Breech presentation
& 911 @ Incidence at
i. 28 weeks = 30%
ii, Term = 3%
®@ Aetiology (Box 11.1)

Box 11.1 Aetiology of breech presentation

Fetal structural Fetal growth

P related Pt
ality neuen tend Sea “tO mt

® Increased parity ® Hydrocephalus @ FGR @ Placenta praevia

® Multiple pregnancy @ Myelomeningocoele © Oligohydramnios ® Short umbilical cord
®@ Prematurity ® Polyhydramnios

© Bicormuate uterus
ribo
® Contracted pelvis

@ Types of breech
i. Extended (or frank breech) = 60-70%
ii, Flexed (or complete breech)
iii, Footling
e Fetal risks of vaginal breech delivery
i. Intracranial haemorrhage
ii, Brachial plexus injury
iii, Limb fractures
iv. Spinal cord injury

3. Reasons for predominance of cephalic presentation

@ Piriform shape of uterus
he ® Calcification of fetal skull (increased skull density)
Obs
Sm 4. Shoulder dystocia
Chpt 10.4 ® Occurs when there is failure of the shoulders to deliver with gentle downwards traction on
the fetal head
@ Incidence = 0.6%
@ Anterior shoulder is commonly involved
 Electronic fetal monitoring 343 Bee

@ Signs
i. External rotation failure
ii, Turtle necking
® Can cause fetal distress due to a reduction in O, supply caused by
i. Uterine contraction
ii, Fetal chest compression
® Fetal complications
i. Asphyxia
ii, Brachial plexus injury
iii, Fracture of clavicle (in 15%) and humerus (in 1%)
@ Brachial plexus injury
i. Occurs in 10% of shoulder dystocia
ii, Permanent neurological damage occurs in 10% of brachial plexus injury
iii, Caesarean section does not eliminate the risk of brachial plexus injury
@ Risk factors
i. Conventional risk factors predict 15% cases of shoulder dystocia
ii, Fetal macrosomia (but note that 48% of shoulder dystocia cases occur in fetuses <4kg)
iii. Maternal diabetes
iv. Maternal obesity
v. Previous shoulder dystocia
vi. Prolonged labour
vii. Instrumental delivery
@ 2300 caesarean sections need to be performed to prevent 1 permanent neurological injury
from shoulder dystocia
®@ Recurrence rate = 15%
@ Fetal pH drops at a rate of 0.04/min

Electronic fetal monitoring

General facts
1, Fetal physiology in labour
® Maternal placental blood flow
i. Is 500mL/min
ii, Stops when uterine contraction exceeds 30 mmHg
® Fetus needs 60-90s between contractions to regain normal blood gases
@ Umbilical cord circulation
i. Is not affected by contractions in first stage of labour
ii, Stops during active stage of pushing (especially in the umbilical vein)
® Cell metabolism
i, Fetal glycogen stores are generated in the third trimester (therefore the preterm fetus
has less glycogen stores)
ii. In hypoxic conditions the fetus undergoes anaerobic metabolism, utilizing blood glucose
and stored glycogen to produce energy
iii. The energy produced via anaerobic metabolism is 1/20th of that produced via aerobic
metabolism

2. Fetal response to
@ Hypoxaemia (decrease in the O, content of arterial blood with normal cell and organ
function) (Fig. 11.1)
@ Hypoxia (OQ deficiency which affects peripheral tissues) (Fig. 11.2)
 344 Chapter11 Intrapartum science Eee
|

Reduced activity (decreased

: Ws, Effective uptake of O72 fetal movements and decreased Decreased growth rate
fetal breathing)

Figure 11.1 Fetal response to hypoxaemia

Surge ofstress hormones Redistribution of blood Peripheral tissue

Reduction in peripheral flow in favour of central
(increased sympathetic blood flow anaerobic metabolism
: activity) ; organs

Figure 11.2 Fetal response to hypoxia

Maximum activation Anaerobic Utilization of

Cardiovascular
_ of sympathetic metabolism in glycogen reserves in
failure
nervous system central organs liver and heart

Figure 11.3 Fetal response to asphyxia

@ Asphyxia (when the cellular energy production is no longer sufficient to meet the fetal
demands) (Fig. 11.3)

3. Criteria for diagnosis of acute intrapartum hypoxia causing brain damage

® Evidence of metabolic acidosis in umbilical arterial vessels
ib fell s// ‘
ii, Base excess >12
@ Early onset of severe or moderate neonatal encephalopathy in term babies
® Cerebral palsy of spastic quadriplegic or dyskinetic type

4, Spalding sign on X-ray represents overlapping of fetal skull bones in advanced maceration of
Tin fetal tissues

Cardiotocography (CTG)
ue 1. CTG records
® Fetal heart rate (by recognizing R-R interval on the ECG)
® Uterine contractions

2. Consists of 2 transducers
® Heart ultrasonic sensor
® Tocodynamometer

3. Speed of recording is usually 1cm/min

 Electronic fetal monitoring 345 ee

4. CTG has a high false-positive rate (about 50%)

5. Baseline heart rate

®@ Is defined as a fetal heart rate recorded between contractions over a period of at least
10 min
® Tachycardia is defined as a baseline fetal heart rate >160 bpm
@ Bradycardia is defined as a baseline fetal heart rate <110 bpm
6. Variability
® ls the beat-to-beat variation of the fetal heart beat
® Normal variability is 5-25 bpm
® Variability >25 bpm is known a saltatory pattern
® Reduced variability (i.e. <5 bpm) is seen in
i, Sleep cycle
ii, Preterminal pattern
® Sinusoidal pattern
i, Seen in fetal anaemia or feto-maternal haemorrhage
ii, Has a frequency of 3-5 cycles/min
iii. Seen as a smooth undulating sine wave pattern

7. Accelerations
® Defined as an intermittent increase in heart rate of more than 15 beats lasting for
more than 15s
@ Areactive CTG should contain 2 acceleration in a 20-min period
® Sign of adequate oxygenation

8. Decelerations
® Defined as a drop in heart rate of more than 15 beats lasting for more than 15s
© Consist of 3 types
i. Early
ii, Late
iii. Variable
® Early decelerations
i. Areflex generated drop in heart rate that occurs during a contraction
ii. The nadir of the drop in heart rate corresponds to the peak of the uterine
contraction
iii. Are not related to hypoxia
iv. Are due to mechanical forces acting on the fetus
@ Late decelerations
i, Often signify hypoxia
ii, May be associated with placental insufficiency
® Variable decelerations
i. Are classified as uncomplicated or complicated
ii. Account for 80% of all decelerations
iii. Uncomplicated variable decelerations last for <60s
iv. Are due to cord compression
yv. Risk of hypoxia increases if decelerations last for >60s

9. CTG is classified according to the National Institute for Health and Clinical Excellence
(NICE) guidelines into 3 categories (Box 11.2)
® Normal (when all 4 features are reassuring)
@ Suspicious (when 1 feature is non-reassuring)
@ Pathological (when 1 feature is abnormal or >2 features are non-reassuring)
 346 Chapter11 Intrapartum science =

Box 11.2 CTG features

° "Baseline = 110-160 oe © Baseline = 100-109 or ® Baseline <100 or > 180 bpm

® Variability =5-25 bpm 161-180 bpm @ Sinusoidal pattern for >10 min
® No decelerations ® Variability <5 bpm for >40 min © Variability <5 bpm for 90 min
® Accelerations present but <90 min © Late or atypical variable
© Early decelerations decelerations with over 50% of
© Variable decelerations with over the contractions occuring for
50% of the contractions occuring 30 min
for 90 min © Single prolonged deceleration
© Single prolonged deceleration over 3 min
up to 3 min

10. There are 4 patterns of hypoxic changes on the CTG

® Acute (when there is a sudden acute drop in baseline) — fetal pH drops by 0.01/min
® Subacute (when the fetal heart rate stays below the baseline during the majority of the
time) — fetal pH drops by 0.01 every 2-3 min
® Evolving — shows the following sequence of changes (Fig. 11.4)
® Chronic

Loss of accelerations Tachycardia Loss of variability

Figure 11.4 Sequence of CTG changes in evolving hypoxia

11, Acute Hypoxia aetiology

® Unknown (50%)
Placental abruption
Scar dehiscence/rupture
Cord prolapse '
Uterine hyperstimulation
Epidural top-up

12. Evolving hypoxia has 3 stages

© Stress stage (is the presence of decelerations without a rise in baseline)
® Distress stage
i. Reaches maximum tachycardia (usually 20-30 bmp above baseline)
ii, Marked reduction in baseline variability (< 2 bpm)
® Collapse stage
i, Is the sudden decline in fetal heart rate in a step-wise manner to terminal bradycardia
ii, Is usually short (20-60 min from the onset of fetal heart decline)
iii, Also known as Hon’s step-ladder pattern to death

ST analysis (STAN)
1, Is based on the concept that the ST interval of the fetal ECG reflects the function of the
fetal myocardium during stress
 Electronic fetal monitoring 347 oe

2. It combines fetal heart rate interpretation along with ST interval analysis

3. The analysis takes into account 30 ECG complexes at a time and calculates the T/QRS ratio

4. Physiology of ST interval changes in hypoxia

® Hypoxia causes fetal adrenaline surge and myocardial anaerobic metabolism
Adrenaline surge activates glycogenolysis
Increased glycogenolysis causes increased K* release
Increased plasma K* leads to an increase in T-wave amplitude
Rate of increase in T-wave amplitude depends on the amount of glycogen the fetus needs to
utilize to maintain its myocardial energy balance

5. There are 3 types of STAN event

@ Biphasic ST
® Baseline rise in T/QRS ratio
® Episodic rise in T/QRS ratio

6. Biphasic ST events
® Seen
i. In initial phase of hypoxia
ii, When fetus is not capable of responding to hypoxia
iii. In myocardial dysfunction, due to cardiac malformation or infections
® There are 3 grades
® Repeated grade 2 and 3 events should be regarded as a sign of abnormality

7. Baseline rise in T/QRS ratio

® Occurs when there is a rise in the T/QRS ratio lasting for more than 10 min
® Reflects fetal response to hypoxia with anaerobic metabolism
@ fit is more than 0.05 it is significant

8. Episodic rise in T/QRS ratio

® Occurs when the rise in the T/QRS ratio returns to baseline within 10 min
Reflects fetal distress
If it is >0.10 it is significant
Corresponds to short-lasting hypoxia
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CHAPTER 12

Medical physics and

clinical applications

I eS

CONTENTS
Ultrasound 349
lonizing radiation 358
Non-ionizing radiation 364

Ultrasound

General facts ofultrasound

1. Physics of sound
The human ear can detect frequencies between 20 and 20 kHz
Ultrasound frequencies are those above 20 kHz
Range normally used in medical imaging is between 2 and 15 MHz
Ultrasound waves are longitudinal compression waves
Speed of sound in all tissues is assumed to be 1540 ms”
C = fA (where ¢ = speed of sound; f = frequency; A = wavelength)
Ultrasound imaging uses the pulse echo principle

2. Ultrasound probes consist of 2 elements

@ Transducer (made from materials that exhibit piezoelectric behaviour; e.g, quartz or
ceramic)
® Receiver

3. Acoustic intensity
®@ ls the measure of energy flux over a certain time period
® |s defined as sound power per unit area
® The Sl unit is watts per square meter (W/m”)

4, Frame rate
® ls the frequency at which an imaging device produces unique consecutive images (frames)
® ls expressed in frame rates per second
@ The higher the resolution the longer it takes for the ultrasound probe to generate an image
limiting the maximum achievable frame rate. Hence, there is a trade-off between resolution
and frame rate (relevant when imaging fast moving objects such as the heart)

5. Interaction of ultrasound wave with tissue (Figs 12.1 and 12.2)

® Reflection
i, Is the change in direction of a wavefront at an interface between two different media so
that the wavefront returns into the medium from which it originates
 350 Chapter 12 Medical physics and clinical applications

Medium 1

Incident wave

Angle of incidence

Angle of reflection

Reflected wave

Figure 12.1 Wave reflection and refraction

Wave diffraction through a narrow gap

Wave diffraction as it goes past an object

Figure 12.2 Wave diffraction

 Ultrasound 351

i, The law of reflection states that the angle at which the wave is incident on the surface
equals the angle at which it is reflected
iii. Strength of reflection from an object depends on its acoustic impedance
© Refraction is the change in direction of a wave due to a change in its speed as it passes from
one medium to another
® Diffraction
i. 1s the apparent bending of waves around small obstacles and the spreading out of waves
past small openings
ii. Occurs when a wave encounters an obstacle that has a diameter comparable to its
wavelength
iii. Higher frequency waves are rarely diffracted
iv. Only changes the direction in which the wave is travelling
® Scatter
® Absorption is defined as the direct conversion of sound energy into heat as it travels though
a medium

6. Ultrasound can produce biological effects in 3 ways

® Cavitation (i.e. the growth, oscillation and decay of small gas bubbles under the influence of
an ultrasound wave)
@ Microstreaming (is the formation of small local fluid circulations and can be both intra- and
extracellular)
© Heating

7. Ultrasound is limited by its inability to image through

® Air
@ Bone

8. 3-dimensional ultrasound imaging consists of a sweep of multiple 2-dimensional scans

in parallel and then reconstruction of a third Z-plane, creating a volume box containing
3-dimensional voxels instead of 2-dimensional pixels

9. 4-dimensional ultrasonography is 3-dimensional ultrasonography with the 4th dimension

being time

General facts about Doppler

1. Physics of Doppler ultrasonography
© The Doppler effect is based on the fact that reflected or scattered ultrasound waves from a
moving interface will undergo a frequency shift
® Doppler shift is the change in frequency of a wave for an observer moving relative to the
source of the wave
Used in medicine to detect and measure blood flow (RBCs are the major reflectors)
® Doppler shift is dependent on the
i. Insonating frequency
ii. Velocity of moving blood
iii, Angle between sound beam and direction of moving blood
© Doppler shift frequency is the difference between the transmitted and received frequencies

2. There are 3 types of Doppler mode in ultrasound machines

® Pulse
® Power
@ Colour

3. Factors affecting the displayed Doppler image in ultrasound machines

® Transmitted power
oo 352 Chapter 12 Medical physics and clinical applications a

® Doppler gain (influences the overall sensitivity)

Frequency (the higher the frequency, the higher the resolution and the lower the
penetration)
Velocity (also known as pulse repetition frequency)
Sample gate
i. Influences axial resolution of Doppler signal
ii. The higher the sample gate the higher the resolution is but at the expense of a lower
frame rate
® Wall filter

