Acromegaly

Dr Marcos Gil Alberto da Veiga◉ and Dr Jeremy Jones◉ et al.

Acromegaly is the result of excessive growth hormone production in skeletally mature
patients, most commonly from a pituitary adenoma. The same excess of growth hormone in
individuals whose epiphyses have not fused will result in gigantism (excessively tall
stature).  

Epidemiology
Acromegaly is most commonly diagnosed in middle-aged adults and can result in severe
disfigurement, serious complicating conditions, and premature death. It has both an
insidious onset and slow progression and may be difficult to diagnose in the early stages,
only being diagnosed when the external features, especially those of the face, become
noticeable.

Clinical presentation
Clinical presentation is often with a variety of relatively non-specific symptoms or medical
problems. These include: 

 headache, described more often as "head pain" (due to dural tension)

 muscle pain, often misdiagnosed as fibromyalgia
 joint pain
 arthritis
 vertebral fractures with or without loss of bone mineral density
 carpal tunnel syndrome
 obstructive sleep apnoea
 cardiovascular
o cardiomegaly
o hypertension
o heart failure
 gastrointestinal
o colon cancer
o cholelithiasis 12
 insulin resistance leading to diabetes mellitus
 renal failure
 palmar sweating and seborrhoea
In contrast, examination of the patient will often reveal a very characteristic constellation of
physical signs:

 overgrowth
o enlargement of the hands, feet, nose, tongue, lips and ears
 o general thickening of the skin (including cutis verticis gyrata)
o internal organs (especially heart and kidneys)
o vocal cords, resulting in a characteristic thick, deep voice and slowing
of speech
o skull, frontal bossing
o mandible: prognathism with gaping teeth
 skin changes
o hypertrichosis
o hyperpigmentation
o hyperhidrosis

Markers
Typically cases show elevated levels of:

 growth hormone
 IGF-1 (insulin growth factor 1)

Pathology
Approximately 95% of cases are the result of a pituitary adenoma 10. The remaining 5% of
cases are the result of other tumours of the pancreas, lungs, or adrenal glands that release
growth hormone. A very small number of cases result from the excessive use of exogenous
growth hormone in athletes. 

Radiographic features

Plain radiograph

Skull
Calvarial thickening, particularly of the inner table 10, frontal bossing, enlarged paranasal
sinuses (especially frontal sinuses) and an enlarged sella turcica.

The mandible also characteristically enlarges resulting in prognathism and gaps between the
teeth 10. This appearance is sometimes referred to as a "lantern jaw" 11 although this is
merely a descriptive term, not unique to acromegaly. 

Spine
Evidence of vertebral body fractures, most commonly in the thoracolumbar region lead
researchers to recently state that radiographic screening of this region is indicated 4.
Vertebral fracture without loss of bone mineral density is related to increased bone
turnover markers seen in acromegaly 4. Other features seen in the spine include a DISH-like
appearance, posterior vertebral scalloping, increased vertebral height, elongation and
widening of the vertebral bodies.
Vertebral body anteroposterior and transverse diameter increase, due to subperiosteal
bone deposition increase can also lead to platyspondyly.

Joints
Joints will show the typical patterns of osteoarthritis, and will continue to deteriorate even
after biochemical remission is achieved, which is why it is prudent in the clinical setting to
monitor the progression of "acromegalic arthropathy" 6,7. There has also been a reported
higher incidence of crystal deposition disease.

Hands
Terminal phalangeal tufts become hypertrophied and have a "spade appearance", which is
called the spade phalanx sign. Joint spaces may be minimally enlarged. Premature
osteoarthritis can occur in the advanced stages of acromegaly.

Feet
Heel pad thickness may be increased (>25 mm).

MRI

Cardiac
Three steps of acromegalic cardiomyopathy have been described 9:

 early phase (reversible): initial cardiac hypertrophy, increased heart rate and

systolic output, defined as the hyperkinetic syndrome
 middle phase of untreated or uncontrolled disease: cardiac hypertrophy with
signs of diastolic dysfunction
 end-stage of untreated disease (not reversible): dilated cardiomyopathy

Joint
Other joints may show ligamentous and cartilaginous hypertrophy, and crystal deposition 7.

Pituitary
Enlarged pituitary with increased gadolinium uptake. The MRI diagnosis of a pituitary
macroadenoma is relatively straightforward. Dynamic contrast-enhanced MRI increases the
sensitivity for detecting microadenomas. Microadenomas are hypoenhancing compared to
the normal pituitary gland.

Spine
Hypertrophy of spinal ligaments and cartilaginous structures and features of osteoarthritis 7.

Treatment and prognosis

The treatment of choice is resection of the secreting adenoma, usually via
the transsphenoidal approach. Alternatively, especially in surgically-refractory cases,
treatment is with a primary somatostatin receptor ligand, with or without concomitant
growth hormone receptor antagonist therapy 3. Radiation therapy is also used in medical
circumstances where other therapies have not been able to control tumour size, growth and
production of excess growth hormone. The most frequently used radiation therapy for
acromegaly is Gamma Knife, with more traditional techniques, including image-guided
radiation therapy, associated with increased risk of cerebrovascular mortality.

The severity of symptoms and comorbidities for acromegaly patients is directly related to
the level of elevated hormone as well as length of time that the patient was exposed to a
high level versus a high-normal, or normal level, making identification and proper diagnosis
of great importance 4,6,7. Mortality rates can decrease to those of the general population if
appropriate diagnosis and treatment are achieved to normalise serum growth hormone and
IGF-1 levels 5.

History and etymology

The word "acromégalie" was coined by the French neurologist Pierre Marie in 1886. He
created the word from the Greek words ακρος (akros) which means "summit, extremity"
and μεγαλως (megalos), an adverbial form derived from μεγας (megas) meaning "great" 13-
15
.

Marie was not the first to describe a case though, that honour falls to Andrea Verga, an
Italian neurologist and psychiatrist, who wrote up a patient he saw in 1864. He named the
condition “prosopo-ectasia”, which means widening of the face. At this lady's autopsy he
discovered a grape-sized tumour within the pituitary fossa and no normal pituitary gland 13.

In 2011 an AIP (aryl hydrocarbon-interacting protein gene) mutation was linked to

acromegalic gigantism, found when studying four Irish families who displayed acromegalic
and gigantism traits, known as childhood-onset acromegaly (i.e. when a child has gigantism
which progresses through adulthood to acromegaly). It is said that there could be hundreds
of carriers of this mutant gene, leading researchers to suggest that all childhood-onset
acromegaly patients, especially those who have a family history of pituitary adenoma or
acromegaly, should be screened and followed 8.