Endocrine System

Diseases
Dr. Fitria Nurul H, M.Sc, SpPD
Interna Department
UMY

Endocrine system - together with the nervous system, acts as

the bodys communication network

- it is composed of various endocrine

glands and endocrine cells

- the glands are capable of synthetizing and

releasing special chemical mesengers - hormone

Hormones - substances which are secreted by specialised cells in

very low concentrations and they are able to influenc

secreted cell itself (autocrine influence), adjacent cell

(paracrine influence) or remote cells (hormonal influen

The main groups of hormones

Classic hormones (produced by specialised glands) are divided into
three groups:

1. low molecular (amine) hormones (catecholamines, thyroid hormone

prostaglandins, leucotrienes, dopamine, serotonine, GABA,
melatonin ...)
2. steroid hormones (e.g.gluco- and mineralocorticoids)

3. polypeptidic and protein hormones (e.g. insulin, leptin...)

Another groups of hormones

A. hypothalamic hormones (discovered in 1969)
B. gastrointestinal hormones (more than 26 GI polypeptides)
C. opioid peptides (endogenic opioids)

D. tissue growth factors (epidermal growth factor, nerve growth fa

PDGF, insuline-like growth factor ...)
E. atrial natriuretic hormone (ANF)
F. transforming growth factors and hematopoietic
and other growth factors (FGF....)
G. endothelial factors (endothelins, EDRF...)
H. cytokines (interleukiny, interfern, TNF....)

General characteristic of hormones

1. they have specific rates and patterns of secretion (diurnal,
pulsatile,
cyclic patterns, pattern that depends on the level of circulating
substrates)

2. they operate within feedback systems, either positive(rare) or neg

to maintain an optimal internal environment

3. they affect only cells with appropriate receptors specific ce

function(s) is initiated
4. they are excreted by the kidney, deactivated by the liver or by
mechanisms

CELLS & SECRETIONS :

A- Anterior pituitary ( Adenohypophysis )

1-Somatotrophs from acidophilic cells Growth

H.
2- Lactotrophs from chromophobe cells
Prolactin
3- Corticotrophs from basophilic cells
ACTH,MSH .
4- Thyrotrophs from pale basophilic cells TSH
5- Gonadotrophs from basophilic cells FSH, LH
B- Posterior pituitary ( Neurohypophysis )

1- Oxytocin
2- ADH

Alterations of the hypothalamic - pituitary system

Deficiency of hypothalamic hormones

Variety of manifestations can be seen:

- In adult women: menses cease- absence of GnRH

- In adult men: spermatogenesis is impaired-absence of GnRH

ACTH response to low serum cortisol levels is decreased due to
absence of CRH
- Hypothalamic hypothyreoidism - absence of TRH

- Low levels growth hormone - absence of GH regulatory

hormones
- Hyperprolactinemia is caused by an absence of usual
inhibitory controls of prolactin secretion

Diseases of the posterior pituitary gland

Syndrome of inappropriate ADH secretion (SIADH):
It is characterised by high levels of ADH in the absence of normal
physiologic stimuli for its release

vated levels of ADH is caused by ectopically produced ADH (cancer

he lung, leukemia, response to surgery, inflammation of lung tissue,
chiatric disease, drugs-barbiturates, general anaesthesia, diuretics...)
water retention total body H2O aldosteron production
solute loss (Na+) hyponatremia hypoosmolality
ADH is released continually

dilutional hyponatremia suppression of renin production

aldosterone production Na+ reabsorbtion in kidney

Diabetes insipidus (DI) - is related to an insufficiency of ADH leadin

to polyuria and polydipsia

Three forms of DI do exist:

a) neurogenic or central form - amount of ADH production
b) nephrogenic form - inadequate response to ADH
c) psychogenic form - extremely large volumes of fluid intake
inhibition of ADH production

athophysiology:

DI - partial to total inability to concentrate urine due to chronic polyuria

washout of renal medullary concentration gradient
- increase in plasma osmolality thirst polydipsia
(looking for
cold drinks)
- urine output, urine specific gravity (1.00-1.005)

- dehydratation (if not adequate fluid intake)