4. Pulse Doppler
@ Allows a sampling gate to be positioned over a vessel visualized on the grey-scale image.
The amplitude of the signal is approximately proportional to the number of
moving RBCs
® Provides information on
i. Direction of blood flow
ii. Velocity of blood flow
iii. Flow characteristics
® Is angle dependent (flow perpendicular to transducer is difficult to detect)

5. Power Doppler
@ Also known as energy or amplitude Doppler
® Allows detection of a larger range of Doppler shifts and thus better visualization of small
vessels, but at the expense of directional and velocity information
® Advantages
i, Free from aliasing
ii, No angle dependences
iii, Higher sensitivity to detect low flow or small blood vessels
iv. Better penetration
® Disadvantages
i. No directional information
ii, No velocity information

6. Colour Doppler
® Provides an estimate of the mean velocity of flow within a vessel by colour coding the
information and displaying it superimposed on the grey-scale image
® The flow direction is arbitrarily assigned the colour red or blue, indicating flow toward or
away from the transducer, respectively.
® Also provides information on
i, Overall view of flow in an organ
ii, Direction of flow
iii. Velocity of flow
® Disadvantages
i, Poor temporal resolution
ii. Is angle dependent

Ultrasound imaging measurements in non-pregnant pelvis

1. Endometrial thickness
® During the reproductive age it ranges between 5 and 14mm
® In postmenopausal women it is <4mm

2. Ovarian follicles
@ Are simple anechoic areas within the ovaries with clear and well-defined walls
 Ultrasound 353

® Grow ata rate of 2mm/day

® Reach a maximum diameter of 20-25 mm before ovulation

3. Corpus luteum can be

® Solid
® Cystic
® Haemorrhagic

4, Ultrasound imaging is used in all stages of in vitro fertilization (IVF) treatment to monitor
oocyte development, retrieval, and transfer
® Stage1 (pituitary desensitization)
i. Patient is given GnRH agonist
ii, This stage of treatment lasts for 2 weeks
® Stage 2 (ovarian superovulation)
i. Achieved with daily injections of gonadotrophin
ii, hCG is given prior to oocyte collection when the largest follicle is 18mm and
endometrial thickness is 6mm
® Stage 3 (oocyte collection)
i. Oocytes are retrieved 36 hours after hCG injection
® Stage 4 (embryo transfer)
i. Performed 2-3 days after oocyte collection
®@ Stage 5 (post embryo transfer)
i. Progesterone supplements are given to support corpus luteal function

Ultrasound imaging measurements in early pregnancy

1. Gestational sac
© Detected transvaginally from 31 days (4*? weeks) of gestation when it measures 2-3 mm
® Detected transabdominally from 5** weeks
® Grows 1mm/day in diameter
® Consist of 2 fluid-filled compartment
i. Inner amniotic cavity
= From 8 weeks gestation it expands rapidly within the chorionic cavity such that it
soon occupies most of the gestational sac
ii. Outer chorionic cavity
= Dominates in early pregnancy
iii. Fusion of chorionic and amniotic membrane
m By the end of the first trimester
=" Obliterates chorionic cavity
© Used to calculate gestational age before embryo is visible

2. Yolk sac
® Becomes visible in chorionic cavity transvaginally at 5 weeks gestation (when it measures
34mm)
@ Should be seen in all pregnancies with a gestation sac diameter >12 mm
® Grows until it reaches a maximum diameter of 6mm (at 10 weeks gestation)

3. Embryonic pole
® ls usually visible when gestational sac diameter is >18 mm
® Can be visualized transvaginally at 37 days gestation (usually measuring 2-3 mm)
® Crown rump length (CRL) is used as a measure of gestation before 12 weeks but is
unreliable after this (as the fetus is more likely to be in a flexed position)
® Biparietal diameter (BPD) is used for measuring gestational age after 12 weeks gestation
 354 Chapter 12 Medical physics and clinical applications

4. Heart action
e |s detectable at 5°* weeks gestation
@ Should be visualized in all embryos of crown—rump length (CRL) >6mm in length

5. Fetal spine can be identified from 9 weeks gestation

Tin
= 6. Nuchal translucency
Chpt 6.12 @ |s increased in chromosomal abnormality (e.g. trisomy 21, 18, Turner’s syndrome) between
11 and 14 weeks of gestation
® Nuchal thickness >6mm - linked to
i. Chromosomal abnormalities
ii. Cardiac anomalies
iii. Fetal viral infection
iv. Rhesus incompatibility
7. Risk of miscarriage based on ultrasound findings of
© Empty gestation sac = 12%
O (ENE
i. <Smm=7%
ii, >10mm= 1%

8. Early pregnancy ultrasound imaging findings for

@ Embryonic death (based on the Royal College of Obstetrics and Gynaecologists guidelines)
i, Absence of cardiac activity in an embryo with a CRL >6mm
ii. Absence of yolk sac/embryo in a gestation sac with a diameter >20mm
® Complete miscarriage
i. Thin and regular endometrium
® Incomplete miscarriage
i. Endometrial thickness >5mm
= ii. Hyperechoic tissue within the uterine cavity

Gre 9. Ectopic pregnancy

Chpt 5.7 ® Is defined as implantation of a fertilized ovum outside the uterine cavity
® Incidence in UK = 9.6/1000 pregnancies
® Ultrasound imaging findings
i, Pseudosac within the uterus
§ In 10-29% of ectopic pregnancies
= Appears avascular on Doppler examination ;
ii, 78% of ectopic pregnancies are ipsilateral to the corpus luteum
ili, Free fluid in pouch of Douglas in 20-25% of ectopic pregnancies
iv. ‘Sliding organs’ sign
® Management
i, Expectant (has a failure rate of 40-50%)
ii. Medical (has a success rate with methotrexate of 74-94%)
ii. Surgical (includes salpingectomy or salpingostomy)
— ® There are 6 types of ectopic pregnancy (Box 12.1)
Gn 10, Placenta praevia
Chpt 8.3 © Term used to describe the placental position in relation to the uterine lower segment after
28 weeks of gestation
® Implies that the leading edge of the placenta lies within 5 cm of the internal cervical os
Statistics
i At 22 weeks gestation — 5% of women will have a low-lying placenta
ii, 25% of women with low-lying placenta will have placenta praevia
 Ultrasound 355

Interstitial Cervical Ovarian

® Occurs in 93% of all © Occurs in 1.1-6.3% of ® Occurs in 0.15% of all ® Occurs in 1: 4,000 to
ectopic pregnancies all ectopic pregnancies ectopic pregnancies 1: 7,000 deliveries

a ‘Abdominal sos ~ Heterotopic _

® Occurs in 1: 3,400 to © Occurs in 1; 6,000
1 : 8,000 deliveries deliveries
® Is the combination of
an intrauterine and
ectopic pregnancy

Box 12.2 Causes of polyhydramnios

- Increased fetal production S _ Decreased fetalswallowing : Idiopathic -

® Maternal diabetes mellitus ® Upper GIT obstruction
© Constitutional fetal macrosomia ® Fetal neurogenic disease
® Fetal hyperdynamic circulation
which is due to
® Fetal anaemia (e.g. Rhesus
disease or parvovirus infection)
@ AV fistula
© Structural fetal abdnormalities
(e.g. open NTDs, teratomas)

® |s broadly classified into

i. Minor (i.e. placenta encroaches into the lower segment of the uterus)
ii, Major (i.e. placenta encroaches to, or covering the internal cervical os)
Tein
Ge Use of ultrasound in assessing fetal well being
pt 610 4, Amniotic fluid index (AFI)
@ ls the sum of measurement of the depth of the largest cord-free vertical pool in each of the
4 uterine quadrants
@ AFI <5cm = oligohydramnios
@ AFI >25cm = polyhydramnios

2. Polyhydramnios
® |s defined as an AFl >25cm or when the largest pocket of amniotic fluid is more than 8cm
in vertical depth
®@ There are 3 main causes of polyhydramnios (Box 12.2)

3. Oligohydramnios
@ |s defined as an AFI <5cm or when the largest pocket of amniotic fluid is <2.cm in vertical
depth
® Causes of oligohydramnios (Fig. 12.3)
 teen :
Ae 356 | Chapter12 Medical physics and clinical applications

Amniotic
membrane
rupture

Abnormal fetal
renal function

Causes of
oligohydramnios

Figure 12.3 Causes of oligohydramnios

4. FGR
@ |s defined as birth weight <10th centile for gestation
® Types of FGR
i. Symmetrical
ii, Asymmetrical

5. Symmetrical growth restriction

® Occurs when there is equal reduction in growth velocity of both the fetal head
circumference and the abdominal circumference
@ Due to
i. Constitutionally small fetus
ii. Pathologically small fetus (due to early-onset uteroplacental insufficiency or triploidy)

6. Asymmetrical growth restriction

® Describes when there is deferential reduction in growth velocity of the fetal head to the
abdominal circumference
@ |s a consequence of uteroplacental insufficiency

7. Doppler high resistance patterns

@ Bilateral notches with mean resistance index (RI) >0.55
® Unilateral notch with mean RI >0.65
© Total pulsatility index (Pl) >2.5

8. Doppler findings in uteroplacental insufficiency

® Uterine artery notches
@ Umbilical artery — absent end-diastolic blood flow
i. Occurs only when over 75% of placental bed has been obliterated
ii, Associated with 85% chance of fetal hypoxaemia
iii. Associated with 50% chance of fetal acidaemia
® Umbilical artery — reversed end-diastolic blood flow
i. Carries a 10-fold increase in perinatal mortality compared with those with normal
umbilical artery waveforms
® Fetal arterial redistribution
i. Is reported when the ratio of the middle cerebral artery (MCA) PI to umbilical artery
(UA) PI is increased above the 95th centile
@ Abnormal fetal ductus venosus Doppler
i, Is associated with severe fetal acidaemia
ii. Normal fetal ductus venosus Doppler in a growth-restricted fetus indicates that there is
adequate fetal compensation
 Ultrasound 357

9. Fetal biophysical profile

® ls used to assess fetal well being
@ Ithas 5 criteria, each scoring a maximum of 2 points
i, Fetal tone (assessed over 30min)
ii, Fetal movements
iii, Breathing movements
iv. Amniotic fluid volume
v. Fetal heart rate
® Score
i. Range from 0 to 10
ii, <6 = abnormal
iii, 7-8 = suspicious

Reduced
biophysical
Abnormal fetal profile;
artery Dopplers abnormal fetal
venous
Dopplers

Figure 12.4 Chronology of fetal growth restriction

wig Examples of fetal abnormalities detected by ultrasound imaging

‘Obs
Sy 1. NTDs
pt 6.13 @ Incidence in the UK is 2-5/1000 births
@ Signs on ultrasound imaging
i. Lemon sign — describes the abnormal scalloping of the frontal bones (used as a marker
between 16 and 24 weeks gestation)
ii, Banana sign — describes a crescent or banana-shaped cerebellum that produces an
abnormally small transcerebellar diameter
iii. Cisterna magna is reduced in size

2. Types of NTD
@ Spina bifida occulta (unfused vertebral arch)
® Spina bifida cystica
i. Neural tubes and their coverings protrude through the vertebral arch
ii. Meningocoele
®™ Neural tube lies in its normal position
= Cyst formed by protruding subarachnoid membrane and space
iii. Meningomyelocoele — neural tube lies ectopic in the cystic space
iv. Associated with hydrocephalus
®@ Rachischisis
i. No neural tube
ii, Neural tissue is fused with skin
@ Anencephaly

3. Anterior abdominal wall defects

® Consist of 2 types
i. Omphalocele
ii, Gastroschisis
e@ Associated with raised maternal serum AFP
® Incidence is 1 : 4000 births
oC 358 Chapter 12 Medical physics and clinical applications :

4. Renal pelvic dilatation

® |s associated with postnatal uropathies
i. Pelviureteric junction obstruction
ii. Duplex kidney
iii, Reflux
® Upper limit of normal of fetal renal pelvic diameter at
i. Second trimester = 5mm
ii. Third trimester = 10mm
Tein
Obs .
Gn Invasive procedures
Chpt 6.14 4. Invasive procedures performed under ultrasound guidance include
@ Amniocentesis
® Chorion villus sampling
@ Intrauterine fetal blood transfusion
@ Fetoscopic surgery (e.g. shunt insertions, aiding primary port insertion for use in laser
ablation for twin-to-twin transfusion syndrome or oesophageal occlusion for diaphragmatic
hernia)
® Amnioreduction
Fetal reduction/intracardiac K* injections

2. Amniocentesis
® |s usually performed at 16 weeks gestation
® Procedure-related risk of miscarriage is = 1%

3. Chorion villus sampling

® ls usually performed at 10-14 weeks of gestation
® Procedure-related risk of miscarriage is = 1—2%

lonizing radiation

Radiation
1. Radiation can be broadly divided into
® lonising radiation
@ Non-ionizing radiation

2. lonization
@ Is the process of converting an atom or molecule into an ion by adding or removing charged
particles
® A positive charged ion is produced when an atom or molecule releases an electron
® A negative charge ion is produced when an atom receives an electron

3. Radioactive decay
® |s the process by which an unstable atomic nucleus spontaneously loses energy by emitting
ionizing particles and radiation
Is a stochastic process (i.e. it is impossible to predict when a given atom will decay)
® Becquerel
i, Is the Sl unit of radioactive decay activity
ii. 1 Bq is defined as 1 decay/s
iii. 1 curie (Ci) = 3.7 x 10"°Bq
® Half-life is the time taken for the activity of a given amount of a radioactive substance to
decay to half of its initial value
 lonizing radiation 359

4. lonizing radiation
® Occurs in radioactive decay
® Includes
i. Alpha radiation
ii, Beta radiation
iii. Gamma radiation

5. Alpha particles
® Are emitted from the nucleus of an atom
® Are similar to helium-4 nucleus
® Consist of 2neutrons and 2 protons
®@ Are heavily ionizing
® Havea
i. High mass
ii, Low penetration depth
ili. High energy
® Can be stopped with a sheet of paper
@ Alpha decay is responsible for 99% of helium production on earth
® Applications include
i. Smoke detectors
ii. Power source for cardiac pacemakers

6. Beta particles
@ Divided in to
i. Beta minus
ii, Beta plus
® Can be shielded by few centimetres of metal
® Beta minus
i. Is an electron
ii, Arises from beta minus decay of a neutron (Fig. 12.5)

Figure 12.5 Beta minus decay

e@ Beta plus
i, Is a positron
ii. Has a high energy
iii. Arises from beta plus decay (where energy is used to convert a proton) (Fig. 12.6)

