Acromegaly

Epidemiology and Pathophysiology of Acromegaly

• Epidemiology
• Pathophysiology
  • The Role of GH and Insulin-Like Growth Factor 1
  • Clinical Aspects of Acromegaly
  • Physiologic and Morphologic Changes
  • Cardiovascular System and Acromegaly

Epidemiology

Acromegaly is a rare disease with a prevalence of 40 to 60 cases per million and an incidence of 3 to 4 new cases per million annually (1). It is estimated that there are 15,000 people with acromegaly in the United States alone. Diagnosis generally occurs 10 to 15 years after the onset of pathological growth hormone (GH) secretion (1).

The Pathophysiology of Acromegaly

The somatic growth and metabolic dysfunction associated with acromegaly result from excess secretion of GH and subsequent elevation of circulating and locally produced insulin-like growth factor I (IGF-1). In healthy individuals, GH secretion is under the dual regulation of growth hormone-releasing hormone (GHRH) and somatostatin, with variations in the secretion of somatostatin being the primary mode of regulation (2).

The interaction of GHRH and somatostatin, as well as fluctuations in levels of somatostatin, regulate GH secretion (6). Hypersecretion of GH and IGF-1 may be caused by (3):

• Primarily, GH-secreting adenoma(s) of the pituitary resulting from clonal expansion of a single mutated cell
• Rarely, GHRH- and GH-secreting neoplasms such as gangliocytomas of the hypothalamus and carcinoid tumors

GH-secreting tumors have a large number of receptors for somatostatin (4) and, thus, are frequently responsive to therapy with analogues of somatostatin such as Sandostatin LAR® Depot (octreotide acetate for injectable suspension).

The Role of Growth Hormone and Insulin-Like Growth Factor 1

Rather than stimulating growth directly, GH induces the release of IGF-1, which promotes DNA, RNA, and protein synthesis, as well as cell and tissue growth (5). GH, or somatotropin, is responsible for the growth of almost all cells and tissues. GH activity is both of the following:

• Direct effects (anti-insulin effects) such as increased lipolysis and increased glucose mobilization. The direct growth promoting actions of GH include (2, 5, 6):
  • Induction of insulin resistance in peripheral tissues
  • Hyperinsulinism
  • Lipolysis
  • Ketogenesis
  • Hyperglycemia
  • Sodium and water retention
• Indirect effects (insulin-like effects) result from GH stimulation of IGF-1 production, causing effects such as growth of skeletal muscle, connective tissue, soft tissue, and bone-epiphyseal cartilage. Indirect growth-promoting actions of GH are mediated by the induction of growth factors, or somatomedins, the most important of which is somatomedin-C, or IGF-1. IGF-1 is produced by cells primarily in the liver, but also is present in the kidney, pituitary gland, GI tract, muscle, and cartilage (2, 5). Like insulin, the indirect IGF-1 dependent growth-promoting actions of GH include (2, 5, 6):
  • Induction of protein synthesis
  • Amino acid transportation
  • Muscle mass, cartilage and bone growth
  • DNA and RNA synthesis
  • Cell proliferation

Clinical Aspects of Acromegaly

Structural Changes

The structural changes that occur with acromegaly cause chronic pain (1). These changes include:

• Skeletal overgrowth deformities, particularly of the hands, feet, and face
• Cardiovascular disease (hypertension, enlarged heart)
• Arthropathy
• Neuropathy
• Respiratory obstruction

In addition to MRI or CT imaging, somatostatin receptor scintigraphy (SRS) may be used to obtain images of pituitary adenomas. In this procedure, radiolabeled octreotide is injected into the systemic circulation. Since pituitary adenomas frequently contain elevated numbers of somatostatin receptors, the radioactive octreotide binds to these receptors and can be detected subsequently as bright spots in the resulting images.

Physiologic and Morphologic Changes

Specific signs and symptoms of the disease can include (7):

Changes in appearance with acromegaly

Cardiovascular System and Acromegaly

The cardiovascular system is particularly affected in acromegaly. Acromegalic cardiomyopathy seems to be correlated with the duration of disease, with a constellation of different abnormalities occurring (8).

Acromegalic cardiomyopathy develops during the disease from the early to the advanced stage. The different abnormalities may be recognized using appropriate cardiological investigations.