Alan Ona Malabanan Acromegaly is a rare, chronic, and insidious disease that results from prolonged excessive secretion of growth hormone (GH). This manifests as excessive bone and soft tissue growth. Untreated or partially treated patients with acromegaly have double the expected mortality rate of age-matched healthy subjects. The increased prevalence of hypertension, diabetes mellitus, and sleep apnea increases cardiovascular morbidity and mortality. Motor vehicle accidents from daytime somnolence and sleep deprivation also contribute to the overall mortality risk. In addition, patients with acromegaly have an increased risk for malignant disease, particularly of the colon. Morbidity also results from arthropathies. When GH excess occurs in children, gigantism results because the epiphyseal plates have not yet closed. Acromegaly is rare, but the diagnosis is commonly delayed or missed. Many studies have suggested a prevalence of 40 to 130 per million persons with an incidence of 3 to 4 cases per million per year.1 Other studies have seen a higher prevalence, including a study with a prevalence of 97 cases per million in a highly polluted area.2 One study in Germany of serum insulin-like growth factor 1 (IGF-1) levels in a 6773 unselected general primary care patients suggest an incidence as high as 1034 per million patients.3 Acromegaly is usually diagnosed in middle age; the mean age at diagnosis is 40 years in men and 45 years in women. GH is secreted by somatotroph cells in the anterior pituitary gland. Its secretion is regulated by two hypothalamic hormones, growth hormone–releasing hormone (GHRH) and somatostatin (SS). GHRH stimulates both GH production and secretion, whereas SS inhibits GH secretion. GH secretion is pulsatile, with brief surges followed by long periods of inactivity. Many physiologic stimuli affect GH secretion, including stress (increased), sleep (increased), meals (increased or decreased), and aging (decreased). The variable nature of a random serum GH level limits its usefulness in diagnosis of acromegaly. IGF-1, or somatomedin C, is a GH-dependent protein produced in the liver. Its serum level is directly proportional to the 24-hour integrated serum GH level, and it is a much better indicator of GH excess than a random serum GH level. IGF-1 and GH increase during puberty and late adolescence and decline throughout adulthood. The bone and soft tissue growth in acromegaly is a direct result of the effects of GH and IGF-1. In addition, GH has several other metabolic effects, including insulin antagonism, lipolysis, and protein anabolism, which in excess results in glucose intolerance, decreased fat stores, and increased muscle mass. The most common cause of GH excess is a GH-secreting pituitary adenoma in more than 95% of cases; 25% of GH adenomas co-secrete prolactin.4 Rare (<1%) causes include GHRH-producing tumors such as hypothalamic tumors, bronchial carcinoid, and pancreatic islet cell tumors. Ectopic production of GH has been described in pancreatic islet cell tumors and other rare tumors. Acromegaly may be associated with familial syndromes such as multiple endocrine neoplasia type I—a triad of pituitary tumor, hyperparathyroidism, and pancreatic tumor—and McCune-Albright syndrome, a genetic disease associated with polyostotic fibrous dysplasia, café au lait spots, and endocrine hyperfunction. Acromegaly develops insidiously; many patients have symptoms for more than 10 years before diagnosis. Symptoms result from the effects of GH excess or from the effect of the pituitary mass on surrounding brain structures. An evaluation of 324 consecutive patients with acromegaly from 1981 to 2006 continued to show marked clinical manifestations of acromegaly at diagnosis, suggesting that it remains underdiagnosed until later stages, even with more advanced diagnostic tools over time.5 Signs and symptoms at diagnosis included enlargement of facial features or hands and feet, joint pain, excessive sweating, headache, menstrual irregularity, snoring, macroglossia, increased spacing between teeth, vision problems, weight gain, deepening voice, paresthesias, acne, hirsutism, and mood instability. At time of diagnosis in patients in whom acromegaly was diagnosed early (within 5 to 9 years of symptom onset), 37% of patients had hypertension, 24% had carpal tunnel syndrome, 18% had diabetes mellitus, and 13% had sleep apnea.5 Rates of these and other comorbidities are further increased with delay in diagnosis. Visual field disturbances and amenorrhea may also be presenting complaints. Acromegaly can be found incidentally in a workup for a pituitary mass, and primary care physicians are most likely to initiate workup.6 The Endocrine Society suggests consideration of