Figure 12.6 Beta plus decay

oo 360 Chapter 12 Medical physics and clinical applications Peis i
~

7. Gamma rays
© Are electromagnetic radiation of high frequency (i.e. above 10” Hz)
® Produced by
i. Radioactive decay
ii. Fusion
iii. Fission
@ Consist of photons emitted by the nucleus of an atom
@ Have short wavelength
@ Applications include
i. Sterilizing medical equipment
ii. Removing decay-causing bacteria from foods or preventing fruit and vegetables from
sprouting to maintain freshness and flavour
iii, Gamma knife surgery
iv. Gamma emitting radioisotopes in nuclear medicine (technetium-99m)
@ lonization occurs via 3 main processes
i. Photoelectric effect
ii, Compton scattering
iii. Pair production
@ Shielding from gamma rays requires large amount of mass (e.g. lead, aluminium, concrete)

8. Geiger—Nuttall law states that short-lived isotopes emit more energetic alpha particles than
long-lived ones

9. Radiation poisoning (Box 12.3)

@ Is also known as radiation sickness or acute radiation syndrome
Is due to exposure to excessive ionizing radiation
Is associated with acute exposure
There is no treatment to reverse the effects of irradiation
Drugs used to mitigate the effects of radiation poisoning
i. 5-androstenediol — was introduced as a radiation countermeasure by the US armed
forces
ii, Potassium iodide — to protect the thyroid gland from ingested radioactive iodine

Box 12.3 Radiation poisoning

: Mild Moderate Severe Very severe

(exposure to 1 - 2 Gy) (exposure to 2 - 3.5 Gy) I (exposure to 3.5 - 5.5 Gy) (exposure to 5.5 - 8 Gy)
® Vomiting within 48 h ® Vomiting within 24 h © Vomiting within ® Vomiting within
of exposure of exposure 1h of exposure 30 min of exposure
© Depression of immune ® Fever © Symptoms of ® Symptoms of severe
system ® Hair loss moderate radiation radiation
© Stillbirth ® Infection © Diarrhoea ® Disorientation
® Spontaneous abortion ® Haematemesis © 50% fatality after 30 ® Dizziness
© 10% fatality after ® Maelena days © Hypotension
30 days © 30% fatality after 30
days

X-radiation
1. X-radiation (or X-ray)
® Ilsa form of electromagnetic radiation
® Is emitted by electrons (either in orbitals outside of the nucleus, or while being accelerated
to produce Bremsstrahlung-type radiation)
 lonizing radiation 361

® Also known as Roentgen radiation

@ Has a wavelength in the range of 10-0.01nm

2. Exposure
® Is the measure of an X-ray’s ionizing ability
® Roentgen
i. Represents the amount of radiation required to create 1 electrostatic unit of charge of
each polarity in 1.cm? of dry air
® Coulomb per kilogram (C/kg)
i. Is the SI unit of ionizing radiation exposure
ii, It is the amount of radiation required to create 1 of charge of each polarity in 1kg of
matter
3. Absorbed dose is the measure of energy absorbed
® Gray (Gy)
i. Is the SI unit of absorbed dose
ii. Is the amount of radiation required to deposit 1] of energy in 1kg of any kind of matter
@ Rad
i. 100rad = 1 Gy

4. Equivalent dose
@ ls the measure of biological effect of radiation on human tissue
® The SI unit is Sievert (Sv)
® Roentgen equivalent man (rem)
i. 1Sv=100rem

5. General facts
@ lonising Radiation Regulations (IRR) 1999 dose limit for pregnant personal working with
ionizing radiation state that fetal exposure dose should be below 1 mGy
® Background ionizing radiation levels in the UK
i. Ranges from 1 to 100 mSv/year
ii, Average is 2.7 mSv/year (which equates to 1mGy for a fetus in utero for 9 months)
® Childhood cancer (i.e. in the first 15 years of life)
i. Risk
™ Background risk = 1 in 500
® Additional risk after fetal exposure to 1mGy of ionizing radiation in utero after
3 weeks gestation is below 1 in 10000
ii. Most common types are
@ Leukaemia
® Brain tumours (gliomas and medulloblastomas)
™ Sarcomas (rhabdomyosarcoma and osteosarcoma)
& Wilms’ tumour
® lonizing radiation threshold dose for fetal malformation is 100-200 mGy
@ lonizing radiation dose for permanent sterility in
i. Males = 3500-6000 mGy
ii, Females = 2500-6000 mGy
Fetal CNS is particularly sensitive to radiation at 25 weeks of fetal life
® Maximum fetal dose from
i. Abdominal X-ray = 4.2 mGy
ii, Chest X-ray = <0.01 mGy
iii, Intravenous urogram (IVU) = 10 mGy
iv. Pelvic CT = 80 mGy
@ Absorption of fetal iodine, often used as contrast in imaging, increases from 11 weeks of
gestation
i 362 Chapter 12 Medical physics and clinical applications

Table 12.1 Additional lifetime risk of cancer (per examination) due to fetal radiation exposure
caused by maternal imaging studies
2 ee ee ee Se SS SS eS
Imaging study Equivalent to natural background
Additional risk of
radiation exposure of cancer
(eben
———E—E——————————EE—E——E—EEeE—————EEEEE
Ee
Abdominal X-ray 1 in 30000 4 months

Chest X-ray (posteroanterior film) 1 in 1000000 3 days

IVU 1 in 8000 14 months

Lung ventilation 1 in 200000 2.4 weeks

Lung perfusion 1 in 20000 6 months

Bone scan 1 in 5000 2 years

Myocardial perfusion study 1 in 1100 8 years

6. Pulmonary embolism (PE)

®@ Deep vein thrombosis (DVT) is found in 70% of patients with PE
® Computed tomography pulmonary angiography (CTPA)
i. Negative predictive value is over 99%
ii. Fetal radiation exposure varies from 3.3 to 130 uGy
iii. Increased lifetime risk of maternal breast cancer by 13.6%
iv. Additional increase in childhood cancer risk of 1 : 1 000 000 above baseline rate
e V/Q scan
i. Fetal radiation dose is 100-370 uGy (i.e. x3 greater than CTPA)
ii. Additional increase in childhood cancer risk of 1: 280 000 above baseline rate

Radiotherapy
1. Radiotherapy is the use of ionizing radiation for the management of both malignant and
non-malignant conditions

2. Examples of non-malignant conditions managed with radiotherapy include

® Trigeminal neuralgia
® Thyroid eye disease
® Prevention of keloid scarring

3. Radiotherapy for the management of malignancy can be

® Curative
@ Adjunct
® Palliative

4. Mechanism of action — radiation causes DNA damage via direct or indirect ionization of the
atoms which make up the DNA chain

5. Limitations — tumour cells in hypoxic environments are more resistant to radiation damage
@ Oxygen is a potent radiosensitizer
® Solid tumours can outgrow their blood supply and thus be in a hypoxic environment

6. Dose for
® Solid epithelial tumour ranges from 60 to 80 Gy
® Lymphoma is 20-40 Gy

7. Fractionation
® Allows normal cells time to recover between treatments
 lonizing radiation 363

Allows tumour cells in radio-resistant phase of the cell cycle during treatment to cycle into a
more sensitive phase for the next treatment dose
Allows time for reoxygenation of hypoxic tumour cells between treatments
Schedule in adults is
i. 2Gy/day
ii, 5 days per week

8. Types of tumour and their radiosensitivity

Sensitive — leukaemia, lymphoma, and germ cell tumours
Resistant — renal cell cancer and melanoma

9. Radiosensitizing drugs include

Cisplatin
Nimorazole
Cetuximab

10. Types of radiotherapy

External beam radiotherapy
Brachytherapy

11. Side effects

Oedema
Infertility
Fibrosis
Epilation
Dryness
Cancer
i. Rate is 1 in 1000
ii, Usually occurs 20-30 years following treatment

Nuclear medicine and radioisotopes

1. Nuclear medicine
Principles
i. Uses radioactive isotopes (taken internally)
ii. Based on radioactive decay
iii, Emissions captured by gamma camera
Is used for
i. Imaging
ii, Treatment
Imaging includes
i. Scintigraphy
ii, Positron emission tomography
iii. Gallium scans
iv. Indium white blood cell scans
v. Octreotide scans
Treatment includes
i. lodine-131 for hyperthyroidism
ii, Strontium-89 for palliation of bone pain
iii, Brachytherapy
Nuclear medicine imaging shows physiological function of a system rather than anatomical
imaging

2. Radionuclide
Is an atom with an unstable nucleus
ca 364 Chapter 12 Medical physics and clinical applications

@ Emits ionizing radiation

® Commonly used in medical practice
i. Barium-133
ii, Thallium-201
iii. Strontium
iv. Technetium-99m
v. lodine-131
vi. Gallium-67
vii. Cobalt-60
viii. Indium-1114
ix. Xenon-133
x. Krypton-81

Non-ionizing radiation

1. Non-ionizing radiation refers to any type of electromagnetic radiation that does not carry
enough energy per quantum to ionize atoms or molecules

2. This includes
@ MRI
@ Light amplification by stimulated emission of radiation (LASER)

MRI
1. General facts about magnetism
® Faraday’s law states that any change in the magnetic environment of a coil of wire will cause
a voltage to be induced in the coil
® Tesla (T)
i, Is the SI unit for magnetic field
ii. 17 =1weber per square meter (Wb/m’)
iii. 1T = 10000 gauss
® Weber (Wb)
i, Is the SI unit for magnetic flux
ii, A change in magnetic flux of 1 Wb/s will induce an electromotive force of 1V
Magnets in MRI produce 0.5—3T
Typical values of magnetic fields '
i. Human brain = 10°? to 10° gauss
ii Earth = 0.31 to 0.58 gauss
iii. Refrigerator magnet = 50 gauss
iv. The surface of a neutron star = 10" to 10"? gauss
2. MRI uses
® Magnetic fields to align atomic nuclei (usually hydrogen protons) within body tissues
® Radiofrequency fields
i. To systematically alter the alignment of this magnetization, causing the hydrogen nuclei
to produce a rotating electromagnetic field
ii, After the field is turned off, the protons decay to their original spin-down state and the
difference in energy between the two states is released as a photon. It is these photons
that produce the signal which is detected by the scanner

3. Types of MR image
® T,-weighted images
i, Also known as spin-lattice (longitudinal) relaxation time
 Non-ionizing radiation 365 Ee

ii. Is the decay constant for the recovery of the z component of the nuclear spin
magnetization
iii. Water- and fluid-containing tissues are dark
iv. Fat-containing tissues are bright
v. Provides good white matter/grey matter contrast in the brain
@ T>-weighted images
i. Also known as spin-spin (transverse) relaxation time
ii, Water- and fluid-containing tissues are bright
iii. Fat-containing tissues are dark
iv. Less dependent on field strength than T, values
v. Is sensitive to water content
© Fluid attenuated inversion recovery (FLAIR) sequence
i. Free water is dark
ii, Oedematous tissue remains bright
® In most situations T, time is greater than T,
T,/T>-relaxation time is long in fluids (e.g. T; = 1350ms and T, = 200 ms for blood)
e T,/T,-relaxation time is short in solid organs (e.g. T; = 490ms and T, = 40 ms for liver)

LASER
1. Is a type of electromagnetic radiation

2. Laser beams are

® Spatially coherent
® Narrow low-divergent beam
@ Monochromatic
®@ Highly collimated (i.e. being parallel diverging)

3. Physics of light
@ Light
i. ls electromagnetic radiation of a wavelength that is visible to the human eye
ii. Velocity in vacuum is 299792 458 ms"
iii. Exhibits polarization
® Electromagnetic spectrum includes
i. Radiowaves
ii, Microwaves
iii. Infrared
iv. Visible light
v. Ultraviolet
vi. X-rays
vii. Gamma rays
® Photon
i, Is the basic unit of light
ii, Is governed by quantum mechanics
iii. Exhibits wave-particle duality
iv. ls mass-less
v. Has no electric charge
vi. Does not decay spontaneously in empty space
vii. Has 2 possible polarization states
@ Wavelength of a light is inversely proportional to the energy of a quantum
i. Short wavelengths have high energy (e.g. blue light — 470nm)
ii, Long wavelengths have low energy (e.g. red light - 670 nm)
oo 366 Chapter 12 Medical physics and clinical applications

4. Physics of laser
® Laser consists of
i. An optical resonator
ii, A gain medium
e Anelectron can transit to other energy levels by absorbing or releasing energy
i. Transition from a lower to higher energy level requires absorption of photons
ii. Transition from higher to lower energy levels requires photons to be released
® Energy of the photon absorbed or released as the electron transits between energy levels
governs the wavelength of light absorbed or emitted
® Each wavelength in the electromagnetic spectrum has an individual colour
@ The transitions of the electron are divided into 3 types
i. Spontaneous absorption (i.e. electron transits from a lower to a higher energy level by
absorbing a proton)
ii, Spontaneous emission (i.e. an electron excited to an upper energy level will drop to a
lower energy level and a photon will be emitted)
iii. Stimulated emission (i.e. photon is emitted from an excited atom when it is stimulated
by other photons)
@ Laser is produced by stimulated emission
@ Laser can be of any state (Box 12.4)

Box 12.4 Types of laser

® Helium-neon © Coumarin 102 ® Ruby

® CO, ® Stibene ® Neodymium : yttrium
® Argon (used for ® Rhodamine 6G aluminium garnet
coagulation) (Nd: YAG)
® Titanium sapphire
® Neodymium glass

® Diode

5. Interaction of laser beam with living tissue

@ Thermal effect — leads to denaturation of tissue and depends on
i. Laser wavelength
ii, Laser power
iii, Time duration to exposure
iv. Tissue optical coefficient
® Mechanical effect — results from creation of
i, A plasma
ii, An explosive vaporization
iii, Cavitation
® Photoablative effect
® Photodynamic effect
 Non-ionizing radiation 367

6. Thermal effects of laser on living tissue

® Hyperthermia
® Coagulation
i. Produced by desiccation, blanching, and a shrinking of the tissues by denaturation of
proteins and collagen
ii. Responsible for haemostasis
® Volatilization
i. Various constituents of tissue disappear in smoke at above 100°C
ii, Coagulation necrosis occurs at the edges of volatilization zone
iii, Cutting effect is obtained when the volatilization zone is narrow

7. Applications in medicine
@ Gynaecology
i. Treatment of cervical intraepithelial neoplasia (CO, laser)
ii, Treatment in endometriosis
iii, Laparoscopic surgery
® Obstetrics
i. Selective laser photocoagulation in treatment of twin-to-twin transfusion syndrome
(Nd: YAG or diode laser)
® Urology
i. Lithotripsy
ii. Photoselective vaporization of the prostate
iii, Laser ablation of the prostate
Laser eye surgery
® Laser hair removal
@ Laser skin treatments

8. Nd: YAG laser

® lsasolid state laser
® Emits light with a wavelength of 1064nm (infrared spectrum)

