acromegaly
Acromegaly
Acromegaly is a rare disease of exaggerated somatic growth arising from increased growth hormone (GH) secretion in an adult after the epiphyses (rounded end of long bones) have fused. It was described in 1886 by Pierre Marie, hence also called Marie’s disease. Excess GH in children leads to Gigantism.
Prevalence
The prevalence is about 7 cases per 100,000, with an annual incidence of 0.3 cases per 100,000.
Cause
About 98% of the cases of acromegaly are due to GH secreting adenoma of the anterior pituitary (a pea-sized endocrine gland at the base of the brain), that is usually benign. The tumor may secrete GH alone or GH and prolactin. Excessive GH stimulates the production of insulin-like growth factor I (IGF-I) mainly in liver, which in turn stimulates general tissue growth. This is referred to as GH/IGF-1 Axis. Other rare causes are hypothalamic tumors, ectopic secretion from carcinoid tumors or non small-cell lung cancers, that release growth hormone-releasing hormone (GHRH) and cause secondary increase of GH.
Symptoms
Manifestations include skeletal and soft tissue growth and deformities, cardiac, respiratory, neuromuscular, endocrine and metabolic complications due to the effect of the GH and IGF-1 on various tissues.
Acromegaly patients may have facial changes such as large lips, nose and tongue, frontal bossing of the skull, prognathism (protrusion of the lower jaw), teeth separation. As a result of excessive bone and soft tissue growth in extremities, requirement for increased shoe and ring size may become necessary. This may be accompanied by increased sweating, heat intolerance, oiliness of the skin, fatigue and weight gain.
Arthritis due to bone growth, skin thickening in the face and hands, sleep apnea due to large tongue and soft tissue growth in the airway which may sometimes complicate endotracheal intubation during medical procedures when the patient cannot breathe on their own.
Biventricular cardiac hypertrophy, hypertension, diastolic dysfunction in acromegaly patients may lead to heart failure as well as cardiac dysrrhythmias in untreated subjects.
The abnormal increase of tissue will compress nearby nerves and leads to sensory and motor changes, e.g. carpel tunnel syndrome. The GH also stimulates gluconeogenesis and induces insulin resistance which may result in diabetes mellitus.
In addition, the adenoma of pituitary itself may cause local symptoms such as headaches, visual problems, loss of both temporal visual fields due to compression of the optic nerve, hyperprolactinemia and decreased anterior pituitary function due to compression of normal tissue by the adenoma.
Diagnosis
Diagnosis may be delayed by at least 10 yrs due to insidious onset and the slow progression of the signs of acromegaly. Mean age at diagnosis is 40-45 years. At the time of diagnosis, about 75% of the patients have macroadenoma (tumor size over 1 cm) of pituitary.
The best single test is the measurement of IGF-1, because of its long half life and stable serum levels as compared to GH. GH levels may also be measured.
The most useful dynamic test is the Oral Glucose tolerance test (OGTT). In a healthy individual, the IGF-1 levels usually drop to below 1 ng/ml, 2 hours after the ingestion of 75 g of glucose.
Pituitary MRI with contrast is the most sensitive test to localize a pituitary adenoma. Other tests such as plain films may show sellar enlargement. Radiographs of the hands and feet may show increased soft tissue thickness which may suggest GH excess.
Treatment
The aim is to manage the GH hyper secretion as well as the tumor size, while trying to preserve normal pituitary function. The goal of therapy is to bring the IGF-1 levels to normal range for patient’s age, and GH levels after OGTT to < 1ng/ml
The initial therapy of choice is surgical removal of the tumor and transsphenoidal approach is commonly used. About 80% of people with small tumors and 50% of those with tumor >1 cm get IGF-1 levels normalized after surgery.
Somatostatin analogs are the first-line medical therapy for acromegaly. Two short acting agents Octreotide and Lanreotide, and their long acting formulations Octreotide LAR and Somatulin Autogel are currently available. Cabergoline, a dopamine agonist may be added to somatostatin analog to normalize the GH and IGF-1 levels.
Pegvisomant, a GH receptor antagonist is the latest medical therapy for acromegaly. It reduces the IGF-1 levels to normal in more than 90% of the patients by interfering with the signaling of GH receptor. Serum GH levels increase and tumor growth has been reported. Current recommendations are to perform an MRI every 6 months on these patients.
Radiotherapy is reserved for patients who have residual or recurrent tumor or for those unresponsive to medical therapy. The effect of irradiation on GH secretion is slow and may take 10-20 yrs. Stereotactic radiosurgery using Gamma knife is also in practice.
Post treatment assessment includes evaluation of GH secretion, anterior pituitary function, and tumor size.
References and further readings
Fleseriu M, Delashaw JB Jr, Cook DM. Acromegaly: a review of current medical therapy and new drugs on the horizon. Neurosurg Focus. 2010;29:E15.
Sherlock M, Woods C, Sheppard MC. Medical therapy in acromegaly. Nat Rev Endocrinol. 2011;7:291-300.
Anat ben-Shlomo, Melmed S. Acromegaly. Endocrinology and Metabolism Clinics of North America, 2008;37:101-122.
David G.Gardner, Dolores Shoback. Greenspan’s Basic and Clinical Endocrinology, 8th Edition, McGrawHill, 2007, p145-150.
Melmed S. 1. Causes and clinical manifestations of acromegaly 2. Diagnosis of acromegaly 3. Treatment of acromegaly. UpToDate, 2011.
Miller RE, Learned-Miller EG, Trainer P, Paisley A, Blanz V. Early Diagnosis of Acromegaly: Computers Versus Clinicians. Clin Endocrinol (Oxf). 2011;1365-2265.
Contributor:
Madhavi Yarlagadda MD
Endocrinology, Diabetes and Metabolism
Medical Group of Kansas City
6675 Holmes Road
Kansas City, MO, USA
Reviewer:
Wenman Wu MD, PhD
Temple University School of Medicine
Philadelphia, PA, USA
May 2011