Acromegaly

 

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Original Editors - Alex Kent from Bellarmine University's Pathophysiology of Complex Patient Problems project.

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Definition/Description 

Acromegaly is a rare systemic disease which affects the entire body. It is characterized by a hypersecretion of growth hormone (GH) which the body is unable to regulate. GH facilitates growth of muscles, internal organs, and bones, as well as stimulating secretion of its target hormone insulin-like growth factor 1 (IGF-1). ^, The extremely high levels of GH and IGF-1 which typify acromegaly cause tissue enlargement and metabolic changes that result in visible deformity as well as an increase in mortality. The disease often begins between the ages of 30 and 50, and has an insidious onset and slow progression, often delaying diagnosis until later stages of the disease.

Prevalence

• The prevalence of acromegaly is approximately 40-70 cases per million persons. 
• However, new research suggests that the prevalence may be as high as 77 cases per million persons.
• The annual incidence of acromegaly is approximately is 3-4 new cases per million persons.

Characteristics/Clinical Presentation

Acromegaly affects many of the body's systems, and various signs and symptoms develop over a period of several years. They range from subtle changes to notable disfigurement.

Clinical Presentation:

• Hand and foot enlargement
• Hyperhydrosis- increased perspiration
• Increased skin thickness
• Darkening and thickening of body hair
• Frontal skull bossing- an abnormally heavy brow and prominent forehead
• Widening of the maxilla accompanied by separation of the teeth
• Jaw malocclusion and overbite
• Soft tissue enlargement
• Skeletal overgrowth and thickening causing many areas to appear swollen
• Deep and husky voice due to thickening of cartilage in the larynx
• Ventilatory dysfunction
• Weight gain
• Joint pain
• Sleep apnea
• Acne
• Vision problems

 

Associated Co-morbidities

IGF-1, the target molecule of GH, enables many of the growth-promoting actions of GH; GH itself is also a regulator of mineral, lipid, and carbohydrate metabolism. Therefore the elevated levels of GH and IGF-1 which are characteristic of acromegaly excessive soft tissue growth, swelling of internal organs, and musculoskeletal, neurological, and metabolic comorbidities. 

Cardiovascular:

• Hypertension
• Arrhythmias
• Valvulopathy
• Cardiomyopathy
• Hypertrophy (biventricular or asymmetric septal)
• Congestive heart failure

Pulmonary:

• Obstructive sleep apnea
• Macroglossia
• Upper airway obstruction
• Ventilatory dysfunction
• Upper airway obstruction

Metabolic:

• Insulin resistance
• Impaired glucose metabolism
• Diabetes mellitus

Visceral:

• Organ enlargement
• Colon polyps
• Fluid retention
• Renal failure

Musculoskeletal:

• Arthropathy/osteoarthritis
• Carpal tunnel syndrome
• Osteopenia

Medications

• Somatostatin analogs- somatostatin inhibits endocrine cells, including GH-secreting cells of the pituitary gland.  Somatostatin analogs (SSAs) mimic the GH-suppressing effects of the body's own somatostatin.  SSAs are one of the most common medications prescribed for acromegaly.  There are currently three SSAs approved in the US: short-acting octreotride, octreotride LAR, and Somatuline Depot. Most common adverse events are glucose intolerance, and gallbladder and sludge stones.
• Dopamine agonists- leads to GH suppression in a portion of acromegaly patients.  Interestingly, this medication stimulates GH release in healthy patients.  Advantages of this medication are relatively low cost, oral administration, and no hypopituitarism associated with medication.  However,  the medication is only effective at lowering GH and IGF-1 to safe levels in approximately 10% of patients, and potentially causes cardiac valvular damage.
• Growth hormone receptor agonists- blocks the GH signal for IGF-1 production.  More effective for patients with higher levels of IGF-1, and demonstrated a more favorable influence on glycemic control. Adverse events often associated with growth hormone receptor agonists are compromised liver function and reactions at the injection site.

Diagnostic Tests/Lab Tests/Lab Values

Diagnostic Tests:

Oral Glucose Tolerance Test (OGTT)- glucose has a neuroendocrine suppressive signal that lowers GH.  In this test, 75 g of glucose is administered with GH measurements at different points over a period of 120 minutes. The failure to suppress GH secretion to less than 1 microgram/liter is currently the standard for diagnosis of acromegaly.

Magnetic Resonance Imaging (MRI)- the preferred imaging method when diagnosing acromegaly.  An MRI of the pituitary gland is taken in order to look for any abnormal growth. It can help determine the tumor size, as well as compression of surrounding structures.

Blood tests- blood may be used to measure serum levels of IGF-1 in addition to GH. High levels of IGF-1 have been used as a marker for acromegaly; IGF-1 is correlated with GH levels as well as the clinical manifestations of acromegaly. IGF-1 levels also tend to remain stable throughout the day, making IGF-1 testing a fairly reliable diagnostic tool. Generally, a diagnosis of acromegaly can be excluded if IGF-1 levels are within the normal range.

Radiographs- an x-ray of the skull can show bone thickening as well as enlargement of the nasal sinuses. Thickening of the carpal phalanges can be seen in x-rays of the hands.

Computed tomography (CT)- this imaging method can be used to identify abnormal growths in the pituitary gland. 

Lab Values:

Growth Hormone (GH)- in individuals without acromegaly, GH values are typically 0.1-0.2 micrograms/liter.  There are, however, 6-10 bursts of GH secretion where levels of the hormone are 5-30 micrograms/liter. This may overlap with the values seen in patients with acromegaly. Growth hormone concentrations of less than 2.5 ng/ml are associated with mortality rates similar to the normal population. Thus normalization of GH levels is currently defined as below 2.5 ng/ml.

Etiology/Causes

• The majority (99%) of acromegaly cases are caused by the proliferation of somatotroph cells in the pituitary which leads to a pituitary adenoma. Somatotroph cells make up more than half of the hormone-secreting cells in the ptuitary.
  
• The pituitary tumor causes an increase in circulating levels of GH.  GH mediates anabolic reactions by binding to growth hormone receptors, creating docking sites for cell signaling proteins, and initiating the synthesis of target genes like IGF-1.  This in turn increases the production of insulin-like growth factor 1 (IGF-1).  IGF-1 causes metabolic changes and somatic growth, stimulating proliferation of cartilage, skeletal muscle and bone which ultimately lead to tissue enlargement.
• Enlargement of tissues and metabolic abnormalities cause the two to three-fold increase in mortality seen in acromegaly.

Systemic Involvement

Cardiovascular System

• Acromegalic cordiomyopathy- common features include biventricular hypertrophy, thickening of cardiac walls, diastolic dysfunction, limited systolic function, and heart failure with signs of dilative cardiomyopathy.

Medical Management (current best evidence)

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Physical Therapy Management (current best evidence)

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Alternative/Holistic Management (current best evidence)

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Differential Diagnosis

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Case Reports/ Case Studies

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Resources

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Recent Related Research (from Pubmed)

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References

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