9. CO, laser
@ |s the highest power continuous wave laser
®@ Emits infrared light (wavelength of 10 tm)

Microwaves
1. Are electromagnetic waves with frequency ranging from 0.3 to 300 GHz

2. Includes ultra high frequency (UHF) and extremely high frequency (EHF) electromagnetic
waves
3. Microwave energy is produced by
@ Klystron tubes
@ Magnetron tubes
®@ Solid state diodes

4, Are absorbed by molecules that have a dipole moment in liquids

5. Applications
®@ Domestic
i. Wi-Fi
ii, Bluetooth
iii. Microwave ovens
®@ Broadcasting, telecommunications, and satellite communications
oe 368 Chapter12 Medical physics and clinical applications

Radar
Global navigation positioning system
@ Medical
i. Microwave ablation for atrial fibrillation
ii. Endometrial ablation
iii. Treatment of benign prostatic hyperplasia

Electrosurgery
1. Electrosurgery
@ |s the application of high frequency electric current (in the frequency of 100 kHz to 5 MHz)
to tissue as a means to cut, coagulate, desiccate, or fulgurate
© Uses alternating current to directly heat (Ohmic heating) the tissue
@ Common electrode configurations
i. Monopolar (high-power unit (400 W) generates high frequency current)
ii. Bipolar (low-power unit — 50 W)
iii, Tripolar
® Generates smoke plumes which contain
i, Chemical by-products (e.g. formaldehyde, hydrogen cyanide, toluene)
ii. Intact cells
iii. Intact viral DNA
iv. Viable bacteria

2. Electrosurgical modalities
® Cutting
i, High-power density is applied to vaporize tissue water content
® Coagulation
i, Uses waveforms with lower average power
® Desiccation
® Fulguration
i Electrode held away from the tissue
ii. The air gap between the electrode and tissue becomes ionized
iii. An electric arc is discharge
iv. Superficial tissue burning occurs

3. Electrocautery
® ls the process of destroying tissue using heat conduction
’
® Used mainly for cauterization
@ Uses direct current to produce heat

4. Physics of electrosurgery
@ Electric current is the flow of electrons (in metal and semiconductors) or ions (in liquid)
Electric conduction in biological tissue is due to interstitial fluid
Ohm's law states that voltage is the product of electric current and resistance
Electric current at 50 Hz produces intense muscle and nerve activation
Sensitivity of neural and muscle cells to electric current is inversely proportional to its
frequency (i.e. the higher the frequency the lower the sensitivity)

5. Diathermy
es dielectric heating
@ sa process in which radiowave or microwave electromagnetic radiation heats a dielectric
material
® Produced by rotation of molecular dipoles in high frequency alternating electric field
CHAPTER 13

Research tools

CONTENTS

Research methodology 369

Medical statistics 371
Clinical testing 380

Research methodology

Study design
All research follows a similar framework

ile Plan the study

®@ Decide the field to be examined
@ Literature review to
i. Ascertain the existing state of knowledge
ii. Identify specific areas requiring investigation

Design the study

® Define the variables to be controlled and observed
® State a hypothesis
Decide which type of study should be utilized
Identify the appropriate population
Design the details of the experimental methodology to be used
Calculate the sample size

Consider ethical issues and apply for ethical committee approval if required

Sample the population, perform the study, and collect the data

Use descriptive and inferential statistics to summarize the population characteristics and
draw conclusions about the hypothesis tested

Interpret the study findings in the context of already existing knowledge

Present the study

® Conference
® Scientific publications
a 370 Chapter13 Research tools

Types of epidemiological studies

1. Epidemiological studies can be divided into

® Interventional studies — individuals or groups are observed after they are subjected to an
intervention
® Observational studies — individuals or groups are only observed
i, Ata single time point — cross-sectional studies
ii, Over a period of time — longitudinal studies

2. Interventional studies can be

@ Randomized controlled trials — individuals or groups are randomly assigned to either a
contro! or an intervention group
i. Double-blinded — neither the participants nor the researcher are aware at the
time of the study being conducted as to which participants are receiving the
intervention
ii, Single-blinded — only the researcher is aware at the time of the study as
to which
participants are receiving the intervention
iii. Non-blinded — both the participants and the researcher are aware as to which
participants are receiving the intervention
@ Non-randomized (also called quasi-experiments) — there is no random allocation. Useful
when randomization is not possible or unethical. Examples of this design include
i. Interrupted time series analysis — one or more observations are made on the individuals
(or groups) several times before and after an intervention
ii. Case (intervention or outcome of interest)—control (no intervention or negative for the
outcome)

3. Observational studies include

® Ecological
i. Populations rather than individuals are studied
ii. Susceptible to confounding factors (‘ecological bias’)
® Cohort
i. Cohort is a group sharing common characteristics
ii, An outcome (e.g. disease)-free cohort sharing a common exposure is followed over time
and monitored for how many will develop the outcome compared with a similar but
unexposed cohort
iii, Can be prospective or retrospective
iv. The effect of rare exposures and multiple outcomes can be observed
v. Can calculate incidence and relative risk
vi. Expensive and time consuming
vii. Typically high drop-out rates
viii. Prospective cohort studies are considered the highest quality epidemiological
observational type of study
® Cross-sectional
i, Characteristics of a population, or sample, are observed at a single point in time
ii, Provide data on the entire population studied
. Can calculate prevalence, absolute, and relative risks but not incidence
® ee
i, Studies association of disease with past exposure
ii, Exposure of cases (individuals with the disease) is compared with that of controls
(individuals without the disease)
iii, Can calculate odds ratios and absolute risk but not relative risk
iv. Useful for rare diseases
 Medical statistics 371

v. Can be relatively quick and inexpensive

vi. Susceptible to ‘recall bias’ since information obtained retrospectively

4. The strength, or degree of trust, ascribed to evidence depends on the source and type of
study it was derived from. In general, in ascending order, this is (Fig. 13.1)

Expert reports and

opinions
In vitro studies Animal models
(committees, respected
authorities)

-_ Cohort studies
- (prospective are _
stronger than
retrospective)

Randomized trials
(double blinded are
Meta-analyses
stronger than single
Systematic reviews
which are stronger than
non-blinded)

Figure 13.1 Strength of evidence (in ascending order)

Statistical bias occurs when there is a systematic distortion of the collected data. There are
many types of bias. Some common ones are
® Selection (which also includes sampling) bias
@ Systematic bias
®@ Recall bias
® Bias of an estimator (or experimenter expectancy bias)
® Measurement bias

Medical statistics

Variables and sampling

1. Variable is a characteristic being measured

2 Data are a collection of information about one or more variables

5 Population is the entire set of values or subjects of interest under study

Sample is a subset of values or subjects derived from the population

Data from samples are analysed in order to extrapolate to the population, using statistics:
® Descriptive statistics utilize observations made in the sample to describe a population and
estimate its properties (e.g. a sample mean gives an estimate of the population mean)
@ Inferential statistics study patterns and relationships between variables in the sample to
generalize results to the population (e.g. hypothesis testing, correlations, interpolation)
 372 Chapter 13 Research tools

6. The estimates and conclusions drawn from the sample about the population may carry an
estimation error (known as a sampling error) because different samples from the same
population will produce different results. This leads to statistical uncertainty

7. How accurate the estimates and conclusions are depends on:

How representative the sample is of the population (a sample not representative of the
population leads to bias error)
The sample size (n) is related to the power of a study (sampling error reduces with larger
sample size)

8. Sampling can be:

Random — every individual unit has the same probability of being selected from the
population
Stratified
i. Parameters of interest differ between non-overlapping groups (strata) but not within
groups
ii. Only an appropriate number ofindividual units need to be randomly selected from each
stratum
Cluster
i. Parameters of interest differ within non-overlapping groups (clusters) but not across
them
ii, An appropriate number of individual units need to be randomly selected from only a few
clusters
Multi-stage
Multi-phase

9. Variables can be
Categorical — data can only be one of a finite number of values or categories
i. Nominal (there is no ranking within the categories, e.g. male or female)
ii, Ordinal (there is ranking within the categories or values, but the difference between
these is not relevant or to a scale, e.g. Apgar scores)
Quantitative — data are numerical, either continuous (e.g. blood pressure) or discrete (e.g.
number of pregnancies)
i. Interval (as for ordinal, but the intervals between the values are equally spaced)
ii. Ratio (as for interval, but a value of 0 denotes that the variable is absent)

10. Analysis of 1 variable is termed univariate analysis

11. Analysis of the association between 2 or more variables is termed multivariate

Distributions
1, Probability distribution refers to the relative frequency of occurrence of the possible values
that a variable can take

2. There are many types of distribution. Those encountered in medicine include

Normal
Positively or negatively skewed
Bimodal
J-shaped or reversed J-shaped
Uniform

3. Values characterizing a distribution

Measures of location within the distribution (useful mainly when the distribution of the
variable is unimodal)
i. Mean (x)
 Medical statistics 373

m The average of the values (x)

X1+++°+xn
es
n
= Sensitive to outliers (extreme values)
™ Cannot be calculated for nominal or ordinal types of variables
ii, Median
= The middle value of a sample after arranging the values in an increasing order
= Robust to outliers
= Cannot be calculated for nominal types of variables
iii. Mode
= The most frequently occurring value
= Can be used to describe all types of variable
Measures of spread of the distribution (not possible to calculate these for nominal or
ordinal types of variables)
i. Standard deviation (s)
= Measure of the average distance that individual values are from the
sample mean
= The mathematical formula is

ii. Coefficient of variation (CV)

® Ratio of the standard deviation to the mean

@ It has no units
iii. Range
= The difference between the lowest and the highest value

Range = X max — X min

® Sensitive to outliers
iv. Interquartile range = The range between the first (Q1) and third (Q3) quartile (each
quartile contains 25% of the values, hence, the boundaries of the above quartiles are the
numbers below which 25% and 75% respectively of the values occur; the interquartile
range includes all the values in between)

4. Normal distribution (also known as Gaussian distribution)

Is bell shaped
The mean, median, and mode are the same
68% of values lie within 1 standard deviation of the mean
95% of values lie within 1.96 standard deviations of the mean (also known as the ‘normal
range’)
99% of values lie within 2.57 standard deviations of the mean
Standard error of the mean (SE)
i, Is.an estimate of how far away from the true (unknown) population mean a sample
mean is. In other words, it is the standard deviation of the sample mean with respect to
the population mean
 374 Chapter 13 Research tools a
a

ii. It depends on
® The variability of the individual values (i.e. the standard deviation of the sample)
= The sample size (decreases with increasing sample size)
iii. The mathematical formula is

cpa
Jn
@ Confidence interval (or region) is the area likely to include the true value of the parameter
(or parameters) in question (e.g. population mean, difference between the mean of 2
populations)
i. The 95% or 99% confidence interval (Cl) is commonly used
ii. It signifies that there is a 95% or 99% chance that the interval contains the true value
i. The mathematical formula for the 95% Cl of a mean is

Gli Gee ,.96<SE

For the 99% Cl substitute 1.96 with 2.57

. The level of confidence of the interval (i.e. 95% or 99%) is a measure of its accuracy
vi. The width of the Cl is a measure of its precision. It is related to
= The chosen level of confidence
& The sample size. Whilst the sample mean remains the same, the Cl width decreases
as the sample numbers increase, implying that the precision of identifying correctly
where the population mean lies increases
vii. If the Cl for a difference of the mean of 2 populations crosses 0 then
B® The finding is not significant, since this implies that it is possible that the true mean
difference could be 0 even if the 2 samples mean difference is not
= |n such a situation, if the sample size is made larger then it is possible that the Cl
width will become smaller and will not cross 0, hence, for the same mean difference
the result will become significant

Statistical hypothesis testing

1, Hypothesis testing involves stating a null hypothesis about a population variable along with
an alternative hypothesis which can be either one- or two-sided (i.e. that the difference can
be in one or in both directions)

2. A hypothesis can only be rejected but never accepted

3. Significance level is the evidence required to reject the null hypothesis and conclude that an
event has not arisen by chance

4. P-value
@ tis the probability of obtaining a statistic result as the one that was observed while
accepting the null hypothesis as true. In other words, the p-value is the probability of
obtaining a false-positive result
@ By convention a p-value of <0.05 is accepted as the significant level of evidence (i.e. the
observed result would have arisen by chance every 1 in 20 times the study was performed)
® Another commonly used p-value is <0.01

5. There are 2 types of error

@ Type | (also known as & error or false positive)
i, Occurs when the null hypothesis is wrongly rejected (i.e. falsely detecting a difference)
ii, Related to the significance level and consequently the p-value
® Type ll (also known as B error or false negative)
 Medical statistics 375

i. Occurs when we wrongly fail to reject the null hypothesis (i.e. failing to detect a true
difference)
ii, Related to the power of a study

6. Power (sensitivity) of a study

@ The probability that the test applied will correctly reject the null hypothesis
@ The higher the power, the lower the probability of a type Il error
@ Power=1-8
® Fora power calculation, two components need to be established first
i. The desired clinical difference to be detected
ii, The variability of the measured parameter
@ Power calculations can be used to
i. Reflect the minimum sample size needed to reject the null hypothesis at a particular
significance level
ii. Predict the minimum detectable difference of the studied effect which is likely to be
observed for a particular sample size
@ The sample size needed for a study is not related to the population size but to the
magnitude or frequency of the effect or event studied
® The larger the effect or more frequent the outcome, the fewer the numbers needed in a
sample to prove a statistically significant difference
@ |n medical practice, the power of a study is usually set at 80-90% (i.e. the probability of
detecting a significant difference, and rejecting the null hypothesis, by doing the study is
80-90%) and the significance level is usually set at 1% or 5% (i.e. the probability of the
detected significant difference having been achieved by chance is 1% or 5%)

Statistical hypothesis tests can be

@ Parametric
i. Assumptions are made about the characteristics of the probability distribution of the
variables
ii, Have a higher statistical power than non-parametric tests, leading to a lower chance of a
type Il error
® Non-parametric
i, Make no assumptions about the probability distributions of the variables
ii, Are more robust than parametric tests, leading to a lower chance of a type | error

. It is important to ascertain if a distribution of quantitative variables is normal in order to

decide what statistical hypothesis test should be performed on the sample

Normality of a sample distribution can be ascertained

@ Visually (by utilizing a plot)
e@ By a goodness-of-fit test for normal distribution
i, Shapiro—Wilk
ii. Kolmogorov—Smirnov

10. Non-normally distributed samples can be converted to a normal one by transforming the
data (e.g. logarithmic transformation)