Diseases of the anterior pituitary gland

Hypopituitarism is caused e.g. by infarction of the gland, removal, or

destruction of the gland

Hyperpituitarism - adenoma

Hypopituitarism - insufficient secretion of one (selective form), mor

than one or all (panhypopituitarism) hormones of
adenohypophysis

auses: idiopathic, organic damage of adenohypophysis or hypothalamus

e.g. pituitary infarction= Sheehan syndrome, pituitary apoplexy,

shock, DM, head trauma, infections, vascular malformations,
tumors

Consequences - they depend on the affected hormones

- if all hormones are defficient

panhypopituitarism:
the patients suffer from:
cortisol deficiency - because of lack of ACTH

thyroid hormones deficiency - because of lack of TSH

defficiency of FSH and LH - gonadal failure and loss of secondary se

characteristics
growth hormone somatomedin (they affect children growth)
absence of prolactin postpartum women are unable to lactate

Pituitary Gland Diseases

Hyperpituitarism
Hypersecretion of growth hormone (GH) by
the pituitary

Gigantism
GH hypersecretion during puberty and growth
years
Person is very tall, proportioned normally

Acromegaly
GH hypersecretion during adulthood
Disfiguring overgrowth of bones & soft tissues

Hyperpituitarism
Other aspects:
Gigantism:
Fairly abrupt onset
Non-life threatening
Growth up to 6 inches/yr

Agromegaly:
Gradual onset
Decreases life expectancy
Headache, sinus problems, skin changes,
paresthesias, joint pain, visual disorders

Hypopituitarism

Deficiency of any or all of the pituitary hormones

Usually involve GH and gonadotropin
LH, FSH, Prolactin, Oxytocin

Less commonly involved:

ACTH and TSH

Panhypopituitarism:
All hormones are deficient

Hypopituitarism

S/S: varies with hormone deficiency and age of disease

onset
In childhood: S/S are dwarfism and delayed development of
2ndary sexual characteristics
In adults: S/S are amenorrhea, infertility, lowering of
testosterone levels, libidy, hair loss.
ACTH & TSH deficiency: general S/S: fatigue, pallor,
anorexia, poor stress response

Hypopituitarism:

Treatment: hormone replacement

Diabetes Insipidus

Hyposecretion of vasopressin
ADH (antidiuretic hormone)

S/S: extreme polyuria, thirst, very dilute urine

produced, leads to dehydration
Etiology: anything that destroys the pituitary or
idiopathic
Treatment: fluid replacement, hormone replacement
(tablet, nasal spray)

Thyroid Gland Diseases

Goiter
Enlargement or hyperplasia of thyroid gland

Simple goiter
Goiter not caused by infection, tumor, other hypo- or
hyperthyroid condition
More common in females
Sporadic and endemic types

Goiter

Sporadic type
Ingestion of certain foods, drugs (goitrogens)

Endemic type
Diet deficiency of iodine

Etiology: hyperplasia due to inability to make sufficient

T3 and T4, compensation
Treatment: T3 or T4 or iodine replacements, surgery,
dietary changes

Thyroiditis
Inflammation of thyroid gland
Females more than males
Etiology & types:
Autoimmune
Antibodies to thyroid hormones
Myxedema, Graves disease
Hashimotos thyroiditis (lymphocytes infiltrate)

Subacute granulomatous
Follows an infection (mumps, influence, adenovirus)

Miscellaneous
Bacterial infections (TB, syphilis, suppurative)

Thyroiditis

S/S: may have no symptoms or thyroid enlargement,

pain and dysphagia
Autoimmune thyroiditis = most common type, common
in females
Treatment varies with type:
Hormone replacement, steroid, antibiotics, antiinflammatories, pain meds

Graves Disease
Hyperthyroidism
Graves disease is most common
hyperthyroid disease

Hypersecretion of T3 and T4
May cause thyrotoxicosis
Diffuse effect, multiple symptoms

Females mostly, 30-40 YOA

Etiology:
Genetic or immunologic

Graves Disease
S/S:
Thyrotoxicosis
Anxiety, insomnia, heat intolerance, sweating,
muscle wasting, weight loss, tachycardia,
hypertension
Thyroid storm: critical episode of thyrotoxicosis

Ophthalmopathy: exophthalmos (protrusion

of eyeballs, frightened appearance)
Dermopathy: thickened skin on legs/feet
(orange skin
Exacerbations & remissions

Graves Disease

Treatment:
Varies with disease severity & patient age
Antithyroid drugs, surgery, radioactive iodine therapy