acromegaly in patients without the typical manifestations but who may have several associated conditions: sleep apnea, type 2 diabetes mellitus, debilitating arthritis, hyperhidrosis, and hypertension.7 The earliest and most common physical changes occur in the skin and extremities. The growth of the soft tissues produces facial puffiness, broadening of the nose, furrowing of the brow, and skin thickening (bogginess) of the hands and feet. Enlargement of the tongue, uvula, and soft palate leads to sleep apnea. Vocal cord thickening results in a deeper and coarser voice. Skin tags (acrochorda) are more common in patients with acromegaly, as are colonic polyps. Patients may also have oily skin and excessive sweating (hyperhidrosis). Facial bone growth leads to coarsened facial features, which are usually recognizable only when they are severe after years of change or after review of the patient’s old photographs. The ubiquity of smartphones has greatly facilitated access to old photographs. These changes include growth of the calvaria and mandible, producing a prominent brow, an enlarged jaw, and dental malocclusion. With growth of the jaw, there is also widening of the spaces between the teeth. Excessive rib growth produces a barrel-shaped chest. Glove and shoe size changes result from bone growth in the hands and feet. Loss of lateral visual fields (bitemporal hemianopia), papilledema, extraocular palsy, or even rhinorrhea may result from impingement of the pituitary tumor on surrounding structures. Enlarged organs (visceromegaly) may also occur in acromegaly. Macroglossia, enlargement of the tongue, may be present. The thyroid may be enlarged, possibly leading to a multinodular goiter. There is an increased association of thyroid cancer with acromegaly. Rarely, the liver and spleen will be enlarged on physical examination. Random serum GH levels are not useful in the diagnosis of acromegaly because GH secretion is pulsatile and levels can be affected by coexisting disease states, exercise, sleep patterns, and other factors. IGF-1 level is a good screening test and, as mentioned previously, is a reflection of the previous day’s GH secretion, and it does not vary as GH does. There are normative reference ranges for IGF-1 that are gender and age adjusted; GH secretion and therefore IGF-1 level decline throughout adulthood. IGF binding protein 3, which is also GH dependent, can be measured and will be high in patients with acromegaly, although measurement of IGF-binding proteins usually does not confer additional information.8,9 Unfortunately, normal and abnormal values for all of these tests may overlap. The dynamic test of choice for diagnosis of acromegaly is the oral glucose tolerance test (OGTT), which most clearly demonstrates pathologic GH secretion. Of note, this test is contraindicated in patients with poorly controlled diabetes mellitus. An OGTT is performed after an overnight fast. Blood is drawn at baseline for serum glucose concentration and GH level. Then 75 g of oral glucose is given. Samples for serum glucose and GH are then taken at 60-minute intervals for a total of 120 minutes after the glucose load. In a normal individual, GH secretion is suppressed by an oral glucose load and should be suppressed to less than 1 ng/mL by the current immunoassays.10 With the use of newer ultrasensitive assays, acromegaly may be missed in a quarter of patients with a cutoff value of 1 ng/mL; suppression to a level of less than 0.3 ng/mL may better distinguish those with and without acromegaly.4 However, it is important to understand the assay being used and its characteristics in interpreting these data. Results of the OGTT should always be evaluated together with the IGF-1 measurement. Acromegaly can be diagnosed with failure to suppress GH appropriately during an OGTT with an elevated age- and gender-matched IGF-1 level.9 Studies have shown, however, that failure to suppress GH on OGTT in the setting of an elevated IGF-1 level does not rule out acromegaly.11,12 After the biochemical diagnosis of acromegaly, magnetic resonance imaging (MRI) of the pituitary gland should be performed. If no pituitary tumor is seen or if generalized pituitary hyperplasia is seen, the possibility of ectopic GHRH production should be considered. A plasma GHRH determination may be helpful, and further abdominal and chest imaging may be pursued to look for the source. Also, more than 10% of normal individuals may have an incidental pituitary adenoma that is nonsecreting. Diagnostics Acromegaly
Acromegaly
Definition and Epidemiology
Physician consultation is indicated for all patients with suspected acromegaly.
Pathophysiology
Clinical Presentation
Physical Examination
Diagnostics
Acromegaly
Chapter 204