1 = . Ifa sample (and by inference the population) is normally distributed, parametric statistical
hypothesis tests can be utilized such as
® t-test
i, Can be
™ Independent — used when comparing 2 unpaired distributions
B Paired — used when comparing 2 paired distributions (effectively each pair acts both
as a case and control)
ii, Can be
co 376 Chapter13 Research tools :

® One sample — observations are drawn from a single sample

= Two sample — observations are made on two different samples
ANOVA (analysis of variance)
i. Very similar to t-test
ii, Used when multiple distributions are compared
iii, Apart from normality, it also assumes that the variance (amount of spread) in each
distribution is the same
iv, Because multiple comparisons are made and some might be significant by chance, the
Bonferroni correction can be applied. This tests each individual comparison separately at
a smaller significance level (which is equal to what it would be if only 1 hypothesis was
tested at a time over the number of comparisons made) thus maintaining the overall
significance level

12. For non-normally distributed quantitative data and for categorical data, non-parametric
statistical hypothesis tests can be utilized such as
Wilcoxon's signed rank test (which is the non-parametric equivalent of the paired t-test)
Mann-Whitney U (which is the non-parametric equivalent of the independent t-test)
Kruskal-Wallis one way analysis of variance (which is the non-parametric equivalent of
ANOVA)
Friedman two-way ANOVA

13. x? test
Tests if there is an association between categorical variables
It is a measure of the difference (distance) between the expected count in each study group
(as predicted by the null hypothesis) to the experimentally observed ones
Prerequisite is that each group should have sufficiently enough data
i. Smallest group should have =1 expected counts
ii. 280% of groups should have =>5 expected counts
It does not give information on the type or degree of the association

Quantifying the association between categorical data

1. Statistical hypothesis tests, such as the x’, can only show an association between categorical
variables but cannot quantify the strength and direction of this association. For this, several
methods can be employed

2. The difference in frequency of occurrence of categorical variables (events) between two

groups (e.g. control and intervention, exposed and non-exposed) can be expressed in
terms of
Risk estimation
i. Deals with proportions
ii, Risk can show either reduction or increase, depending on the direction of the
association
Odds calculations — deals with probabilities (see Fig. 13.2)

3. Risk is the chance of the event being investigated occurring

The risk in a given group (control or observed) = the number of events occurring in that
group divided by the total population (with or without the event) in the group
Absolute risk difference (AR) is the difference in risk between the two groups
AR = risk observed group — risk control group
Relative risk (RR) is the risk of 1 group relative to the other (i.e. the ratio of the risk of the
2 groups)
RR = risk observed group/risk control group
 Medical statistics 377 oe

i. RR of 1 means that there is no difference between the groups

ii. RR of >1 means that there is greater risk in the observed group compared with the
control group
ii. RR of <1 means that there is lower risk in the observed group compared with the
control group

4, Odds is the probability of an event occurring versus the probability of the event not
occurring
® The odds in a given group (control or observed) = the number of subjects with the event
occurring in that group divided by the number of the subjects without the event in the
group
® Odds ratio (OR) is the odds of an event occurring in one group divided by the odds of it
occurring in the other group (meaning it quantifies how much more likely it is for an event
to occur in one group versus the other)
® OR = odds observed groups/odds control group

5. Cls can be calculated for RRs, ARs, and ORs

6. Ifa Cl for RR crosses 1, then the risk difference between the two groups is not significant

7. The advantages of utilizing ORs are

@ ORs from different studies can be compared and combined
@ They are amenable to logistic regression
@ They can be calculated in case-control studies (RRs cannot since the number or ratio of
cases to controls in the population is not known)

8. If an event is rare in the control group then the OR is approximately equal to the RR

Number of Number of Total number of — Risk for event occurring |,Odds (probability)
subjects with # subjects subjects in : _ a # of event occurring
‘ in observed group = — fi.
event without event observed group e § in observed group -
occurring in occurring in =atb=e
observed observed
group =a group =b

Number of Number of Total number of Risk for event occurring Odds (probability)
subjects with ff}subjects subjects in in control group = = ofevent occurring
event without event control group f in control group
occurring in occurring in =o
control group — control
ae group =d

a ey HO
Absolute risk = “— £ [jOdds ratio = —
eat cld
Relativecuk=
elative ris of

Figure 13.2 Summary of risk and odds calculations. For ease of identification, each individual
calculation included is derived from the boxes with the same colour or border

9. Number needed to treat (NNT)

@ A measure of the effectiveness of an intervention
 378 Chapter 13 Research tools a

@ \t corresponds to the number of subjects needed to receive an intervention for one event
to occur (or be prevented, depending on the direction of the association)
@ The lower the NNT the more effective the intervention
@ By definition

NNT =—~
AR
10. In summary, when comparing categorical variables
e A statistical hypothesis test (e.g. x° test) will show if there is an association
@ ORs will quantify this association
@ Cls for the ORs will indicate how precise this quantification of association is

Correlation and regression

1. Variables can be assigned as being dependent or independent
@ Independent variables are not altered by other variables, are taken as given and are selected
or controlled in order to study their relationship to the dependent variables
e@ Dependent variables are observed and are altered by the independent variable. Evidence is
sought to prove if, and how, their values are influenced by the alteration of the independent
variables

2. Covariance occurs when variables change together

3. Correlation
@ ls the degree of association between variables
®@ |thas no units
@ Expressed by using correlation coefficients
i. Pearson's correlation coefficient r
Most commonly used parametric test of correlation
Accesses linear associations only
r values range from —1 to +1
r =O implies no association between variables
r= +1 implies perfect positive linear correlation
r =—1 implies perfect negative linear correlation
Its calculation includes the use of the standard deviation, hence, making it susceptible
to outliers
Spearman's rank correlation coefficient
Non-parametric equivalent of Pearson's rtest ‘
The values of each variable are ranked in ascending order
Pearson's r is then calculated utilizing the ranks for the variables
Robust to outliers

4. Correlation does not imply causation because there might be confounding variables

5. Confounding variables
@ Are variables that correlate with both the dependent and the independent variables
® Cause spurious relations
® Lead to type! error

6. Regression
© A set of methods to establish the relationship between variables in order to
i. Explain the acquired data or
ii, Predict other values of a variable based on those collected experimentally
@ When the relationship between an independent (regressor or predictor) and dependent
(regressand or response) variable is linear, then the method of linear regression in employed
 Medical statistics 7 ae

Linear regression is a parametric method, therefore the variables need to be quantitative

and with a normal distribution
Transformation
i. A mathematical function is applied to all the values of a variable
ii. Non-linear relations can be transformed to linear (e.g. via squaring the values)
ii. If the variables are not normally distributed, it may be possible to transform them into a
normal distribution (e.g. via logarithmic transformation) and then study the relationship
with linear regression
A regression equation is generated which describes the average linear relationship between
the variables
Regression parameters include
i. The slope of the line
ii. The intercept of the line along the y (dependant) axis
iii, The SEs for the above
iv. The p-value of the statistical test for rejecting the null hypothesis that there is no
association between the regressor and regressand
The regression equation describes the average relationship between the variables (i.e. the
slope of the line) but does not give information about the closeness of the association (i.e.
how close the points are to the line). Since the regression line is an average one, it can be
generated both with points closely positioned around the line and with points widely
scattered and at a distance from the line.
i. The regression coefficient is the slope of the line (i.e. the relation)
ii, The coefficient of correlation measures the closeness of the association
Not all values (points) affect the slope of the fitted line equally
i. Points at either end have a greater effect in pulling the line (and hence altering the slope)
towards them compared with those in the middle
ii. Leverage is a measure of this effect
iii. Residual is a measure of how good the fit of the line is to a point
iv. Therefore, outliers or omission of values at the edges will affect the slope more than
those situated in the middle of the regressor’s range
Using the regression model, values for the dependant variable can be ascertained for any
value of the regressor
i. Interpolation is the use of regressor values from within the range used to construct the
model
ii. Extrapolation is the use of values from outside the range used to construct the model.
This relies more heavily on the regression assumptions and can more readily lead to
erroneous dependant values
Multiple linear regression is applied to describe the linear relationship between 1 dependent
and many independent variables (co-variates)
Logistic regression
i. Studies an independent variable in order to predict the probability of a dependent
(categorical) variable occurring
ii, Despite using categorical data, it is a parametric test since in the analysis the association
between the 2 variables is expressed in terms of ORs — these are transformed
logarithmically and then a linear model is constructed
iii, Multiple logistic regression
m™ Studies the effect of many independent variables (co-variates) in predicting the
probability of an event occurring
= Must first demonstrate that the co-variates are independent of each other
There are numerous non-linear regression models which try to best fit a given set of data to
a predefined equation instead of a line (e.g. quadratic regression fits the equation of a
parabola)
os 380 Chapter13 Research tools :

@ Various non-parametric regression methods exist for ascertaining the relations between
variables which do not have a predetermined shape (structure)
i. The structure of the relationship is constructed based on the data
ii. Larger sample numbers are needed since both structure and parameters of the resulting
model need to be derived

oT

Clinical testing

Diagnostic test performance

is In ascertaining the usefulness of a test, several parameters can be calculated

Dy These can be derived from studies where the cases and controls are known and the test
under investigation is studied for its ability to correctly or incorrectly detect those subjects
with or without the condition

Definitions
® True positive (TP) is a subject with the condition who is correctly identified as having it by
the test
@ True negative (TN) is a subject without the condition who is correctly identified as not
having it by the test
@ False positive (FP) is a subject without the condition who is incorrectly identified as having it
by the test
e@ False negative (FN) is a subject with the condition who is missed by the test

True positive rate (TPR) = sensitivity = Power = 1-B

True negative rate (TNR) = specificity = 1-a

False positive rate (FPR) = type | error = & = 1 — specificity

False negative rate (FNR) = type Il error = B = 1 — sensitivity

eh
8
SS Likelihood ratio (LR) is a measure of the effectiveness of a test
® LR usually refers to the LR of a positive result which measures how many times more likely
a positive test is in someone that has the condition tested for compared to finding a positive
test in someone that does not have it = TPR/FPR = sensitivity/(1 — specificity)
@ LR=1 means that the post-test probability of the subject being positive for the condition
tested is no different from the pretest probability ;
LR = >1 means that the post-test probability is higher than the pretest probability
LR = <1 means that that the post-test probability is lower
LR of a negative result measures how many times more likely a negative test is in subject
who does not have the condition tested for compared with finding a negative test in subject
who does have it = TNR/ FNR = specificity / (1-sensitivity)

Positive predictive value (PPV) is the probability that a subject with a positive test has the
condition = TP/(TP + FP)

10. Negative predictive value (NPV) is the probability that a subject with a negative test does
not have the condition = TN/(TN + FN)

11. Accuracy is a measure of how many correct results the test gives in relation to all the tests
performed = (TP + TN)/all tests performed

q2s For screening tests, it is desirable to have a high sensitivity, thus minimizing missed
cases
 Clinical testing 381

13. For diagnostic tests, it is desirable to have high specificity, thus minimizing misdiagnoses

14, Since the specificity and sensitivity are inversely related, which one will be of more
importance depends on the consequences of a missed diagnosis versus a misdiagnosis. The
cut-off value for a test can be chosen using a receiver operator characteristic (ROC) curve

Subjects with Subjects without

condition tested = condition tested =
a+c b+d

Subjects testing Correctly identified as Wrongly identified as Positive predictive

positive for the test = positive for condition positive for condition Bie)
a+b tested = true positive tested = false positive Value (PPV) = nay
(TP),a (FP), b

Subjects testing Wrongly identified as Correctly identified as Negative predictive

negative for the test = negative for condition negative for condition
c+d tested = false negative | tested = true negative value (NPV) =
c+d
(FN), ¢ (TN), d

a Ane d
SES
abore
Figure 13.3 Summary of calculations for clinical test performance. For ease of identification, each
individual calculation included is derived from the boxes with the same colour or border

15. ROC curve

® tis a graphical plot
@ Can bea plot of
i. Sensitivity versus (1 — specificity)
ii, TPR versus FPR (also called relative operating characteristic curve)
@ It essentially depicts the trade-offs between true and false positives

16. Incidence of an event is the risk of the event occurring per unit time

17. Prevalence of an event = total number of events in the population (often at a specified time)
divided by the population size
@ Represents how common an event is
®@ Can calculate what the prior odds of an event (or condition) occurring is

18, Bayes’ theorem states that: the prior odds of having a condition x, the LR derived from the
test utilized = posterior odds

19. In practice, this means that tests with the same sensitivity and specificity may have very
different predictive values depending on the background odds (prevalence) of a condition
occurring. This is especially true when comparing the predictive value of the same test for
a condition in a low- and in a high-risk population. Mathematically, sensitivity and specificity
will remain the same however, the PPV for the low-risk population will be lower than
that for the high-risk population due to the absolute differences in the TP and FP for the 2
populations caused by the different prevalence. Hence, the usefulness of a test depends on
the population it is used on

20. Other useful measures of a test include

@ Precision (reproducibility) — a measure of the test’s ability to produce the same result every
time it is repeated on the same subject
@ \ntra-observer variability — a measure of how precise a test is if the same operator repeats it
ce 382 Chapter13 Research tools

Inter-observer variability - a measure of how precise a test is if different operators

perform it

Screening programmes
ie A screening programme is an attempt to detect a condition in individual members of a
population who are not exhibiting its symptoms or signs

Screening can be
Universal — all members of a population are screened
Targeted — only members with a high prior odds of having the condition are screened

