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Acromegaly: a challenging condition to diagnose

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This article was published in the following Dove Press journal:

International Journal of General Medicine

Salma AlDallal Abstract: Acromegaly is an uncommon, chronic disease, characterized by hypersecretion of

Haematology & Blood Bank
a pituitary growth hormone by somatotroph adenomas, along with increased levels of insulin-
Department, Amiri Hospital, Kuwait like growth factor-1. Although acromegaly presents a wide array of clinical manifestations,
Ministry of Health, Sharq, Kuwait the salient symptoms include acral and soft tissue enlargement, joint pain, heart and respira-
tory failure, diabetes mellitus, and hypertension, leading to increased morbidity and mortal-
ity. Hence, early diagnosis of the disease is critical to enhance life expectancy and quality of
For personal use only.

life. New approaches are being developed for diagnosis and surveillance (both screening and
follow-up), including sensitive biochemical assays and the use of MRI to visualize extremely
small tumors, and are helpful in the early diagnosis of acromegaly, subsequent treatment, and
disease control. This m
­ ini-review summarizes the most common and effective tools used in the
diagnosis of acromegaly.
Keywords: pituitary growth hormone, pituitary gland, diabetes mellitus, biochemical assays,
acromegaly

Introduction
Acromegaly is a rare, chronic, endocrine disorder, usually caused by hypersecretion
of growth hormone (GH) for a prolonged period from a somatotroph adenoma.1 The
term “acromegaly” is derived from two Greek words: “akrom”, meaning extremity,
and “megas”, meaning great; the meaning reflects one of the familiar symptoms of
the disease, which is abnormal growth of hands and feet.2

Epidemiology of acromegaly
The exact prevalence of acromegaly is not quite clear; however, the estimated incidence
is three to four cases per million per year, with an occurrence rate of ~40–125 people
per million of the population.3,4 Even though the mean age of occurrence of the disease
is 32 years, the mean age of diagnosis is 40–45 years, primarily owing to a delay in
diagnosis.2,3 The incidence of acromegaly does not vary with gender, race, and ethnic-
ity, although epidemiological studies conducted in Spain reported a predominance of
acromegaly among women.5 A study in a highly polluted area in the Messina province
of Italy revealed an increased prevalence of acromegaly, indicating the pathogenic role
of environmental factors in the development of acromegaly.6
Correspondence: Salma AlDallal
Kuwait Ministry of Health, Amiri
Hospital, 25 Gulf Road, Bin Misbah Causes of acromegaly
Street, Sharq, Capital District, Kuwait
Tel +965 90 98 1981
The pea-sized pituitary gland, located at the sella turcica, is responsible for secreting a
Email [email protected] multitude of hormones, including GH or somatotropin, the action of which is controlled

