Complications and Comorbidities> Endocrine>

DEFINITION

• A clinical syndrome resulting from excessive secretion of growth hormone (GH).
• GH excess prior to closure of the epiphyseal plates results in gigantism; after epiphyseal plate closure, the result is acromegaly.
• Somatic and metabolic effects of chronic GH hypersecretion are predominantly mediated by high levels of insulin-like growth factor-1 (IGF-1).
• Acromegaly is an uncommon secondary cause of diabetes.
• Excess GH: 1) stimulates gluconeogenesis and lipolysis, causing hyperglycemia and elevated free fatty acid levels; 2) leads to both hepatic and peripheral insulin resistance, with compensatory hyperinsulinemia. Conversely, IGF-1 increases insulin sensitivity. However, in acromegaly, increased IGF-1 levels are unable to overcome the insulin-resistant state caused by GH excess.

EPIDEMIOLOGY

• Prevalence 40-130 per million inhabitants, although may be as high as 100-1000 per million (Chanson).
• Almost always due to a GH-secreting pituitary adenoma.
• Very rare causes include excess secretion of growth hormone-releasing hormone (GHRH) by hypothalamic tumors, ectopic GHRH secretion by neuro-endocrine or non-endocrine tumors (i.e. carcinoid tumors, small cell lung cancer).
• May occur as part of a genetic syndrome, including McCune-Albright syndrome, MEN-1 syndrome, or the Carney complex. Mc-Cune Albright syndrome is characterized by polyostotic fibrous dysplasia, cafe-au-lait spots, precocious puberty, and endocrine hyperactivity (thyrotoxicosis, gigantism, and Cushing's disease). MEN-1 results in primary hyperactivity of the pituitary, parathyroids, and pancreas. Carney complex results in myxomas, lentigenes, endocrine hyperactivity, and schwannomas (Keil).
• Slow progression of signs and symptoms and insidious course of disease often lead to delayed diagnosis; mean age at diagnosis is 40.
• Mortality rates nearly two-times higher than general population, due to cardiovascular, cerebrovascular, or respiratory disease; increased risk of colonic neoplasia and possibly other tumors as well. Mortality risk reduced by therapy, almost to normal in patients deemed surgically cured (Melmed).
• 19-56% of acromegalics have overt diabetes and 16-46% have impaired glucose tolerance (Colao).  
• Higher GH levels, older age, and longer disease duration predict development of symptomatic diabetes. Family history of diabetes and concomitant hypertension may increase risk (Colao).
• Diabetic ketoacidosis (DKA) rare feature of acromegaly. Severe diabetic retinopathy also a rare complication (Colao). 

DIAGNOSIS

• Best single test for diagnosis is IGF-1, elevated in almost all patients with acromegaly.
• IGF-1 levels decrease with age and therefore an apparently "normal" value for an elderly patient may actually be high.
• GH measured in patients with equivocal IGF-1 levels, or when further biochemical confirmation required in patients with high IGF-1 levels.
• GH harder to interpret because: secretion pulsatile and diurnal; affected by factors such as exercise, stress, sleep, and fasting. Since GH levels vary widely during the day, best not to obtain random measurements (Bonert).
• Uncontrolled diabetes can elevate serum GH levels, as can liver disease and malnutrition.
• Most specific confirmatory test to establish diagnosis is oral glucose tolerance test (OGTT). Serum GH should fall to < 1 ng/ml within 2 hours of 75 g glucose ingestion. Post-glucose values >2 ng/ml found in >85% of patients with acromegaly. With more highly-sensitive immunoradiometric or immunochemiluminescent assays, a serum GH level >0.3 ng/ml after OGTT establishes diagnosis.
• Once GH hypersecretion confirmed, obtain MRI of the pituitary gland to look for adenoma. Most patients have a macroadenoma (tumor > 1 cm) at time of diagnosis.

SIGNS AND SYMPTOMS

• Due to local tumor effects and/or systemic effects of elevated IGF-1 levels.
• Signs: visual field deficits (commonly bitemporal hemianopia), cranial nerve (3, 4, 5, 6) palsies, nystagmus, papilledema, acral enlargement (thickening of soft tissues of hands and feet), prognathism, widely spaced teeth, hypertrophy of frontal bones, jaw malocclusion, arthritis, proximal myopathy, oily skin, skin tags, hypertrichosis, colon polyps, hypertension, left ventricular hypertrophy, cardiomyopathy, macroglossia, goiter, visceromegaly (salivary glands, liver, spleen, kidney, prostate), acanthosis nigricans, hypercalciuria and renal calculi, hypertriglyceridemia, impaired glucose tolerance and diabetes, weight gain.
• Symptoms: headache, visual disturbances (loss of visual acuity, double vision), arthralgias, acroparesthesias, carpal tunnel syndrome, fatigue, heat intolerance, hyperhidrosis, sleep disturbances, obstructive and central sleep apnea, menstrual irregularities, galactorrhea, decreased libido, impotence.
• Changes in ring, glove, or shoe size suggesting acral enlargement.
• Other lab findings: hyperphosphatemia and hypercalciuria due to direct effects of GH or IGF-1 in the kidney.
• Serum insulin increased in 70% of patients
• Imaging studies: plain films of skull show thickened calvarium, enlarged frontal and maxillary sinuses, and thickened jaw. Hand radiographs show increased soft tissue, increased width of intraarticular cartilage, "arrowhead tufting" of distal phalanges, cystic changes of carpal bones.