In 1968 the WHO published a report called Principles and practice of screening for disease (by
Wilson and Jungner). The conclusions are summarized here
The condition screened for should be an important health problem
The natural course of the condition must be known
A latent or early symptomatic stage of the condition must exist
There should be treatment and this should be more effective if commenced early
Facilities for diagnosis and treatment must be available
A test for the condition must exist
The test must be acceptable to the screened population
There should be agreement on who to treat
The cost of diagnosing and treating cases found should be cost-effective in comparison with
the possible medical cost as a whole
The process of finding cases should be continuous and not just ‘once only’
Index

abdomen 52-9 agranulocytes 274

ligaments, canals and fossae 54—7 air 130
lymph gland drainage 95 airway resistance 132
peritoneal cavity 57-9 aldosterone 211
wall 52-3, 357 alkaloids 330
abiotics 255 alkylating agents 330
ABO system 127 allantois 23, 37
abscess 251 allylamines 314
Acanthosis nigricans 243 alpha particles 358, 360
acarbose 332 alveolar period 167
accuracy in clinical testing 380 alveoli 133
acetabulum 60 ambiguous genitalia at birth 41, 42, 43
acetic acid derivatives 329 amino acids 158, 188-9
acetylcholine receptors 158, 181-2 aminoglycosides 313
aciclovir 314-15 5-aminosalicyclic acid 330
acid-base balance 111-15 amniocentesis 358
acidosis, long-term 115 amnion 22, 23, 166
Actinomyces israelii 288 amniotic fluid 165-6
action potential 156-8 embolism 249
activins 202 index (AFI) 355
acute fatty liver of pregnancy 266-7 Amsel criteria for bacterial vaginosis 289
Addison’s disease 216 anaerobes 284
adenohypophysis 107 anaerobic metabolism 186
adenomyosis 258 anal canal 37, 71-2
adenosine-5’-triphosphate (ATP) 184, 233 analgesics 306-9
adipose tissue 188 anal sphincter, external 65-6
adrenal changes in pregnancy 221 anatomy 51-110
adrenal cortex 109, 210-11, 226 abdomen 52-9
adrenal development in fetus 171, 226 biliary system 74
adrenal glands 108-9 endocrine 104-9
adrenal hormones 210-12 female genital tract 82-9
adrenaline 212 fetal skull 109-10
adrenal medulla 212 gastrointestinal tract 66-73
adrenarche 211 liver 73-4
adrenergic receptors 177-81 lymphatic system 94-5
adrenocorticotropic hormone (ACTH) 207-8 male genital tract 79-82
a-fetoprotein (AFP) 243 neuroanatomy 95-104
agonists 181, 306, 321 pancreas 74—5
 384 = Index

anatomy (cont.) asphyxia 343, 344

pelvis 60-6 aspirin 329
spleen 75 atosiban 320-1
trunk surface 51-2 atrial septum 30
urinary system 75-9 atrioventricular valves 29
vascular tree - arteries 89-93 atrophy 231, 232
vascular tree - veins 93-4 autonomic nervous system 103-4, 160-1
androgens 199, 260 axonal degradation pathway 156
insensitivity, partial or complete 41 azathioprine 330
aneuploidies 7-9
Angelman syndrome 9 bacteria 283-93
angiotensin converting enzyme (ACE) 213 antimicrobial resistance 285
angiotensinogen 212-13 gram-negative 284, 285, 288-91
anion gap 113 gram-positive 284, 286-8
ANOVA (analysis of variance) 376 necrotizing fasciitis 291-2
ansamycin 312 pelvic inflammatory disease 292-3
antacids 327 Reiter’s syndrome 293
antagonists 179, 181 toxins 285
anterior (urogenital) triangle 64 wound infection 291
antibiotics 309-14 bacterial vaginosis (BV) 289-90
bactericidal 309-10, 312-14 baroreceptors 125
bacteriostatic 310, 311-12 Barr body 9
antibody-antigen complex mediated Bartholin’s glands 83-4
hypersensitivity 270 basal ganglia 95-6
anticoagulants 325-7 basal plate 20
antidiarrhoeals 328 base excess 114, 135
antidiuretic hormone (ADH) 209 baseline heart rate 345
antiemetics 328 Bayes’ theorem 381
antiepileptic drugs 323-5 b-cell lymphoma 2 gene family 234
antifungals 314 b-cells 275
antigen-presenting cells 276 Becquerel 358
antihypertensive agents in pregnancy 322-3 beta blockers with intrinsic sympathomimetic
anti-inflammatory and immune activity (ISA) 179
modulators 328-31 beta particles 359
antimalarials 317-18 Bezold-Jarisch reflex 131
antimetabolites 330 bicarbonateton 114
antineoplastic agents 330 bile 137
antiphospholipid antibodies 248 biliary system 74
antiphospholipid syndrome (APS) 247-8 bilirubin 137
anti-thrombotic agents 244 biochemical markers of bone turnover 120
antivirals 314-17 biochemistry 177-97
aorta 89 acetylcholine receptors 181-2
aortic arches 31 adrenergic receptors 177-81
aorticopulmonary septum 30 carbohydrates 184-7
apoptosis 233-4 cells 177-9
appendices epiploicae 70 fat 187-8
appendicular skeleton 27-8 hormones 190-5
appendix 72 intracellular receptors/messengers 182-3
arcuate line of Douglas 52 prostaglandins 195-6
arcuate nucleus 204 proteins 188-90
arterial system 31-2, 89-93 starvation 196-7
 Index 385

biomimetics 255 canals 54-7

biotransformation 304 cancer:
B-Lactamase resistance 313 cervical 256, 257, 260
B-Lactams 312 childhood 361
bladder 78, 142 and combined oral contraceptive pill 336
blastocyst 15-16 endometrial 258, 259
blood 127 genetic predisposition to 240-1
circulation, placental 170 Krukenberg 260-1
flow 126-7 malignancy 240, 362
group (ABO) 127 metastasis 240, 241
oxygen content 135 neoplasia 239-44
pressure (BP) 126 risk and X-radiation 362
substitutes 255 vaginal 264
tests, specific 267-8 vulval 263, 264
transfusion 254-5 see also tumour
vessels 126-7 carbamazepine 323
blotting 4 carbimazole 331
body cavities 24-6 carbohydrate 184-7, 225
Bohr effect 135 antigen (CA) 243
bones 46, 152-3 carbon dioxide:
formation 26 partial pressure of 114, 131, 135
innominate 60 transport 135-6
and osteoporosis 120-1 carcinoembryonic antigen (CEA) 243
and parathyroid hormone 117 carcinogenic agents 242
pelvis 60-3 carcinoid syndrome 243
skull 109 cardinal ligaments 64
bradykinin 229 cardiopulmonary adjustments at birth 168-9
brain 45-6, 95-6, 159 cardiotocography (CTG) 344-6
branching morphogenesis 28 cardiovascular system 29-33, 122-8
Braxton Hicks 87 carotid sheath 108
BRCA genes 241 cartilages 46
breastfeeding/lactation 224-5, 305-6, 311-13 catabolic phase of injury 236
breasts 88-9 catecholamines 158, 243
breech presentation 342 categorical data 376-8
Brenner’s tumour 261 cat-scratch disease 231
bronchi 129 cells/cellular 177-8, 225
bulbourethral (Cowper's) glands 80 adaptation 231-2
bulbus cordis 29 ageing process 235-6
buserelin 334 cycle 4
division and replication 4-6
calcitonin 117, 243 injury 232-7
calcitriol 117-18 mediators 269, 270, 274-7
calcium channel blockers 323 response to inflammation 228-9, 230
calcium homeostasis 115-22 surface receptors 179
bone and osteoporosis 120-1 central venous pressure (CVP) 123, 253
disorders 118-20 cephalic presentation 342
pregnancy 122 cerebrospinal fluid (CSF) 96
regulatory hormones 116-18 cerebrum 95
calcium ion influx 233 cervix/cervical 86, 87
calories 138-9 cancer/neoplasia 256, 257
canalicular period 167 pathology 255-6
 386 ~—Index

cervix/cervical (cont.) corpus luteum 148, 199, 221, 353

ripening 223 correlation (statistics) 378-80
screening 255 corticospinal tracts 98, 99
somites 26 corticotrophin-related peptides 205
Charles’ law 131 costal margin 61
chemical mediators of inflammation 229 Coulomb per kilogram 361
chemoreceptors 125 covariance 378
chemotaxis 228 cranial nerves 96, 97
childhood cancer 361 C-reactive protein (CRP) 272
Chlamydia trachomatis 291 cristae terminalis 31
chloramphenicol 311 Cushing’s syndrome 217, 243
cholesterol 191 cyclizine 328
chorion 20-1, 23, 167, 358 cyproterone acetate 333
chromaffin cells 109 cystic duct 74
chromosomes 2, 3 cystic fibrosis 11-12
abnormalities 6-9 cytochrome P450 complex 192
circulation, fetal 168-9 cytokines 229, 273
clinical testing 380-2 cytomegalovirus (CMV) 297
clitoris 83 cytoplasm 178
coagulation 244-50 cytotrophoblast layer 21
abnormalities 247-50
cascade 245-6 daily recommended intake 139
laser effects on living tissue 367 dalteparin 326
system 244-7 Dalton’s law 131
coagulopathy, transfusion induced 255 danazol 334
cocaine 307-8 dead space 133
coccygeus 64 decidua (endometrium) 19-20, 87
coccyx 60 decompression sickness 249
codons 2 deletion (genetics) 9
coeliac axis 67 depolarizing blocking agents 182
collagen 190 dermatomyositis 243
combined oral contraceptive pill dermis 162
(COCP) 335-7 detoxification 189
compensatory anti-inflammatory response detrusor inhibitory sympathetic impulses 143
(CARS) 236 diabetes insipidus (DI) 214, 215
complement mediated hypersensitivity 270 diagnostic test performance 380-2
complement system 229, 271-2 diaphragm 24-6
confounding variables 378 diathermy 368
conjoint tendon 54 diazepam 325
conjugation (drug distribution) 304 dictyate 146
Conn’s disease 217 digestive tract 136-8
contraceptives 334—40 dihydrofolate reductase inhibitors 310
combined oral contraceptive pill 335-7 dinoprostone 319-20
emergency contraception 340 2,3-diphosphoglycerate 136
intrauterine coils 339-40 disseminated intravascular coagulation
progesterone-only contraception 337-9 (DIC) 248-9
Coombs’ test 267-8 distal convoluted tubule (DCT) 141
Cori cycle 186 distributions (statistics) 372-4
cornea 50 DNA 2, 362
coronary circulation 126 domperidone 306
corpus albicans 148 dopamine 204
 Index 387

agonists 306 diseases, endocrine 214-18

Down’s syndrome 7 fetal and neonatal endocrine system 226
drugs see pharmacology hypothalamic hormones 203-5
ductus arteriosus 32, 169 labour 223-4
ductus venosus 32 pancreatic hormones 213-14
duodenum 35, 68-70 pituitary gland hormones 205-9
dynamic fluid response 253 placental hormones 220-2
dysplasia 232 puberty 218-20
puerperium 224
ear development 50 renin-angiotensin system 212-13
ebb phase (shock phase) of injury 236 sex hormones 199-203
echinocandins 314 systems, endocrine 223
ectoderm 18 thyroid gland hormones 209-10
ectopic pregnancy 354, 355 endoderm 18, 33
Edward’s syndrome 8 endometrial cancer 258, 259
ejaculatory ducts 80 endometrial hyperplasia 258
electrocardiogram (ECG) 124, 128 endometrial stromal cells 19
electrocautery 368 endometrial thickness 352
electromagnetic spectrum 365 endometriosis 257-8
electronic fetal monitoring 343-7 endothelial changes in pregnancy 128
electrosurgery 368 endothelium 244
EllaOne 340 endotoxins 285
embolism 249 energy expenditure increase in cell injury 237
embryology 15-50 enolic acid derivatives 329
body cavities and diaphragm 24-6 enoxaparin 326
cardiovascular system 29-33 Enterococcus genus 287
ear development 50 entry inhibitors 316
embryo 24 enzyme-linked receptor 179
embryo folding 17 eosinophils 274
embryogenesis 15-19 ependyma 155
embryological remnants (testes) 81 epidemiological studies 370-1
eye development 49-50 epidermis 162
face and neck development 46-9 epididymides 80
fetal membranes 22-4 epiploic foramen 58
gastrointestinal system 33-7 epithelium/epithelial 71, 79
musculoskeletal system 26-8 component of respiratory system 28
nervous system 43-6 origin malignancy 240
nutrient requirements of embryo 19 ergometrine 320
placenta 19-22 erythrocyte 127
reproductive system 38-43 sedimentation rate (ESR) 272
respiratory system 28-9 erythropoietin (EPO) 273
urinary system 37-8 ethanol 308-9
embryonic death 354 evidence, strength of 371
embryonic pole 353 exenatide 332
emergency contraception 340 exons 2
endocrine agents 331-2 exophthalmos 216
endocrine anatomy 104-9 exotoxins 285
endocrinology 199-226 expiratory reserve volume (ERV) 132
adrenal hormones 210-12 extracellular fluid (ECF) volume, hormones
breastfeeding/lactation 224-5 regulating 111
changes in pregnancy 220, 221 extramammary Paget’s disease 263
 388 Index wa,

extrapyramidal pathway 98 erythropoiesis 169

extravasation 228 gonadal development 226
extra-villous trophoblast 170, 281 growth restriction 356, 357
exudation 228, 230 immunology 280
eye development 49-50 lung 167-8
maternal gas values 135
face and neck development 46-9 membranes 22-4, 166-7
factorV Leiden 246 monitoring, electronic 343-7
fallopian tubes 87 movements (quickening) 171
false negative 374-5, 380, 381 oxygen transport 134-6
false positive 374-5, 380, 381 parathyroid development 226
Faraday’s law 364 pituitary development 226
fasciae 63-4 respiratory system 134-6, 167
fat 187-8, 225 risk and pharmacology 311-13
fatty acids 187 skull 109-10
female genital tract 82-9 swallowing 166
female reproductive system 144-50 thyroid development 226
folliculogenesis 144-5 tissues 165-9
menarche 148-9 urine 165
menopause 149-50 weight 172
oogenesis 145-6 fibrinoid deposits 22
reproductive cycle 146-8 fibrinolytic cascade 246-7
femoral arteries 91-2 fibrinolytic system 176
femoral nerve 101 fibroblast growth factor (FGR) 355-6
femoral ring 56 fibroma-thecomas 261
femoral sheath 55, 56 Fick's law 131
femoral triangle 55 FIGO classification:
fenamic acid derivatives 329 cervical cancer 257, 260
fentanyl 307 ovarian carcinoma 263
Ferguson reflex 224 first breath following delivery 167
fetus/fetal: flow phase of injury 236
abnormalities detected with fluids 111-13
ultrasound 357-8 folate metabolism 310
acid-base changes 115 follicles 145
adrenal development 171, 226 follicle stimulating hormone (FSH) 151, 205-6
alcohol syndrome 309 folliculogenesis 144-5
arterial redistribution 356 fontanelles 27, 109, 110
arterial values 114 Food and Drug Administration (FDA)
biophysical profile 357 pregnancy category 305
calcium 122 foramen caecum 47
cells 281 foramen ovale 30
circulation 168-9 foregut 34-5
compartment and proteins 222 fossae 54-7, 59
development in 1st week oflife 16 fractionation 362-3
development in 3rd week of life 17 functional residual capacity 133
development from week 4to 7 18 fungi 293
development from week 7 to 20 18
development from week 25 to 37 19 gall bladder 35, 74
ductus venosus Doppler, abnormal 356 gamma rays 360
endocrine system 226 Gardnerella vaginalis 289
erythrocytes 169 gaseous exchange 131
 Index 389

