Acromegaly 

Acromegaly is a rare, insidious, and potentially life-threatening condition for which there is good, albeit incomplete, treatment that can add years of high-quality life for the patient.^[1] Increased and unregulated growth hormone (GH) production, usually caused by a GH-secreting pituitary tumor (somatotroph tumor), characterizes acromegaly. Other causes of increased and unregulated GH production, all very rare, include increased growth hormone–releasing hormone (GHRH) from hypothalamic tumors, ectopic GHRH from nonendocrine tumors, and ectopic GH secretion by nonendocrine tumors.

Symptoms develop insidiously, taking years to decades to become apparent, with a mean duration of symptom onset to diagnosis of 12 years. Excess GH produces a myriad of signs and symptoms and significantly increases morbidity and mortality rates. Additionally, the mass effect of the pituitary tumor itself can cause symptoms. Annual new patient incidence is estimated to be 3-4 cases per million population per year. The mean age at diagnosis is 40-45 years.

GH secreted from the anterior pituitary somatotrophs is normally controlled by 2 hypothalamic factors.

1. GHRH stimulates GH secretion and synthesis and is synthesized in the hypothalamus and transported via the hypothalamic pituitary portal system to the somatotrophs of the anterior pituitary.
2. Several tissues, including the endocrine pancreas, produce somatostatin in response to GH. Somatostatin inhibits GHRH secretion in a negative feedback pathway.

Once released into circulation, GH stimulates the production of insulinlike growth factor-I (IGF-I), also known as somatomedin C (SM-C). The main source of circulating IGF-I is the liver, though it is produced in many other tissues. IGF-I is the primary mediator of the growth-promoting effects of GH.

More than 95% of acromegaly cases are caused by a pituitary adenoma that secretes excess amounts of GH. Ectopic production of GH and GHRH by malignant tumors accounts for other causes.

Of these tumors, up to 40% have a mutation involving the alpha subunit of the stimulatory guanosine triphosphate (GTP)–binding protein. In the presence of a mutation, persistent elevation of cyclic adenosine monophosphate (cAMP) in the somatotrophs results in excessive GH secretion.

The pathologic effects of GH excess include acral overgrowth (ie, macrognathia; enlargement of the facial bone structure; enlarged hands and feet; visceral overgrowth, including macroglossia and enlarged heart muscle, thyroid, liver, kidney), insulin antagonism, nitrogen retention, and increased risk of colon polyps/tumors.

The role of genetic mutations was highlighted in a report suggesting that patients with pituitary tumors from 4 Irish families share a common mutation with a patient from the 18th century who had pituitary tumor–mediated gigantism.^[2]

Frequency

United States

Acromegaly is unusual, with a new case incidence of 3-4 per million subjects per year and a mean age of 40-45 years.

Mortality/Morbidity

Studies estimate an all-cause mortality rate at least twice that of the normal population. The major sequelae of acromegaly include cardiorespiratory and cerebrovascular diseases, diabetes, and neoplasia, particularly colon cancer.

A study by Berg et al found an increased prevalence of cardiovascular risk factors in patients with acromegaly compared with controls. The retrospective, comparative study used a Framingham risk score calculation compared with age- and gender-matched controls of the general population and an evaluation of effect of IGF-I normalization.^[3] This study documents the importance of aggressive management as early as possible in the disease process; however, it should be remembered that this study looks at risk factors only and not the cardiac disease process itself. Although treating a disease is a basic tenet, treatment of acromegaly is difficult, expensive, and apart from the biochemical evidence, hard to show responsiveness in a way that is satisfying to the patient.

The increase in mortality is attributed to excess GH and IGF-I. Because IGF-I is a general growth factor, somatic hypertrophy occurs across all organ systems, including but not limited to, acromegalic heart, increased muscle and soft tissue mass, and increased kidney size. Articular overgrowth of synovial tissue and hypertrophic arthropathy occur. Joint symptoms, back pain, and kyphosis are common presenting features. Other symptoms of soft tissue overgrowth include thick skin, hyperhidrosis (often malodorous), carpal tunnel syndrome, and other entrapment syndromes. Macroglossia may result in sleep apnea.

Visceral hypersomia includes heart, liver, and kidneys. Multinodular goiter is often present. With heart hypersomia comes hypertension, left ventricular hypertrophy, and, frequently, acromegalic cardiomyopathy with dysfunction and arrhythmias.

There also appears to be a relationship between GH/SM-C excess and premalignant colon polyposis, though this is not as clear as the other effects. In studies, the polyps were generally multiple and proximal to the splenic flexure, making them less likely to be discovered during sigmoidoscopy.

In a study by Bates et al, patients with GH concentration greater than 10 ng/mL had double the expected mortality rate, whereas patients with GH concentration less than 5 ng/mL approached normal mortality.^[4] The differential mortality underscores the necessity to reduce GH and IGF-I concentration.

Race

No clear relationship exists between incidence and race.

Sex

Acromegaly occurs with equal frequency in males and females. No clear sex predilection is apparent.

Age

Median age at diagnosis is 40 years in males and 45 years in females.