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by a complex feedback mechanism.7 The most common cause clinical manifestations of acromegaly. Facial changes include
of acromegaly is the presence of a benign tumor or adenoma enlarged lips, tongue, and nose; deep nasolabial furrows;
originating from pituitary somatotroph cells and secreting frontal skull bossing; mandibular prognathism; and separa-
excess GH.1,7 This excessive secretion of GH leads to a persis- tion of maxillary teeth.2 Changes in the skin and soft tissues
tent elevation of insulin-like growth factor-1 (IGF-1),8 which involve thickening of the skin owing to glycosaminoglycan
is produced by the liver, kidney, pituitary gland, muscle, and deposition, leading to hyperhidrosis or oily skin texture,
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gastrointestinal tract; with liver being the primary source.9 acanthosis nigricans (dark skin patches), and skin tags.2,12
IGF-1 facilitates the growth-promoting effects of GH.9 In
95% of acromegalic cases, enhanced levels of GH and serum Local effects of tumor
IGF-1 are responsible for the distinctive features of the dis- In a 2015 demographic study conducted on 271 patients,
ease and numerous comorbidities. Alternatively, increased 6.6% and 83% were found to have microadenoma and mac-
levels of growth hormone-releasing hormone (GHRH) pro- roadenoma, respectively.24 According to another study, the
duced in the hypothalamus account for 0.5% of acromegaly prevalence of macroadenoma was found to be higher than
cases.10 Hence, serum IGF-1 concentration is considered as that of microadenoma.25 The adenoma may compress local
a sensitive measure of integrated GH levels in patients with organs and even cause neurological symptoms along with
acromegaly.9 Furthermore, some correlation between acro- visual disturbances, which include headaches, defects in
megaly and familial syndromes, such as McCune–Albright the visual field, cranial nerve palsies, hypopituitarism, and
syndrome, multiple neoplasia type I, Carney complex, and hypothyroidism.2 The optic chiasm is an X-shaped structure
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isolated familial acromegaly, has been detected.5 formed by crossing of the optic nerves (CN II) in the brain.
Upward growth of a pituitary adenoma leads to optic chiasm
Clinical manifestations and compression, thereby producing visual field disturbance,
associated comorbidities of which starts in the mid-periphery of the superior temporal
acromegaly sectors and finally leads to bitemporal hemianopsia. The
Acromegaly is an insidious disease, which typically takes cavernous sinus is an important structure in the brain which
about 10–12 years from the onset of symptoms to diagnosis.2 is formed by a large channel of venous blood forming a cav-
The exact reasons for the insidious nature of acromegaly ity surrounded by sphenoid and temporal bones. This cavity
remain unclear. It is likely that the gradual, progressive is significant because of its location and content. It contains
course of the disease leads to alterations ignored by the the third (oculomotor) and fourth (trochlear) cranial nerves.
patient, family members, and even physicians. In addition, It also contain parts one (the ophthalmic nerve) and two (the
some of the comorbidities resemblance common disorders. maxillary nerve) of the fifth cranial (trigeminal) nerve, and
As a result, before obtaining the correct diagnosis, patients the sixth cranial (abducens) nerve. Cavernous sinus invasion
usually have to visit primary care physicians and even other by a pituitary adenoma is of clinical significance it makes
specialists several times.11 The clinical manifestations of surgery more difficult and less efficient.31
acromegaly depend on several factors, including levels of
GH and IGF-1, the sensitivity of different tissues and organs Associated comorbidities
to increased levels of GH and IGF-1, age, and tumor size, as Manifestations of acromegaly include soft and acral tis-
well as delays in diagnosis.12 In general, the clinical features sue overgrowth, joint pain, hypertension, and heart and
of acromegaly include somatic effects due to excessive GH respiratory failure.12 Many studies have provided diagnostic
and IGF-1 levels and local effects caused by expansion of algorithms from the associated comorbidities to identify
the pituitary tumor.2 acromegaly.8 A scoring system called “ACROSCORE” has
been used to investigate and confirm acromegaly in the very
Somatic effects early stages (Figure 1).28
Somatic effects include increases in the thickness of the skin
and connective tissue; uneven proliferation of cartilage, bone, Cardiovascular complications
and other epithelial tissues; and visceromegaly in the form One of the most prevalent comorbidities related to acro-
of goiter, hepatomegaly, splenomegaly, and macroglossia.12 megaly is cardiovascular disorder,8 occurring in 60% of
Acral enlargement, such as enlargement of hands, feet, and patients with acromegaly.12 Cardiovascular disorders act
fingers, and typically coarse facial features, are the universal as negative determinants for life expectancy in acromegaly

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 Dovepress Acromegaly: a challenging condition to diagnose

Clinical signs of
acromegaly

Basal (random) GH and IGF-1

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Elevated Normal for age

GH >0.4 µg/L and or and sex
elevated IGF-1 GH <0.4 µg/L and normal IGF-1

GH during OGTT Acromegaly ruled out

GH <0.4 µg/L GH >0.4 µg/L

Pituitary MRI
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Acromegaly conform

Figure 1 Diagnostic flow of acromegaly. 