gases 158 glucose 184-5, 186

gastric secretions 136 glycogen 184
gastrointestinal agents 327-8 glycogenolysis 197
gastrointestinal system 33-7 glycolysis (Embden-Meyerhof) pathway 185
gastrointestinal tract 66-73, 139, 175 glycopeptides 312
anal canal 71-2 glycoproteins 205
appendix 72 gonadal cells 194
duodenum 68-70 gonadal development in fetus 226
large intestine 70-1 gonadal veins 93
Meckel’s diverticulum 73 gonadotropin 219-20
portal vein system 72-3 gonorrhoea 289
rectum 71 G protein-coupled receptors 179
small intestines 70 Graafian follicle 145
stomach 66-8 gram-negative organisms 288-91
gastro-oesophageal reflux disease drugs 327 gram-positive organisms 286-8
gastroschisis 36 gram stain 284-5
gastrosplenic ligament 34 granisetron 328
gastrulation 17 granules 274
Geiger-Nuttall law 360 granulocytes 274
gel electrophoresis dimensions 4 granulosa cells 144, 194
genetics 1-14 granulosa-theca cell tumour 261
cellular division and replication 4-6 Gray (Gy) 361
chromosomal abnormalities 6-9 greater omentum 58-9
disorders 10-14 greater saphenous veins 94
inherited genetic predisposition to greater sciatic foramen 61
cancer 240-1 griseofulvin 314
molecular biology 14 growth factors and healing 238
transfer 6 growth hormone 207, 208
genital ducts 39 growth-hormone-releasing hormone (GnRH)
genitalia 40, 41, 42, 43, 79, 82 151, 204, 219-20
genital tract: growth restriction, fetal 356, 357
female 82-9 growth spurt in puberty 219
male 79-82 gynaecology and pharmacology 332-4
genital tract disorders 255-64
cervical pathology 255-6 HO balance 111
ovarian tumours 260-2 H, receptor blockers 327
polycystic ovary syndrome 258, 260 haematological changes in pregnancy 128
uterine pathology 256-8 haemoglobin (Hb) 114, 135, 190
vulval and vaginal pathology 262-4 haemolysis 267, 268
genitofemoral nerve 100 haemolytic uraemic syndrome 249
gestational diabetes 186-7 haemorrhage 254
gestational sac 353 haemostatic plug formation process 245
Gimbernat’s ligament 56 Hageman factor activation 229
glands of Montgomery 88 Haldane effect 135
glial cells 155 half-life 358
glibenclamide 331 Hasselbach’s triangle 57
global hypoperfusion markers 254 Hay/Ison criteria for bacterial
glomerulus 141 vaginosis 289
glucagon 213-14 hearing 163
glucocorticoids 211 heart 29-30
gluconeogenesis 197 action 354
 390 ~— Index

heart (cont.) hypothalamus 104, 105

sounds 123-4 hypothesis testing, statistical 374-6
see also cardio hypothyroidism 214-15
helminths 294 hypoxaemia 343, 344
Henderson-Hasselbach equation 113 hypoxia 169, 343, 344, 346
heparin:
contraindications 327 idiopathic thrombocytopenic purpura
-induced thrombocytopenia syndrome 248 (ITP) 250
-low molecular weight (LMWH) 326 ileocaecal fold 72
-unfractionated 326 ileum resection 136
hepatic diverticulum 35 iliac arteries 89-91 _
hepatic duct, common 74 iliohypogastric nerve 100
hepatic muscle protein metabolism and cell iliopectineal eminence 60
injury 237 imidazole 314
hepatitis 300-1 immuno-contraception 281
hereditary non-polyposis colorectal cancer immunoglobulins 243, 276-7
(HNPCC) 241 immunological response to cell injury 236
heroin 306-7 immunology 269-81
herpes simplex 297 adaptive immune system 269-70
hindgut 36-7 cellular mediators 274-7
histamine 229 disorders, immunological 277-80
HIV 299-300, 317 hypersensitivity 270
homologous male and female structures 89, 93 immunohistochemistry (IHC) 277, 278
hormones/hormonal 190-5 innate immune system 269
bone development 152 pregnancy 280-1
changes leading to labour 223 soluble mediators 271-4
changes in ovarian cycle 147 tolerance, immune 270
control 151 transplantation 270-1
therapy 333-4 vaccines 271
see also endocrinology Implanon 339
human chorionic gonadotropin 220, 243 impulse conduction 158-9
human drug clinical testing phases 303 incidence (clinical testing) 381
human papillomavirus (HPV) 300 incisura angularis 66
human placental lactogen (hPL) 220, 222 indifferent gonad 38
human T-cell lymphotrophic virus (HTLV) 301 indometacin 328-9
hyaloid artery 49 infarction 250
hydatidiform mole 24 inferior gluteal nerve 102
hydralazine 322 inferior hypogastric plexus postganglionic
hydroxysteroid dehydrogenase (HSD) 192, 194 sympathetic innervations 104
hypercalcaemia 118-19 inferior vena cava (IVC) 93, 94
hyperparathyroidism 118 inflammation 227-31
hyperplasia 231-2, 232 inhibins 151, 201-2
hyperprolactinaemia 206 inspiration 130
hypersensitivity 270 inspiratory capacity (IC) 133
hyperthyroidism 215-16 inspiratory reserve volume (IRV) 132
hypertrophy 232 insulin 213
hypobranchial eminence 47 integrase inhibitors 316
hypocalcaemia 119-20 inter-cotyledon septa 21
hypoparathyroidism 120 interferons (IFN) 272
hypoprolactinaemia 206 interleukin-1 (IL-1) 273
hypothalamic hormones 203-5 inter-observer variability 382
 Index 391

interventional studies 370 large intestine 70-1, 136

intervillous space 21 larynx (voice box) 28, 129
intestines 70-1, 117, 136 LASER 365-7
intracellular accumulation of metabolites or laxatives 327, 328
pigments 234-5 lens vesicle 49
intracellular receptors/messengers 182-3 lesser omentum 58, 59, 73
intra-embryonic coelom 19, 25 lesser sac (peritoneal cavity)
intra-observer variability 381 35, 57-8
intrapartum science 341-7 lesser sciatic foramen 62
electronic fetal monitoring 343-7 leucocytes 127,274
labour 341-3 adhesion diapedesis 228
intrapleural pressure (IP) 130-1 levator ani 64
intrauterine coils 339-40 levonorgestrel 340
introitus 84 Leydig cells 81, 194
introns 2 tumour 261-2
in vitro fertilization treatment 353 lichen sclerosis 262
ion channel 156-7 lichen simplex chronicus 262
-linked receptors 179 lidocaine 307
ionizing radiation 358-64 lienorenal ligament 34
nuclear medicine 363 ligaments 54-7
radionuclide 363-4 cardinal 64
radiotherapy 362-3 of Cooper 88
X-radiation 360-2 gastrosplenic 34
iron 139 infundibulopelvic 87
ischaemia-reperfusion syndrome 253 inguinal 54
ischiorectal fossa 65, 66 lacunar (Gimbernat’s) 56
islets of Langerhans 74 pelvic 60-3
peritoneal cavity 59
jejunum versus ileum 70 round 64
J-receptors (proprioceptors) 131 sacrospinous 61
juxtaglomerular apparatus 141, 212 sacrotuberous 61
spleen 75
ketone bodies 187 uterine 87
kidney 75-6, 117, 141, 212 uterosacral 64
Kleihauer’s test 268 light, physics of 365
Klinefelter’s syndrome 9 likelihood ratio (LR) 380
Kreb’s cycle 186 lincosamide 311
Krukenberg cancer 260-1 linea alba 52
Kupffer cells 35 linea similunaris 61
linea terminalis 61
labetalol 322 lipid hormones 191
labia majora 83 lipids 234
labia minora 83 lipoid congenital adrenal hyperplasia
labour 223, 341-3 (CAH) 194-5
dystocia 341-3 lipolysis 197
endocrinology 223-4 Listeria monocytogenes 288
lactate 184 liver 35, 73-4
lactose 184 longitudinal venous channels 32-3
fermenters/non-fermenters 285 loop of Henle 141
lanugo 172 loperamide 328
Laplace’s law 132 lumbar plexus 100
 392 ~— Index

lung: membranes, fetal 22-4, 166-7

anatomy 129 menarche 148-9
buds 28 Mendel’s law/Mendelian inheritance 6
compliance 132 meninges 45, 98-9
disease 133 menopause 149-50
epithelium 28-9 menstrual cycle 147, 149, 224
fetal 167-8 mesenchyme 26, 50
volumes 132-3 condensation around notchboard 27
luteal cells 194 origin malignancy 240
luteinizing hormone (LH) 151, 206-7 mesentery, dorsal 33
lymphatic drainage of uterus 86 mesoderm 18-19, 25, 28, 33
lymphatic drainage of vagina 85 mesoduodenum 35
lymphatic system 68, 94—5, 161 mesogastrium, dorsal 33
lymph nodes 275-6 mesonephros 37, 38, 39
lymphocytes 274-5 metabolic compensation 114
Lynch’s syndrome 241 metabolic response to cell injury 236
Lyon’s hypothesis 9 metabolism (drug distribution) 304
metabotropic glutamate receptor family 180
McBurney’s point 61 metanephric blastema 38
macrolides 311 metanephros 37, 38
magnesium sulphate 324 metaplasia 232
magnetic resonance imaging (MRI) 364-5 metastasis 240, 241
major histocompatibility complex (MHC) 276 metformin 331
malaria 295-6 methotrexate 330, 331
malignancy 240, 362 methyldopa 322
maltose 184 metoclopramide 328
mast cell mediated hypersensitivity 270 metronidazole 313
maternal arterial values 114 microbicidal substances 228-9
maternal compartment and proteins 222 microbiology 283-301
maternal gas values 135 bacteria 283-93
maternal respiratory system 134-6 fungi 293
materno-fetal transport 161 protozoa 294-6
Mayer-Rokitansky-Kuster-Hauser syndrome 43 viruses 296-301
mean arterial pressure (MAP) 126 microwaves 367-8
Meckel’s diverticulum 36, 73 micturition 142-3
meconium 171 midgut 35-6"
medical physics and clinical applications 349-68 mifepristone 332-3
non-ionizing radiation 364-8 minerals 139
see also ionizing radiation; ultrasound miscarriage 354
medical statistics 371-80 misoprostol 319
categorical data 376-8 missed pill rule 337, 338
correlation and regression 378-80 mitochondria 178
distributions 372-4 mitosis 5
statistical hypothesis testing 374-6 mixed venous oxygen saturation 254
variables and sampling 371-2 molar pregnancy 24
medroxyprogesterone acetate molecular biology 1-4
(Depo-Provera) 338-9 mons pubis 83
mefloquine 217-18 morphine 306
meiosis 5, 6 morphological patterns of inflammation 230
Meissner’s corpuscles 164 mosaics 7
melatonin 205 M-protein 286
 Index 393

mucosa 70 neuropeptides 158

multiple sclerosis (MS) 279 neurotransmitters 158-9
muscarinic receptors 181-2 neurulation 17, 43
musculoskeletal system 26-8, 46, 64, 152-4 nicotinic receptors 181, 182
myasthenia gravis 243, 279-80 nifedipine 321
mycophenolate mofetil 330 nitric oxide 183, 229
Mycoplasma hominis 290-1 nitrofurantoin 310, 314
myeloid progenitor cells 274 nitrogenous base 1
myofibrils 154 nitrogen requirements 139
non-depolarizing blocking agents 182
nasal cavity 48-9 non-ionizing radiation 364-8
nasopharynx 129 non-nucleoside reverse transcriptase inhibitor
neck see face and neck development (NNRTI) 316
necrosis 234, 235 non-steroidal anti-inflammatory drugs
necrotizing fasciitis 291-2 (NSAIDs) 328, 329
negative predictive value (NPV) 380, 381 nuchal translucency 354
Neisseria family 288-9 nuclear medicine 363
neonatal endocrine system 226 nucleic acids 1-2
neonatal narcotics abstinence syndrome 307 nucleoside reverse transcriptase inhibitor
neonatal skin 172 (NRTI) 316
neoplasia 239-44 nucleotide reverse transcriptase inhibitor
nephrons 141 (NtRTI) 316
nerves 46 nucleotides 1
cells 44 nucleus 178
fibres 155-6 number needed to treat (NNT) 377-8
innervation 48 nutrient requirements, embryonic 19
plexuses 70, 100, 105 nutrition 138-9
supply in stomach 68
nervous system 43-6, 154-61 observational studies 370-1
action potential 156-8 obstetric cholestasis 266
autonomic 160-1 obturator arteries 92, 93
brain 159 obturator externus 63
nervous tissue 155-6 obturator foramen 60
neurotransmitters 158-9 obturator internus 63
reflexes 159-60 obturator nerve 100-1
neural crest 43, 44, 48 occult hypoperfusion 253
neural folds 43 odds calculations 377
neural plate 43 oedema 112-13
neural tube 43-4, 45 oesophagus 34
defects (NTD) 44, 357 oestradiol 200
neuraminidase inhibitors 315 oestrogen 194, 199-201, 285, 336
neuroanatomy 95-104 olfaction 164
autonomic nerves 103-4 oligohydramnios 355, 356
brain 95-6 omphalocoele 36
cranial nerves 96, 97 ondansetron 328
peripheral nerves 100-3 oocytes 146
somatic pathways 96, 98 oogenesis 145-6
spinal nerves 98-9 oogonia 146
neuroendocrine response to cell injury 236-7 optic stalk 49
neurohypophysis 107 optic vesicles 49
neuronal structure 155 organelles 178
 394 = Index

oropharynx 129 parvovirus B19 298-9

oseltamvir 315 Patau’s syndrome 8
osmosis 111-12 pathological calcification 118
ossification 26, 152 pathology 227-68
osteoblast modulators 120 blood tests, specific 267-8
osteoclast 120 cell injury 232-7
osteoporosis 120-1 cellular adaptation 231-2
ostium primum 30 coagulation 244-50
ostium secundum 30 genital tract disorders 255-64
otic placode 50 inflammation 227-31
otic vesicle 50 neoplasia 239-44
ovaries/ovarian 39, 87-8 pregnancy, disorders in 264-7
follicles 144, 352-3 sepsis 251
fossa (Waldeyer’s) 88 shock 252-5
tumours 260-2 wound healing 237-9
ovotesticular disorder of sexual Pearl index and contraception 335
development 42 pectinate line 37
ovulation 147-8 pelvis/pelvic 60-6
ovum development stages 146 brim 60-1
oxygen: diaphragm 64
-derived free radicals 233 female compared to male 62
dissociation curve 135 floor 64-6
partial pressure of 114, 131, 135 inflammatory disease 292-3
saturation 114, 135, 254 joints 60
transport, maternal and fetal 134-6 measurements 62, 63
oxytocin 208-9, 318-19 muscles 63
outlet 61
p53 242, 244 splanchnic nerve 104
Pacinian corpuscles 164 penicillin 310
pain 164-5 perineum 65
palate 49 peripartum cardiomyopathy 267
Palmer's point 52 peripheral nerves 100-3
pancreas/pancreatic 34-5, 74—5 peritoneum 35, 57-9, 71
changes in pregnancy 221 peri-ventricular nucleus 204
hormones 213-14 pH 113, 114, 135
juices 137 phaeochromécytoma 217-18
paracentesis 52 pharmacology 303-40
paramesonephric duct 39 analgesics 306-9
paraneoplastic syndromes 242, 243 antibiotics 309-14
parasympathetic nervous system 161 anticoagulants 325-7
parathyroid: antiepileptic drugs 323-5
changes in pregnancy 221 antifungals 314
development in fetus 226 antihypertensive agents in pregnancy 322-3
glands 108, 226 anti-inflammatory and immune
hormone (PTH) 116, 117 modulators 328-31
hormone-related peptide (PTHrP) 116-17 antimalarials 317-18
paraventricular nucleus (PVN) 203-4, 204 antivirals 314-17
partial pressure of carbon dioxide biotransformation 304
Ae Aetioie 1So contraceptives 334—40
partial pressure of oxgyen 114, 131, 135 distribution of drug 303-4
parturition see labour endocrine agents 331-2
 Index 395

