Acromegaly by Dr. B. Kamanga - Clinical Features, Diagnosis and Management of GH-Secreting Adenomas

Acromegaly B. Kamanga, MD Robert Wadlow, the “Alton Giant” is said to be the tallest human in history, stood at 8’11 ½” and died at age 22 from an infected leg ulcer Growth Hormone Growth hormone (GH) is the principal hormone responsible for growth during childhood and adolescence. GH is secreted by acidophilic somatotrophs IGF-1 mediates growth promoting and anabolic actions Prophet of Pit-1 (PROP1) gene is responsible for the development and proliferation of somatotrophs Growth Hormone Growth hormone–releasing hormone (GHRH) stimulates the synthesis and secretion of GH Somatostatin suppresses the secretion of GH Ghrelin from the gastrointestinal tract also promotes the release of GH Somatotrophs express receptors for GHRH, ghrelin, and somatostatin Growth Hormone Normal GH production from the pituitary gland is pulsatile Most GH values fall in the range of 0.1-0.2 μg/L in normal subjects Maximum GH production occurs at night Assess overall daily GH production by obtaining a mean GH over 24 h by frequent GH sampling Acromegaly A rare disorder; Prevalence of 38-69 cases per million Results from excessive secretion of growth hormone (GH) by a pituitary adenoma, very rarely from an ectopic GHRH source Pituitary adenomas result from a monoclonal proliferation of somatotrophs, leading to increased GH secretion. Occurs in individuals with fused epiphyseal plates. Pathogenesis More than 95% of patients with acromegaly harbor a GH-secreting pituitary adenoma Mammo-somatotroph adenomas produce both GH and PRL from a single cell Pluripotent adenomas may express GH with any combination of PRL, TSH, or ACTH Patients with pluripotent adenomas present with clinical features of acromegaly as well as hyperprolactinemia, Cushing’s disease, or, rarely hyperthyroidism Pathogenesis GHRH produced by the hypothalamus Abdominal and chest neuroendocrine tumors may secrete GHRH Hypothalamic tumors, including hamartomas, choristomas, gliomas, and gangliocytomas, may produce GHRH GHRH causes somatotroph hyperplasia with resultant unrestrained GH secretion and acromegaly Multiple Endocrine Neoplasia Type 1 Multiple endocrine neoplasia type 1 syndrome (MEN1) is an autosomal dominant condition Presents with a GH-producing adenoma, and parathyroid as well as pancreatic tumors Results from the inactivation of the MENIN tumor suppressor gene Clinical Features Enlargement of acral parts of body (nose, lips, hands and feet) Enlargement of soft tissues &internal parts of the body (except the brain) Mass effects of tumor: Headache, Visual field defects, Hyperprolactinemia (Stalk effect), Hypopituitarism (Hypothyroidism, hypogonadism, hypocortisolism) Acromegaly is an insidious disease, which is often diagnosed late (between 4 and more than 10 years after onset). Clinical Features Systemic effects of GH/IGF-I excess: Visceromegaly, Soft tissue enlarment, skin changes (hyperhidrosis,oily skin, skin tags, thick skin, acathosis nigricans, scalp skin folding), thickening of acral parts, macroglossia, Jaw malocclusion Cardiovascular system: Left and right ventricular hypertrophy, asymmetric septal, systolic and/or diastolic ventricular dysfunction, CAD, Arrhythmias, Hypertension Clinical Features Mechanisms for Hypertension: Increased plasma volume, alterations in renin-angiotensin, insulin resistance, and increased vascular resistance Insulin resistance: Growth hormone alters the ability of insulin to suppress glucose production and stimulates the utilization of glucose Clinical Features Respiratory system: Hypertrophy of the laryngeal mucosa and cartilage, Upper airway obstruction, Sleep apnoea (due to airway obstruction, or central), Ventilatory dysfunction Clinical Features Obstructive sleep apnea predominates over central sleep apnea Impaired respiratory function is due to alterations in the bone and muscle structures of the chest and lung elasticity. Patients develop a barrel chest due to changes in their vertebral and costal morphology. Obstruction of the upper airways result from macroglossia & hypertrophy of the laryngeal mucosa and cartilage Clinical Features Endocrine changes: Impaired glucose tolerance, DM, Insulin resistance, Hypercalcemia (secondary to hyperparathyroidism), Goiter (IGF-I stimulates thyrocyte growth), Hypercalciuria and nephrolithiasis (due to hyperparathyroidism, renal tubular acidosis, increased calcium absorption, and increased 1, 25 (OH)2 D3), Galactorrhea, Hypogonadism (Decrease libido, Impotence), Menstrual abnormalities Clinical Features Bone and joint manifestations: Increased articular cartilage thickness, Arthralgias, Arthritis, Carpal tunnel syndrome, Osteopenia Clinical Features Mouth: Jaw prognathism and mandibular overbite, widened incisor tooth gap, thick lips Bowels: Colonic cancer, adenomatous polyps, dolichomegacolon, colonic diverticular disease Increased activity of the epithelial sodium channel (may contribute to volume expansion) Adenoma may compress local structures and cause neurological changes and visual disturbances Clinical Features Other manifestations: Psoriasis, Osteophytes in cervical and lumbar spine, Intervertebral disk space widening, vertebral enlargement, joint deformity, Decreased bone mineral density at the lumbar …