Note: Data from Rosario et al26 and Cordido et al.27
Abbreviations: GH, growth hormone; IGF-1, insulin-like growth factor-1; OGTT, oral glucose tolerance test; MRI, magnetic resonance imaging.

patients. Acromegaly is associated with a typical cardio- Gastrointestinal complications

myopathy, characterized by biventricular hypertrophy, and Development of colon carcinoma, adenomatous polyps, and
hypertension is one of the most common cardiovascular dolichocolon are some of the common gastrointestinal prob-
comorbidities in acromegaly, with an average prevalence lems detected in acromegaly patients.12 It is accepted that the
of ~35%. In ­addition, congestive heart failure, cardiomy- risk of colon cancer is higher in acromegalic patients than in
opathy, arrhythmias, coronary disease, and hypertension the general population.32
commonly occur.
Orthopedic comorbidities
Pulmonary and respiratory complications Arthropathy widely occurs in patients with acromegaly, along
Patients suffering from acromegaly have altered structures with vertebral fractures, joint disease, and loss of weight-bear-
of the respiratory apparatus, which lead to severe respira- ing ability. Early diagnosis of acromegaly may decrease the risk
tory problems.2,8 Respiratory complications associated of bone and joint disease, resulting in improved quality of life.
with acromegaly include sleep breathing disorders, gener-
ally represented by sleep apnea, which affects up to 80% Metabolic disorders
of patients, and respiratory insufficiency. The anatomical Increased secretion of GH and IGF-1 leads to abnormal
changes in respiratory structures affect lung volumes, respira- glucose regulation, causing diabetes mellitus. A defect in
tory mucosa/cartilage, lung elasticity, chest muscle structure, lipid metabolism is also observed in some patients with
and respiratory muscle activities. Some patients develop a acromegaly.13
barrel chest as a result of the changes in vertebral and costal
morphology. Other complications include hyperventilation, Cancer
and hypertrophy of the laryngeal mucosa and cartilage, caus- The high level of IGF-1 in acromegaly is related to an
ing sleep apnea and excessive snoring.8,12 increased risk of some cancers, particularly colon cancer

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and thyroid cancer.8 An increased incidence of micronucleus at diagnosis, indicating that there is a high prevalence of
(MN) and oxidative DNA damage in lymphocytes of patients underdiagnosed acromegaly.11,13 In general, primary care
with acromegaly was found by Hamurcu et al.22 An increased physicians diagnose ~40% of patients with acromegaly.33
MN frequency (chromosomal DNA damage) in peripheral ­Nevertheless, patients often consult other specialists and
blood lymphocytes is predictive of an increased risk of can- dentists, besides primary care physicians, before obtain-
cer in humans. Thus, the increase in chromosomal/oxidative ing the correct diagnosis, and are then treated according
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DNA damage and the positive association between MN to the ­presenting symptoms, instead of being treated for
frequency and serum IGF-1 levels may predict an increased acromegaly.16
risk of malignancy in acromegalic patients.23 The phenotype of acromegaly develops gradually over
several years; usually, the first clinical manifestation of
Other complications the disease includes the growth of acral parts and physiog-
Women suffering from acromegaly have higher probabilities nomic alterations.12 Thus, comparison of new and old facial
of menstrual irregularities and infertility. Hyperprolactinemia photographs was conventionally used in early detection of