gastrointestinal agents 327-8 placenta/placental 19-22

in gynaecology 332-4 accreta 24
human drug clinical testing phases 303 blood circulation 170
interactions of drugs 304 changes in pregnancy 221
pregnancy 304-6 compartment and proteins 222
tocolytics 320-1 disorders 24
uterotonics 318-20 hormones 220-2
volume of distribution (Vd) 304 increta 24
pharyngeal arches 46, 47 membrane 22
pharyngeal clefts 46 percreta 24
pharyngeal pouches 46-7 praevia 354-5
pharynx 128-9 septa 21
phenytoin 324 tissues 169-71
phosphate functions 116 placodes 49
phosphaturic hormone 117 plasma membranes 156, 177
phospholipids 187 plasma osmolarity 112
photon 365 platelet-activating factor 229
physiological jaundice 137 platelets 245
physiological response to cell injury 236 pleura 29
physiology 111-76 Poiseuille’s law 132
acid-base balance 111-15 polycystic ovary syndrome 258, 260
calcium homeostasis 115-22 polycythaemia 243
cardiovascular system 122-8 polyene 314
digestive tract 136-8 polyhydramnios 355
female reproductive system 144-50 polymerase chain reaction 3
fetal tissues 165-9 porta hepatis 73
gastrointestinal tract changes in portal vein system 72-3
pregnancy 139, 175 positive predictive value (PPV) 380, 381
hearing 163° posterior (anal) triangle 65
lymphatic system 161 posterior column 98
male reproductive system 150-2 posterior cutaneous nerve 102
musculoskeletal system 152-4 power (sensitivity) of a study 375
nervous system 154-61 Prader stages 43
nutrition 138-9 Prader-Willi syndrome 9
olfaction 164 pre-antral follicle 145
pain 164-5 precision (reproducibility) 381
physiological changes in pregnancy 173-6 pre-eclampsia 264-6
placental tissues 169-71 pregnancy:
respiratory system 128-36 acid-base changes 115
sight 162-3 adrenal changes 221
skin 161-2 antihypertensive agents 322-3
taste 163-4 antimalarial drugs 317, 318
touch 164 calcium 122
urinary system 141-3 cardiovascular changes 128, 173
pillars of fauces 129 coagulation system changes 247
pineal gland 107 decidua (endometrium) 20
piriformis 63 disorders 264—7
pituitary changes in pregnancy 221 ectopic 354, 355
pituitary development in fetus 226 endocrine changes 220
pituitary gland 45, 106-7 endothelial changes 128
hormones 205-9 gastrointestinal changes 139, 175
 396 ~— Index

pregnancy: (cont.) protein S 246

genital tract changes 86-7 proteins 188-90, 225
haematological changes 176 protein synthesis 3
immunology 280-1 proteomics 4
liver changes 175 pro-thrombotic agents 244
maternal oxygen consumption 134-6, 174 proton pump inhibitors (PPIs) 327
metabolic changes 176 protozoa 294-6
molar 24 proximal convoluted tubule (PCT) 141
musculoskeletal changes 154 pseudoglandular period 167
pancreatic changes 221 puberty 218-20
parathyroid changes 221 pubic symphysis separation 154
pharmacology 304-6 pudendal arteries, internal 93
physiological changes 173-6 pudendal nerve 103
pituitary changes 221 puerperium 128, 224
placental changes 221 pulmonary embolism (PE) 362
pulmonary changes 173-4 pulmonary surfactant 132
renal changes 174, 175 pulmonary vascular resistance (PVR) 129
respiratory changes 133-4 P-value 374
sense changes 165 pyloric antrum 66
sickle cell disease 13 pyrimidine analogue 314
skin changes 163
thromboprophylaxis 325 QT interval 124
thyroid changes 210, 221 quantitative data 376
ultrasound 253-5 quinolone 313
urinary system changes 143
uterine changes 176 rachischisis 44, 357
see also entries under maternal Rad 361
pre-optic nucleus 204 radiation poisoning 360
preovulatory follicle 145 radioactive decay 358
prevalence (clinical testing) 381 radiofrequency fields 364
primary follicle 145 radionuclide 363-4
primordial follices 144 radiosensitizing drugs 363
primordial germ cells 146 radiotherapy 362-3
processus vaginalis 41 receiver operator characteristic (ROC)
prochlorperazine 328 curve 381
progesterone 133, 201, 336-7 rectum 71 +
-only contraception 337-9 rectus sheath aponeurosis 52, 53
proinflammatory cytokines 236 5a-reductase 203
prolactin 207, 208, 224 reflexes 159-60
prolactinoma 218 refractory periods 158
pronephros 37 regression (statistics) 378-80
propionic acid derivatives 329 Reiter’s syndrome 293
propylthiouracil (PTU) 331 relaxin 202
prostaglandin dehydrogenase (PGDH) 196 renal fascia 76
prostaglandins 195-6, 319 renal metabolic changes 143
prostate 81-2 renal pelvic dilatation 358
prostate-specific antigen (PSA) 243 renin-angiotensin system 212-13
prostatic acid phosphatase (PAP) 243 repaglinide 332
prostatic plexus 82 replicative senescence 235
protease inhibitor (Pl) 316 reproductive system 38-43
protein C 246 development disorders 41-3
 Index 397

male 150-2 seminiferous tubules 81

see also female sensitivity (clinical testing) 380, 381
research tools 369-82 sepsis 251
clinical testing 380-2 septum primum 30
research methodology 369-71 septum secundum 30
see also medical statistics septum transversum 25
residual volume (RV) 132 serotonin 229
respiratory compensation 114 Sertoli cells 81
respiratory distress syndrome (RDS) 167-8 sex chromosome aneuploidies 8
respiratory diverticulum 28 sex determination 218
respiratory system 28-9, 128-36 sex hormone-binding globulin (SHBG) 203
breathing, mechanics of 130-2 sex hormones 199-203
changes in pregnancy 133-4 shock 252-5
fetal 134-6, 167 shoulder dystocia 342-3
function 132-3 sickle cell disease (HbS) 12-13
maternal 134-6 sight 162-3
respiratory tree 128-9 sinovaginal bulb 40
resting membrane potential 157 sinus venarum 31
retina 49 sinus venosum 30-1
rhodopsin-like receptor family 180 skeletal muscle protein metabolism and cell
ribavirin 315 injury 237
ribs 27 skin 161-2
risk (categorical data) 376-7 neonatal 172
ritodrine 321 skull 27
RNA 2 small intestine 70, 136
Roentgen 361 soluble mediators 269, 270, 271-4
rosiglitazone 332 somatic pathways 96, 98
Rotterdam criteria 260 somatomammotrophin peptides 205
rubella 298 somatostatin 204-5
Rules of 2 73 somites 18-19
Spalding sign 344
sacral plexus 102 specificity (clinical testing) 381
sacrospinous ligament 61 spermatic cord 54-5
sacrotuberous ligament 61 spermatocyte, secondary 150
sacrum 60 spermatocytogenesis 150
salbutamol 321 spermatogenesis 150
salivary glands 136 spermatozoa 151-2
sampling (statistics) 371-2 spermiogenesis 151
saphenous nerve 101-2 sphincters 66
sarcoidosis 231 spina bifida cystica/occulta 44, 357
scars 239 spinal cord 44-5, 99
sciatic nerve 102-3 spinal nerves 98-9
screening tests/programmes 380, 382 spinothalamic tract 96-7
scrotum 79-80 spirometry changes in lung disease 133
secondary follicle 145 splanchnic nerve 104
secretin receptor family 180 splanchnopleuric mesoderm 28, 33
selective COX2 inhibitors 329 spleen 34, 75
selective oestrogen receptor modulator ST analysis (STAN) 346-7
(SERM)is83=4 Staphylococcus 288
semen 151 Starling’s law 112, 125
seminal vesicles 80 starvation 196-7
 398 Index

statistical bias 371 tetracycline 312

statistical hypothesis tests 376 thalassaemia 13-14
stem cells 5 theca cells 144, 194
sternum 27 thoracic duct 94
steroidogenesis 193, 194-5 thoracoepigastric veins 94
steroids 191-4, 329-30 thrombocytes 127
stomach 34, 66-8 thrombocytopenia 249-50
Streptococcus 286-7, 291-2 thrombopoietin 274
stress response 210 thromboprophylaxis in pregnancy 325
stroke volume (SV) 125 thrombosis 247
study design 369 thrombotic thrombocytopenic purpura 249
subphrenic spaces 59 thyroid changes in pregnancy 221
succenturiate lobe 24 thyroid development in fetus 226
sucrose 184 thyroid gland 47, 107-8
sulcus limitans 44-5 hormones 209-10
sulcus terminalis 47 thyrotrophin-releasing hormone (TRH) 205
sulfonamides 310, 312 tibolone 333
superior gluteal nerve 102 tidal volume (TV) 132
supraoptic nucleus 204 tinzaparin 326
suprarenal (adrenal) glands 108-9 tissue in bone 152-3
surfactant 167, 226 tissue, placental 169-71
sutures of skull 109 tissue plasminogen activator (t-PA) 326-7
sweat glands 162 tisues, fetal 165-9
sympathetic nervous system 160-1 amniotic fluid 165-6
synaptic transmission 158-9 circulation 168-9
syncytiotrophoblast 170, 281 lungs 167-8
syndrome of inappropriate antidiuretic membranes 166-7
hormone hypersecretion (SIADH) tocolytics 320-1
214, 243 tolerance, immune 270
syphilis 290 tongue 47-8
systemic lupus erythematosus (SLE) 277-9 topoisomerase inhibitors 330
systemic response to cell injury 236 total lung volume (TLV) 133
systemic vascular resistance (SVR) 126 touch 164
Toxoplasma gondii 294-5
taenia coli 70 T/QRS ratio 347
tail of Spence 88 trachea 129 +
Tanner’s stages for male and female 219 tramadol 308
taste 163-4 translocation (genetics) 9
T-cells 275 transplantation 270-1
mediated hypersensitivity 270 transverse mesocolon 36
telomerase 235 tricarboxylic acid cycle (TCA) 185-6
Tensilon test 279 Trichomonas vaginalis 294
teratogenicity 323 triglycerides (TAGs) 187
teratogens 304—5 trigone 78
teratomas 261 trisomies 7
terbutaline 321 Trousseau’s phenomena/syndrome 243, 248
terminal sac period 167 true negative 380
Tesla (T) 364 true positive 380, 381
testes 38-9, 80-1, 202 truncus arteriosus 30
testicular descent 41 trunk surface anatomy 51-2
testosterone 202-3 t-test 375-6
 Index 399

tuberculosis 231 vascular tree - veins 93-4

tuberous sclerosis 11 vasodilation 227
tumour 260-2 vein of Mayo 66
markers 243, 262 velocardiofacial (DiGeorge) syndrome 9
necrosis factor (TNF) 273 venous drainage of heart 30-1
Turner’s syndrome 9 venous system 32-3, 123, 253
twins 23 venous thromboembolism 337
twin-to-twin transfusion syndrome (TTTS) 24, venous thrombosis 243
25 ventilation 130, 131
muscles 129
ubmilicus/umbilical: ventral mesentery 33
cord 22 ventricular septum 30
ultrasound 349-58 ventricular system 45
Doppler 351-2, 356 vernix caseosa 172
in early pregnancy 353-5 vertebral column 26-7
fetal abnormalities 357-8 vertebral levels 61
fetal well being assessment 355-7 vestibule 83
in non-pregnant pelvis 352-3 vildagliptin 332
umbilicus 32, 61, 356 villi 20-1, 170
under-masculinization 42 Virilization 42
urea cycle 189 viruses 296-301
ureter 76-7, 142 cytomegalovirus (CMV) 297
ureteric bud 38 DNA 296
urethra 78-9 hepatitis 300-1
urinary system 37-8, 75-9, 141-3 herpes 296, 297
urodynamic values 143 HIV 299-300
urogenital (anterior) triangle 64 human papillomavirus (HPV) 300
urogenital sinus 40 human T-cell lymphotrophic virus
urorectal septum 37 (HTLV) 301
uterine fibroids (leiomyomas) 256-7 parvovirus B19 298-9
uterine immune system cells 280 RNA 296
uterine pathology 256-8 rubella 298
uteroplacental insufficiency 356 varicella zoster 297-8
uterotonics 318-20 vital capacity (VC) 132
uterovaginal canal 39 vitamin D 117
uterus 85-6 -related disorders 119
vitamins 139, 140, 225
vaccines and immunology 271 vitelline artery/veins 32
vagina/vaginal 84-5 volatilization and laser effects on living
cancer 264 tissue 367
discharge in children 291 volume of distribution (Vd) 304
flora 285 vulval cancer 263, 264
pathology 262—4 vulval intraepithelial neoplasia (VIN) 262-3
valproate 323-4 vulval pathology 262-4
variables (statistics) 371-2
varicella zoster 297-8 warfarin embryopathy 325-6
vasa deferentia 80 Weber (Wb) 364
vascular network of pituitary 106, 107 weight, fetal 172
vascular permeability 228 Wharton’s jelly 22
vascular response to inflammation 227-8, 230 World Health Organization: Principles and
vascular tree - arteries 31-2, 89-93 practice of screening for disease 382
 400 Index

wound healing 237—9 yolk sac 23, 353

wound infection 251, 291
zanamivir 315
x test 376 zwitterions 188
X-radiation (X-ray) 360-2 zygote 15, 23
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