Acromegaly

Article Author:
Oluwaseun Adigun
Article Editor:
Fassil Mesfin
Updated:
6/23/2017 4:12:36 AM
PubMed Link:
Acromegaly

Introduction

Acromegaly is a disorder caused by an excessive production of growth hormone from the anterior pituitary gland, resulting in excessive growth of body tissues and other metabolic dysfunctions. Adult patients with acromegaly have the characteristic facial features of a large lower jaw, prominent forehead, and large hands and feet. This takes place after the growth plates are fused, distinguishing acromegaly from gigantism which occurs before fusion of growth plates.

Etiology

Pituitary Tumor: In more than 95% of cases, the excessive growth hormone is caused by a pituitary tumor, usually a benign microadenoma of the pituitary gland.

Non-Pituitary Tumor: Tumors of the adrenals, lungs, and pancreas are implicated in a few cases. These tumors secrete growth hormone or growth hormone releasing Hormone (GH-RH).

Elevated levels of growth hormone stimulate the liver to produce Insulin-like growth factor-1 (IGF-1). Elevated levels of Insulin-like growth factor-1 stimulate the excessive growth of body tissues.

Epidemiology

Acromegaly has a worldwide prevalence of about 4600 per million population, with about 116.9 new cases per million per year. Mean age at diagnosis 40 for men and 45 for women.

Pathophysiology

In about 95% of cases, acromegaly is associated to a pituitary microadenoma, while the remaining 5% are from non-pituitary ectopic sources of growth hormone or GH-RH. The common effect of the abnormal rise in growth hormone is the production of Insulin-like growth factor-1 (IGF-1) from the liver. The effect of IGF-1 on body tissues results in the multisystemic manifestation of acromegaly. IGF-1 also known as Somatomedin C is encoded by the IGF-1 gene on chromosome 12q23.2.

The pathologic effect of IGF-1 after fusion of the growth plates result in the acral growth spurts manifested as large hands and feet and a prominent jaw and forehead. It is clearly different from the linear size increase that occurs in gigantism in which the effect of elevated IGF-1 occurs before closure of the growth plate.

Acromegaly leads to elevated IGF-1 that affects the following pathways of metabolism:

  • Competes with insulin for insulin receptor, resulting in relative insulin resistance which may be responsible for the co-existing diabetes mellitus in 10% to 20% of patients with acromegaly.
  • Results in general somatic hypertrophy seen as enlarged body organs, for example, macroglossia, acromegalic heart, large kidneys, and bulky skeletal muscles.
  • Somatic growth by binding insulin-like growth factor-1 Receptor (IGF-1R) which is relatively ubiquitous. IGF-1R is a receptor tyrosine kinase which brings about phosphorylation and activation of several intracellular signaling pathways, one of which is the AKT pathway activation that results in somatic cell growth and proliferation.

Toxicokinetics

IGF-1 is an insulin-like protein produced majorly in the liver. It is a single chain of 70 amino acids and three disulfide bridges with a molecular weight of approximately eight kilodaltons. IGF-1 level peaks around puberty, with low levels at extreme ages.

Synthetic IGF-1 analog is used in the treatment of growth disorders, for example, dwarfism.

IGF-1 almost always exists in the bound form. It is bound by the IGF-binding proteins (IGF-BPs), and the most abundant of them is IGFBP-3.

Nutrition also plays some role, as high protein intake tends to increase growth hormone and IGF-1 levels.

History and Physical

Acromegaly is usually a slow progressing disorder, with onset usually in the third or fourth decade of life. The presenting complaints include the following:

  • joint pain due to hypertrophic arthropathy
  • wrist pain and numbness from carpal tunnel syndrome
  • snoring and sleep disorders, like sleep apnea, due to macroglossia
  • headaches and visual disturbances (bitemporal hemianopia) and pressure effects of pituitary adenoma on adjoining structures in the brain, for example, compression of the optic chiasma
  • erectile dysfunction or low sex drive
  • abnormal menses in women
  • sweaty palms and soles (hyperhidrosis)

Signs upon physical examination include the following:

General Examination

  • coarse facial features, prominent forehead, prominent brow, and prognathism (mandibular enlargement)
  • prominent forehead crease and nasolabial folds
  • large tongue and widely spaced dentition
  • thick eyelids, large nose, and lower lip