Hypothyroidism

Hyposecretion of thyroid hormones

More common in women, esp. over 40 YOA
Two versions:
Cretinism
Congenital form

Myxedema
Starts in childhood or adulthood

Hypothyroidism
Etiology:
Dietary, metabolic, iatrogenic, congenital,
inflammatory, chronic autoimmune

S/S:
Children: growth retardation, delayed
sexual development, impaired intelligence
Adults: cold intolerance, fatigue,
constipation, weight gain, anorexia, dry
skin, brittle hair &nails, cardiomegaly,
myxedema coma

Treatment: Hormone replacement meds

Parathyroid Diseases

Hyperparathyroidism
Affects women more than men (2:1)
Excessive secretion of PTH by gland causes
abnormalities of calcium (Ca++) and phosphates
(PO4--)
Effects:
Hypercalcemia (most important effect)
hypophosphatemia

Hyperparathyroidism/
Hypercalcemia
Primary disease: parathyroid adenoma
Secondary disease: chronic RF, calcium
deficient diet, calcium malabsorption
Any condition that tends to reduce
circulating levels of calcium

S/S: many patients are asymptomatic

Brittle bones, arthralgias, calcium renal
stones, polyuria, nausea, vomiting, fatigue,
muscle weakness or atrophy, cardiac
arrythmias

Hyperparathyroidism

Treatment:
Surgical removal of gland(s)
Increasing fluid & sodium intake
Meds that increase calcium excretion
Treatment varies with the etiology, primary or secondary

Hypoparathyroidism

Undersecretion of PTH by gland

Hypocalcemia
Excessive calcium deposition into bones

Etiology: iatrogenic (surgical) or inherited

S/S: paresthesias of extremities, muscle cramps
(tetany), depresion, irritability, laryngospasm, seizures,
brittle nails, hair loss

Hypoparathyroidism

Treatment:
Vitamin D and calcium supplements
Periodic lab tests to determine serum levels
High calcium, low phosphorus diet

ENDOCRINE PANCREAS

 Diseases mainly include :

Diabetes
Islet Cell Tumors

DIABETES

DIABETES :

Chronic disorder in which there is abnormal metabolism, of

carbohydrate, fat & protein , characterized by either relative or absolute
insulin deficiency, resulting in hyperglycemia.
Most important stimulus that triggers insulin synthesis from cells is
GLUCOSE
Other agents stimulate insulin release
Level of insulin is assessed by the level of
C - peptide

Diagnosis :
1- Random glucose 200g / dL + symptoms
2- Fasting glucose of 126 / dL on more
than one occasion
3- Abnormal OGTT when glucose level is
more than 200g / dL 2hrs. after standard
glucose load of 75 g.

Classification :
Causes could be Primary in the pancreas OR
secondary to other disease conditions
Primary diabetes is classified into :

A- Type 1
B- Type 2
C- Genetic & Miscellaneous causes
Whatever the type, complications are the same

Type 1 :-

Absolute deficiency of insulin due to cell destruction

( 10%)
90% of cells lost before metabolic changes appear
Age 20 yrs but may be latent
Normal or decreased weight
Ketoacidosis is common

Type 2 :
Due to a combination of peripheral resistance to insulin
action & inadequate secretory response by the
pancreatic cells
Commoner ( 80 - 90% )
Insulin normal (relative insulin deficiency)
Patient is overweight
Rare ketoacidosis

Type 3 : Miscellaneous
Genetic defects :
causes

cell function
e.g. Maturity Onset Diabetes of the
Young
( MODY)caused by a variety of
mutations
Genetic defects of insulin processing
or action
e.g. Insulin gene or Insulin receptor
mutations

Secondary Miscellaneous
Causes :

Diseases of exocrine pancreas e.g. chronic pancreatitis

Endocrinopathies e.g. Cushings Syndrome,
Acromegally
Infections e.g. CMV
Drugs e.g. glucocorticoids
Gestational diabetes
Other genetic syndromes associated with diabetes

PATHOGENESIS

Pathogenesis of Type 1
Diabetes :
1- Genetic susceptibility
2- Autoimmunity
3- Environmental factors
It is a combination of autoimmunity &
environmental insult in a person with a
known genetic susceptibility leading to
destruction of cells

