Acromegaly

Acromegaly is a chronic debilitating disease with an insidious onset, resulting from the effects of either hypersecretion of growth hormone (GH) or increased amounts of an insulin-like growth factor I (IGF-I). Once recognized, acromegaly is treatable in most patients, but because of its slow progression of symptoms and signs, its diagnosis is often delayed for 15 or 20 years. Untreated, acromegaly can result in serious complications and premature death. It is, therefore, important to recognize the early symptoms of acromegaly and to understand its cause in order to facilitate early diagnosis and treatment.
The name acromegaly is derived from the Greek words for “extremities” and “enlargement” and reflects one of its most common clinical features, the abnormal growth of the extremities and body organs. The onset of the disease is so gradual that neither the patients nor their families notice it. Enlargement of the hands and feet is often an early symptom, with patients noticing changes in ring or shoe sizes. Gradually, facial features become enlarged, especially the frontal bone and mandible. Head size increases because of growth in both soft tissue and skull mass. Ribs thicken, creating “barrel” chests. Overgrowth of bone and cartilage often leads to crippling joint pain from accelerated osteoarthrosis, and as the disease progresses, generalized muscular weakness becomes a serious feature. In addition, other symptoms that may occur are headaches and visual disturbances that could lead to blindness. There may be enlargement of body organs such as the liver, spleen, kidneys and heart.

SYNONYMS
Marie’s disease
EPIDEMIOLOGY & DEMOGRAPHICS
INCIDENCE: 3 to 4 new cases/1,000,000 persons
PREVALENCE: 50 to 60 cases/1 million persons, with some estimates as high as 90 cases/1 million persons
PREDOMINANT SEX: No sexual predominance
MEAN AGE AT DIAGNOSIS: Males: 40 yr; females: 45 yr

RISK FACTORS
• Increased mortality, primarily from cardiovascular and respiratory causes
• Death in 50% of untreated patients by age 50 yr (twice the rate of the general population)
• Increased prevalence of colon carcinoma and other malignancies
PHYSICAL FINDINGS & CLINICAL PRESENTATION
• Coarse features resulting from growth of soft tissue
• Coarse, oily skin
• Hands and feet that are spade-like, fleshy, and moist
• Prognathism, which can give an underbite
• Carpal tunnel syndrome
• Excessive sweating
• Arthralgias and severe osteoarthritis
• History of increased hat, glove, and/or shoe size

• Hypertension
• Skin tags
• Muscle weakness and decreased exercise capacity
• Headache, often severe
• Diabetes mellitus
• Visual field defects
ETIOLOGY
Cause is usually a pituitary adenoma, affecting the anterior lobe.
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
Ectopic production of growth hormone-releasing hormone (GHRH) from a carcinoid or other neuroendocrine tumor
WORKUP
1. First screening test: measure serum IGF-I level.
a. Direct measurement of the GH level is not as useful, because it is secreted in a pulsatile fashion and a random level may be falsely normal.
b. Upper limits of a normal IGF-I level, depending on the assay: >380 ng/ml or 2.5 U/ml.
2. Failure to suppress serum GH to less than 2 ng/ml after 100 g oral glucose is considered conclusive.
a. Patients may show suppression of GH or a paradoxical response.
b. Patients will not suppress GH to 2 ng/ml or less (the normal response).
c. GHRH level >300 ng/ml is indicative of an ectopic source of GH.
LABORATORY TESTS
• Elevated serum phosphate
• Elevated urine calcium
IMAGING STUDIES
• Imaging studies of choice: MRI of the pituitary and hypothalamus
• CT of the pituitary and hypothalamus used initially
TREATMENT
SURGERY
Treatment of choice: transsphenoidal microsurgical adenomectomy
• Surgical failure rate: about 13.3% for microadenomas (tumors <10 mm) and 11.1% for macroadenomas (tumors >10 mm confined to the sella)
• Preoperative IGF-I level: indicator of surgical outcome with higher levels in the surgical failure group
RADIOTHERAPY
• Irradiation to reduce further growth of the tumor in most patients
• Major complication: hypopituitarism, which may occur in up to 50% of patients; this complication is more likely in patients who had surgery irradiation
MEDICAL Rx
• Indicated when patients have failed surgical therapy, when surgery is contraindicated, and in patients waiting for the effects of radiotherapy to begin
• Octreotide
1. A somatostatin analog given tid at a dose of 100 mg subcutaneously
2. Important side effects: biliary sludge and gallstones; nausea, cramps, and steatorrhea; suppression of GH levels to about 5 ?g/L in 52% of patients; IGF-I levels normalized to about 53%
3. Important in the preoperative shrinkage of pituitary tumors and softening of adenomatous tissue
• Bromocriptine
1. A dopamine analog given at a dosage of 10 to 60 mg PO tid to qid
2. Less effective than octreotide
3. Important advantages: less expensive than octreotide and taken orally
4. Important side effects: orthostatic hypotension, lightheadedness, nausea, constipation, and nasal stuffiness
5. Suppresses GH levels to <5 mg/L in about 20% of patients; normalizes GH levels in approximately 10%, and shrinks pituitary adenomas in 10% to 20%; IGF-I levels normalized to about 10%
• Pegvisomant is a growth hormone receptor antagonist that has shown promising results in the treatment of acromegaly.
CHRONIC Rx
Combination of bromocriptine and octreotide may be synergistic, allowing a lower combination dosage than alone.
DISPOSITION
• Patients receiving radiotherapy need long-term follow-up to monitor the potential development of hypopituitarism.
• Continuation of medical therapy should be based on the normalization of IGF-I levels.