was also found to develop in 30% of patients.12 the disease. The main drawback in considering phenotypic
alterations for the initial recognition of acromegaly is that
Mortality only 50% of patients with somatotroph adenomas reveal
The mortality rate in patients with active acromegaly is two distinct phenotypic changes, whereas the other 50% either
to four times higher than in the general population.3 This is show insignificant symptoms or are completely asymptom-
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mostly due to cardiovascular disorders, pulmonary compli- atic, even having elevated levels of GH and IGF-1, and even
cations, and diabetes mellitus. Cardiovascular disease has after several years of observation.13 Another possible method
historically been reported to represent the primary cause for early diagnosis of acromegaly is to use software to depict
of death in these patients, contributing to nearly 50% of the features that have developed as a result of acromegaly
increased mortality. However, according to recent studies, in a single photograph of the patient’s face.12 However, the
the most common cause of mortality in acromegaly was sensitivity and specificity of the computer modeling system
malignancy, followed by cardiovascular diseases,29,30 then in early acromegaly are not yet clear. Once there is a clinical
respiratory problems and neoplasias, accounting for ~25% suspicion of acromegaly, biochemical tests should be per-
and 15% of mortality, respectively.14 There is a direct cor- formed for every patient to confirm the diagnosis.
relation between the mortality rate and excess GH and IGF-1
secretion. Normalization of GH and IGF-1 has been found Biochemical tests
to reduce the mortality rate and disease-related morbid- GH level
ity.3 A positive correlation also exists between mortality in The biochemical diagnosis of acromegaly is traditionally
acromegaly patients and colorectal cancer.12 However, with based on the levels of oversecreted GH and IGF-1. However,
advances in the management strategies of acromegaly and its in normal healthy individuals the levels of circulating GH
associated comorbidities, there have been marked improve- secreted from the pituitary fluctuate greatly throughout the
ments in the survival rate and quality of life of patients with day owing to the pulsatile nature of GH production.17 Maxi-
acromegaly.13 mum secretion of GH occurs at night in accordance with sleep
stages. The value of GH usually ranges between 0.1–0.2 µg/L
Diagnosis of acromegaly and 5–30 µg/L during the secretory bursts, and these values
Acromegaly is a chronic, debilitating disorder with slow overlap with the values observed in acromegaly patients.12 A
disease onset, which impedes accurate diagnosis in the early random GH value <0.04 µg/L with a normal level of IGF-1
stages.15 None of the signs and symptoms is sensitive enough (matched for age and gender) excludes the diagnosis. Thus,
to be detected at the beginning of the disease. Failure to rec- determination of the GH level is of minimal diagnostic
ognize appropriate symptoms causes a delay in disease diag- utility in acromegaly. Instead, a GH level <0.4 ng/mL in an
nosis, leading to a high incidence of acromegaly.4 According oral glucose tolerance test (OGTT) is the gold standard for
to a study by Reid et al, involving 324 acromegaly patients diagnosis.13 In normal individuals, the GH nadir value during
from the periods 1981–1994 and 1995–2006, the majority an OGTT is undetectable as secretion is suppressed, but the
of patients showed many clinical symptoms and complica- value is very high in acromegaly patients owing to the lack
tions consistent with the disease being at an advanced stage of suppression.2