CLINICAL TREATMENT

• Mainstay of treatment of GH-secreting pituitary adenomas is transsphenoidal surgery. Cure rate for microadenomas as high as 80% with experienced neurosurgeon; cure rate for macroadenomas <50%.
• Most patients with macroadenomas require adjuvant therapy (medical vs. radiotherapy). Radiation therapy generally reserved as a third-line treatment because of risk of hypopituitarism.
• Recent data show that pre-surgical treatment with somatostatin analogues may improve the chance of surgical cure in patients with macroadenomas (Carlsen).

• Somatostatin analogues (SSAs) (below) inhibit somatotroph cell proliferation and GH secretion. Efficacy as primary treatment: 50-70% effective at achieving biochemical control and 50% effective at reducing tumor size . Efficacy as secondary treatment (i.e. following surgery): 20%. 
• SSAs include octreotide, octreotide LAR (long-acting release), and Lanreotide Autogel (long-acting depot formulation). Octreotide administered by sub-Q injection, usually 100-250 mcg three times daily. Octreotide LAR administered as IM injection monthly, usually starting at 20 mg and increasing by 10 mg increments to clinical and biochemical response. Lanreotide Autogel administered by sub-Q injection monthly, with typical starting dose of 90 mg.
• Pegvisomant is a competitive inhibitor at the GH receptor level that prevents the action of native GH. Efficacy: 80-90% effective at controlling acromegalic symptoms, but does not reduce tumor size or GH levels.
• Dopamine agonists (i.e. cabergoline, bromocriptine) may also be considered.

• Impaired glucose tolerance and diabetes generally improve following treatment of underlying disease.
• Conflicting data regarding effects of SSAs on glucose homeostasis. SSAs may reduce insulin resistance, but also impair insulin secretion. Neither SSA or surgery was associated with deterioration of glucose tolerance in one study (Colao); BMI appears to be the major predictor of worsening glycemic control.
• Reduced fasting glucose levels and hemoglobin A1C are reported following treatment with pegvisomant (Barkan).
• Management of diabetes in acromegaly is similar to general management of Type 2 Diabetes.
• Oral secretagogues and/or insulin sensitizers theoretically offer the greatest potential for glycemic control based on the pathophysiology of diabetes in acromegaly.
• Insulin should be started if oral agents are unsuccessful at controlling glucose.

FOLLOW UP

• Monitor IGF-1 levels every 6 months. If not normal, maximally titrate medications. Consider combined treatment (SSA + dopamine agonist).
• Obtain MRI 3-4 months post-operatively, then every 3-6 months after starting medical therapy. If surgically cured, MRI surveillance frequency may be reduced to every 2-3 yrs. If disease not fully controlled, MRI should be performed every 6-12 months.
• Perform hormonal testing after surgery or radiation to assess anterior and posterior pituitary function (hypopituitarism/Diabetes Insipidus). Pituitary deficiencies can develop 10 or more years after radiation therapy.

EXPERT COMMENTS

• Acromegaly is a rare cause of diabetes characterized by a state of insulin resistance.
• Glycemic control is best achieved by treatment of underlying state of GH excess.
• Treatments for acromegaly (i.e. SSAs) may have potentially detrimental effects on glycemia, although the literature is conflicting.
• If diabetes persists after treatment, hyperglycemia should be managed according to standard guidelines for type 2 diabetes.

Basis for Recommendations

• Melmed S, Colao A, Barkan A, et al.; Guidelines for acromegaly management: an update.; J Clin Endocrinol Metab; 2009; Vol. 94; pp. 1509-17;
  ISSN: 1945-7197;
  PUBMED: 19208732
  Rating: Basis for recommendation
  Comments:This is an updated review of current management practices and guidelines.
  
  
• Chanson P, Salenave S, Kamenicky P, et al.; Pituitary tumours: acromegaly.; Best Pract Res Clin Endocrinol Metab; 2009; Vol. 23; pp. 555-74;
  ISSN: 1532-1908;
  PUBMED: 19945023
  Rating: Basis for recommendation
  Comments: Detailed descriptions of clinical manifestations of acromegaly.
  
  

REFERENCES

RELATED MODULES

• Hyperosmolar Hyperglycemic State