1- Genetic susceptibility
Principal susceptibility genes located in
region of MHC class II on chromosome 6p21
90% Associated with HLA- DR3,or HLADR4, or both
Racial predisposition, (Caucasians) but
majority have no family history
6- 20% familial ,< 40% in identical twins
Second susceptibility gene encodes a T cell
inhibitory receptor (CTLA-4) interfering with
normal T cell function

2- Autoimmunity Presence of CD 8+ & CD 4+ in islet cells

Insulinitis
Presence of islet cell antibodies ( insulin & GAD) in 80% of
patients & in relatives several months or years before onset
Antibodies are highly selective against cells
Relatives at risk have similar AB years before onset
10% - 20% other autoimmune disease

3- Environmental factors

An environmental insult may damage cells

rendering them antigenic.

Viruses : measles , coxsackie , rubella

Chemicals

Cows milk

Pathogenesis of Type 2
diabetes :

1- Genetic factors
2- Insulin resistance & obesity
3 - cell secretion dysfunction

Genetic
factors
are more
important
1- Genetic
factors
:
than in
type 1 diabetes, but this is
multifactorial
50% - 90% in identical twins
risk by 20%-40% in first degree
relatives
No association with HLA & no
autoimmune basis
Point mutation in insulin receptor
identified affecting signaling pathway

2 Insulin resistance :
Decrease ability of peripheral tissue to respond to insulin
Early : insulin resistance insulin secretion due to compensatory of
cell
mass
Later : relative insulin & cell mass to
20-50%
MAIN FACTOR IN INSULIN RESISTANCE IS
OBESITY

Explanation :
Adipocytokines :

Resistin obesity Insulin

resistance
Leptin & Adiponectin contribute to
insulin sensitivity but are in obesity
resistance
PPAR is a nuclear receptor that
regulates level of adipocytokines
FFA in tissues (lipotoxic effect)
insulin resistance

3- cell
Dysfunction
:
Defective
glucose recognition due to
intracellular levels of a mitochondrial protein
( UCP2) in cells

Amylin :

A protein normally produced by cells

secreted with insulin in response to food
ingestion
Amylin accumulates outside cells, forming
amyloid like deposits & may impair cell
glucose sensing.
Seen in up to 90% of cases of Type II diabetes

Pathogenesis of
complications :

1- Nonenzymatic glycosylation of proteins

Glucose + Free amino acids
Later Irreversible combination
Advanced Glycosylation End products =AGES

Measured by level of glycosylated Hb

( HbA1c)
AGES inactivate proteins & cross link
with
more proteins, deposited in vessels,
renal glomeruli, ..etc

Effects :

Induce cytokine production, GF :

vascular permeability
procoaggulant activity
fibroblasts & SM in ECM

Complications in blood vessels, kidney, nervous system .etc

Complications are proportional to the degree
of hyperglycemia of whatever type

2- The Polyol Pathway

Persistent hyperglycemia facilitates

entry of glucose & its accumulation
into some cells & metabolized into

SORBITOL (a polyol) &

FRUCTOSE
Creation of osmotic gradient Influx
of fluid + Toxic
lens, retina, peripheral nerves, kidneyetc

3- Activation of Protein Kinase C :

Activation of signal transduction
Leads to production of pro-angiogenic factors (VEGF)
Important in retinal neovascularization
Production of pro-fibrogenic factors ECM & BM thickening

COMPLICATIONS

COMPLICATIONS

1- Atherosclerosis :
- Cardiovascular
- CNS complications
- Peripheral circulation
2- Diabetic microangiopathy
- Hyaline arteriolosclerosis , exaggerated in
hypertension
- Diffuse thickening in capillaries of skin, retina
peripheral nerves, renal medulla Leaky
vessels nephropathy, retinopathy, neuropathy

3- Diabetic nephropathy

I - Glomerular lesions- Capillary BM thickening

- Nodular glomerulosclerosis
15% -30%
( Kimmelstiel - Wilson lesion)
- Diffuse mesangial sclerosis
II - Renal vascular lesions
- Renal atherosclerosis
- Hyaline arteriolosclerosis

III Pyelonephritis
- Acute & chronic interstitial
inflammation
- Necrotizing papillitis / papillary
necrosis

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 December 2005 01:50 PM)
2005 Elsevier

4- Ocular complications :