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 Dovepress Acromegaly: a challenging condition to diagnose

IGF-1 level ultrasensitive GH assays based on strong reference standards

IGF-1, the level of which is correlated with mean GH level, are required.19
has been used as a biomarker of acromegaly since the turn
of the millennium.5 Measurement of circulating IGF-1 is Imaging studies
considered a vital biochemical tool because of its long half- MRI with contrast administration is considered to be the most
life of 18–20 hours and stability throughout the day.5 An effective imaging technique to locate the pituitary source
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elevated IGF-1 level along with inability to reduce GH levels of excess GH.12 MRI is a sensitive and reliable technique,
<1 µg/L in an OGTT is considered an important criterion for which enables the identification of very small tumors, even
acromegaly detection.1 Although a correlation exists between smaller than 2 mm, tumor invasiveness, proximity to the optic
the levels of serum IGF-1 and GH, some acromegaly patients chiasm, and compression of surrounding structures by the
show high IGF-1 levels in spite of a normal daily GH con- tumor which previously remained undetected.5 The majority
centration, indicating a complex correlation between them, of somatotroph adenomas (75%–85%) are macroadenomas
which cannot be simply explained by GH elevation.13 Regard- (>10 mm in diameter) at the time of diagnosis, which rarely
less of the substantial advantages of IGF-1 as a biochemical grow into the cavernous sinus.12 MRI helps to identify a
tool, there are certain limitations to its use. The IGF-1 level pituitary macroadenoma in acromegaly patients.2 Advanced
is affected by multiple physiological factors such as age, MRI techniques such as post-contrast, volumetric interpo-
gender, and body mass index, and these should be considered lated breath-hold MRI can detect acromegaly in patients with
during data interpretation. The IGF-1 level is raised during pituitary tumors, which was otherwise unidentified by tra-
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normal pregnancy and puberty and rarely represents a clini- ditional spin-technique T1-weighted MRI. Hence, improved
cal problem. In contrast, malnutrition, liver and renal failure, MRI techniques have advantages over conventional methods
hypothyroidism, and insulin-dependent diabetes reduce the for the diagnosis of acromegaly.13
level of IGF-1. Major technical problems of IGF-1 assay Rarely, acromegaly occurs as a result of ectopic tumors
include interference caused by endogenous IGF-1-binding producing GH or GHRH. When a biochemical diagnosis
protein and the tendency of IGF-1 to plateau at mean GH has been established for acromegaly without any pituitary
levels.5 All these factors lead to variability in IGF-1 assay tumor or diffused pituitary enlargement is detected, phy-
performance. Therefore, technical refinements of IGF-1 sicians should suspect ectopic sources.12 Measurement of
biochemical assays, validation of assay performance, and the plasma GHRH level is beneficial in identifying ectopic
assay-specific reference data are essential to detect specific sources of tumor.5
clinical conditions related to acromegaly.18
Treatment of acromegaly
Immunoassays Improved understanding of the disease mechanism has led
For accurate diagnosis of acromegaly, it is imperative to have to the development of successful treatment modalities of
a highly sensitive GH assay, with the ability to detect GH acromegaly. Novel surgical techniques are used to operate
levels <1.0 ng/mL. The development of a radioimmunoassay on pituitary tumors.
(RIA) to measure serum GH and IGF-1 levels presented a The majority of pituitary tumor operations in patients
biochemical device to diagnose acromegaly. RIA has several with acromegaly are performed by transsphenoidal
limitations as a result of which more sensitive immunoas- surgery.30 Some surgeons use an image intensifier for
says, such as immunoluminometric and immunoradiometric navigation while others choose neuronavigation. A sub-
assays based on the use of monoclonal antibodies, have been mucosal tunnel is dissected, usually followed by a medial
developed to measure plasma GH and IGF-1 levels precisely nasal incision. The mucosal tunnel is kept open by a nasal
in patients with suspected acromegaly. These assays can speculum. Then the operating microscope is introduced.
determine GH concentrations <0.05 µg/mL;19 the sensitivity Sphenoidotomy is performed using the vomer as a midline
of these immunoassays is up to 100 times greater than RIA.20 orientation. A direct perinasal intervention to the sphenoid
However, one limitation of these assays is proper reproduc- sinus is usually chosen by endoscopic transsphenoidal
ibility. Variability of measured GH values occurs owing to surgeons. The transnasal/transsphenoidal technique seems
the lack of universal standards, recognition of non-uniform to be accurate and safe, with good surgical results. Based
antibodies by GH isoforms, and the presence of circulating on the preoperative MRI, the decision is made to carry
GH-binding protein. Hence, more authentic and reliable out a curative or debulking procedure. The resectioning of

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the adenoma depends on the size and invasive character 3. Nachtigall L, Delgado A, Swearingen B, Lee H, Zerikly R, Klibanski
A. Extensive clinical experience: changing patterns in diagnosis and
of the tumor. For patients who are not cured by surgery, therapy of acromegaly over two decades. J Clin Endocrinol Metab.
or for those whose health status prohibits surgery, medi- 2008;93:2035–2041.
cal therapy using somatostatin analogs and GH-receptor 4. Schneider HJ, Sievers C, Saller B, Wittchen HU, Stalla GK. High
prevalence of biochemical acromegaly in primary care patients with
antagonists is considered to be the principal therapy.1,13 For elevated IGF-1 levels. Clin Endocrinol. 2008;69(3):432–435.
those patients in whom both surgical and medical therapy 5. Cordero RA, Barkan AL. Current diagnosis of acromegaly. Rev Endocr
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therapy is the best curative technique. Sometimes, more aly in a highly polluted area. Eur J Endocrinol. 2010;163(4):509–513.
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Acknowledgment GH assay: should we achieve strict normal GH levels for a biochemical
cure? J Clin Endocrinol Metab. 2002;87(7):3142–3147.
The author is thankful to www.manuscriptedit.com for 21. Giustina A, Chanson P, Bronstein MD, et al. A consensus on criteria for
­providing English language editing and proofreading services cure of acromegaly. J Clin Endocrinol Metab. 2010;95(7):3141–3148.
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Disclosure 23. Bayram F, Bitgen N, Donmez-Altuntas H, et al. Increased genome
instability and oxidative DNA damage and their association with
The author reports no conflicts of interest in this work. IGF-1 levels in patients with active acromegaly. Growth Horm IGF
Res. 2014;24(1):29–34.
24. Dutta P, Hajela A, Pathak A, et al. Clinical profile and outcome of
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