Visual field examination

  • bitemporal hemianopsia

Neck

  • feel for thyroid mass
  • observe for raised JVP (in acromegalic cardiomyopathy)

Integuments

  • skin is thick and rough
  • skin tags
  • oily skin
  • abnormal or excess hair distribution, e.g., hirsutism(in women), hypertrichosis
  • hyperpigmentation
  • acanthosis nigricans especially in the axilla

Breast Exam

  • galactorrhea
  • dry atrophied skin

Cardiovascular

  • problems of  acromegalic cardiomyopathy
  • elevated blood pressure
  • cardiac murmur (a pansystolic murmur may indicate a mitral valve regurgitation)

Chest

  • bibasal crepitation may indicate a congestive heart failure in a patient with acromegalic cardiomyopathy

Limbs

  • acral enlargement: large hands (with stubby fingers) and feet
  • proximal myopathy
  • genu varum
  • rolling gait

Evaluation

Laboratory investigations

GH suppression test:

  • administer 100 g glucose to the patient orally
  • one hour later measure serum growth hormone levels
  • result: normal GH levels which are less than five ng/ml excludes acromegaly, while elevated levels of greater than ten ng/ml is suggestive of acromegaly

IGF-1 Levels

  • a direct dose-response relationship with growth hormone levels
  • levels measured for age and sex
  • useful for diagnosis and treatment monitoring
  • pregnancy can cause elevated IGF-1 levels

Growth Hormone Releasing Hormone (GHRH) Levels

  • elevated levels usually > 300ng/mL is suggestive of extra-pituitary sources

Prolactin

  • Elevated prolactin levels due to pituitary stalk compression by adenoma or by a co-prolactin producing pituitary adenoma.

Imaging Studies

Brain scan

  • MRI is more sensitive in visualizing the Sella turcica and adjacent structures, but a CT scan can be done if this is not available

X-rays

Skull x-ray: thickened calvaria, enlarged sella, long and thick mandibles, exaggerated ridges, dilated sinuses

Chest x-ray: barrel rib cage with long ribs

Hand x-ray: cortical thickening, ungal tufting, wide distal phalangeal bases, osteophytes and soft tissue hypertrophy

Treatment / Management

Surgical Treatment

  • Endonasal Transphenoidal Surgery:  A minimally invasive surgery using an endoscope through a small incision in the nose or at the upper lip to remove the pituitary adenoma will promptly relief the pressure symptoms as well as lower elevated growth hormone (GH) levels. Recovery time is shorter compared to traditional transsphenoidal surgery.
  • Transnasal Transsphenoidal Microscopic Surgery:  This is a traditional pituitary surgery that utilizes direct visualization of the tumor using a microscope. Recent retrospective studies showed gross total resection with a resolution of IGF-1 endonasal approach which is comparable to transnasal transsphenoidal microscopic surgery.

Medical Therapy: Either as an adjunct to surgery or when surgery is not desirable.

  • Somatostatin analogs (octreotide, Lanreotide): These act on the somatostatin receptor to bring about inhibition of growth hormone secretion. It is usually administered as once-monthly intramuscular injections. It also can be used to shrink large pituitary adenomas before surgery.
  • Dopamine receptor agonists (cabergoline, bromocriptine): These act on D2 receptors and are not as effective as the Somatostatin analogs. They are often used as adjuncts. Cabergoline is more potent than bromocriptine in lowering GH levels.
  • GH- Receptor antagonist (Pegvisomant): This novel drug blocks growth hormone at the receptors, lowering IGF-1 levels while GH levels remain unaffected.

Radiotherapy

  • Conventional radiotherapy: Often administered as an adjunct to surgery to either prevent relapse or when surgery is not able to bring about the acceptable lowering of GH levels. It is associated with the risk of irradiating adjacent brain tissues.
  • Stereostatic radiosurgery: This is precision radiotherapy, directing high dose radiation to the tumor, and minimizing risk to nearby healthy brain tissues.

Pearls and Other Issues

Minoxidil use has been associated with a condition characterized by facial features of acromegaly, but with normal growth hormone and IGF-1 blood levels. This condition is known as pseudoacromegaly.