I - Retinopathy :
- Nonproliferative : hemorrhage,
exudate, microaneurysm, edema
- Proliferative : Neovascularization,
fibrosis, retinal detachment
II - Cataract formation
III - Glaucoma

5- Diabetic neuropathy

I - Peripheral sensory & autonomic

nerve dysfunction
( microangiopathy &
demyelination )
II - Neuronal degeneration
III - Degenerative spinal cord lesions
6- Recurrent infections : Bacterial & mycotic

Clinical Features in Diabetes :

Type 1 :
Age < 20 , but some are latent (LADA)
May present with metabolic acidosis, weight loss, dehydration,&
electrolyte imbalance.
Polyuria , Polydipsia, Polyphagia ( 3Ps)
Findings :

- Hyperglycemia
- Glucosuria Ketonuria
- Electrolyte imbalance

Type 2 :

Age > 40yrs., often present incidentally

Patients may have the 3 Ps symptoms of complications
Hyperosmolar nonketotic coma caused by dehydration due to
uncompensated hyperglycemic diuresis.
No keto acidosis
Increased susceptibility to infections

ISLET CELL TUMORS

Islet Cells & Secretions :

cells insulin
cells glucagon
cells somatostatin
Pancreatic polypeptide ( PP) VIP

Islet Cell Tumors of

Pancreas :
Include insulinomas, gastrinomas,
glucagonomas.etc
Less frequent than pancreatic CA
Maybe functioning or nonfunctioning
Tumors 2 cm. diameter likely to be benign
Associated clinical syndromes :
1- Hyperinsulinism (Insulinomas)

2- Zollinger - Ellison Syndrome

( Gastrinomas)
3- Multiple endocrine neoplasia
(MEN)

Insulinoma :
Commonest type
Hypoglycemia 50 mg./dl.
Attack precipitated by fasting or exercise, relieved by eating or glucose
administration
Lab. : serum glucose , serum insulin
Most tumors in pancreas but can be ectopic
Most tumors solitary ( < 2cm.), can be multiple
Majority are benign, 10% can be malignant
Histologically difficult to diagnose malignancy

Gastrinomas :

More in middle aged females

Located in pancreas , duodenum or peripancreatic tissue
Single or multiple, or associated with other tumors
> 50% locally invasive or have metastasized at diagnosis
Present with Zollinger- Ellison Syndrome

Zollinger - Ellison
Syndrome :
Peptic ulcer disease
Ulcer features :

Multiple ulcers
Unusual locations specially jejunum
Intractable
Gastrin hypersecretion
Diarrhea in > 50% & may be the
presenting
symptom

Rare tumors :

- Cell tumors : Middle aged women

Glucagon secretion , mild diabetes, skin rash, anemia
- Cell tumors : Somatostatin secretion
Diabetes, malabsorption, GB stones
VIPomas : VIP secretion
Watery diarrhea, hypokalemia, achlorhydria

Diabetes Mellitus

Chronic carbohydrate metabolism disorder due to insulin

deficiency or inadequate insulin utilization by cells
Insulin

Pancreatic endocrine secretion (hormone)

Made by islet of Langerhans
Lowers serum glucose level
Allows cellular uptake and use of glucose

Diabetes Mellitus (DM)

Disorder characterized by:

Hyperglycemia
Ketosis (ketones in the blood)
Acidosis (excess hydrogen ions in the blood)
Ketoacidosis

Diabetes Mellitus
Types of DM:
Type 1 (juvenile onset)
Immune-mediated absence of insulin
Often seems to appear abruptly & emergently

Type 2 (adult onset)

Able to make insulin
Often obesity related

Gestational (GDM)
Occurs during pregnancy & resolves after delivery
25% risk of DM development later in life
Tend to have large babies (over 9 lbs)

Diabetes:

Etiology:
Autoimmune, genetic, pancreatic disorders, drugs, tumors,
Cushings, cells become insensitive to insulin in some

S/S:
Three Ps: polyuria, polydipsia, polyphagia
Increased susceptibility to infections & vascular diseases,
retinopathy, renal failure

Diabetes:

Treatment:
Type 1: insulin administration
Type 2: diet & exercise
Oral hypoglycemics
insulin

Diabetic Emergencies:

Insulin shock (severe hypoglycemia)

Diabetic Ketoacidosis
Severe hyperglycemia & ketoacidosis
Altered mental status, possible coma
Severe dehydration

Thank you