Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management

0163-769X/04/$20.00/0 Printed in U.S.A. Endocrine Reviews 25(1):102–152 Copyright © 2004 by The Endocrine Society doi: 10.1210/er.2002-0022 Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management ANNAMARIA COLAO, DIEGO FERONE, PAOLO MARZULLO, AND GAETANO LOMBARDI Department of Molecular and Clinical Endocrinology and Oncology (A.C., P.M., G.L.), “Federico II” University of Naples, 80131 Naples, Italy; and Department of Endocrinological and Metabolic Sciences and Center for Excellence for Biological Research (D.F.), University of Genova, 16132 Genova, Italy This review focuses on the systemic complications of acromegaly. Mortality in this disease is increased mostly because of cardiovascular and respiratory diseases, although currently neoplastic complications have been questioned as a relevant cause of increased risk of death. Biventricular hypertrophy, occurring independently of hypertension and metabolic complications, is the most frequent cardiac complication. Diastolic and systolic dysfunction develops along with disease duration; and other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis, and endothelial dysfunction, are also common in acromegaly. Control of acromegaly by surgery or pharmacotherapy, especially somatostatin analogs, improves cardiovascular morbidity. Respiratory disorders, sleep apnea, and ventilatory dysfunction are also important contributors in increasing mortality and are beneficially advantaged by controlling GH and IGF-I hypersecretion. An increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment, has been reported by several independent investigations, although malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level. Finally, the most important cause of morbidity and functional disability of the disease is arthropathy, which can be reversed at an initial stage, but not if the disease is left untreated for several years. (Endocrine Reviews 25: 102–152, 2004) I. Introduction A. Epidemiology and causes of mortality in acromegaly B. The clinical basis of increased mortality in acromegaly C. The experimental basis for the GH/IGF-I effects at different body organs D. Management of acromegaly II. The Complications at the Cardiovascular System A. Epidemiology B. Pathogenesis C. The acromegalic cardiomyopathy D. Arrhythmias E. Hypertension F. Atherosclerosis and endothelial dysfunction G. Effect of GH and IGF-I control on cardiovascular disease III. The Metabolic Complications A. Epidemiology B. Pathogenesis C. Effect of GH and IGF-I control on metabolic complications IV. The Complications at the Respiratory System A. Epidemiology B. Pathogenesis C. The sleep apnea syndrome D. The respiratory dysfunction E. Effect of GH and IGF-I control on respiratory disease V. The Neoplastic Complications A. Epidemiology B. Pathogenesis C. The gastrointestinal tract D. Neck and lung tumors E. Tumors of the reproductive system F. Other tumors VI. The Complications at the Skeletal System A. Epidemiology B. Pathogenesis C. The acromegalic arthropathy D. The carpal tunnel syndrome E. Bone mass alterations F. Effect of GH and IGF-I control on the skeletal system VII. Summary VIII. Conclusions Abbreviations: ALS, Acid-labile subunit; ANP, atrial natriuretic peptide; Apo, apolipoprotein; CETP, cholesteryl ester transfer protein; DISH, diffuse idiopathic skeletal hyperostosis; ECG, electrocardiogram; ER, estrogen receptor; GH-R, GH receptor; HDL, high-density lipoprotein; IGFBP, IGF binding protein; IGF-IR, IGF type I receptor; IGT, impaired glucose tolerance; IMT, intima-media thickness; LAR, longacting repeatable; LDL, low-density lipoprotein; Lp-a, lipoprotein-a; LPL, lipoprotein lipase; MRI, magnetic resonance imaging; PR, progesterone receptor; PRL, prolactin; PSA, prostate-specific antigen; SCLC, small cell lung cancer; SIR, standardized incidence ratio; TGHM, transgenic for the GH gene. Endocrine Reviews is published bimonthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community. I. Introduction I N 1864, THE skull of a woman affected by prosopectasia (derived from the Greek words prosopon, face, and ektasis, stretching) was described by Verga (1) and added to the collection of the Anatomical Museum of Modena, Italy. During her lifetime, this patient suffered from typical somatic disfigurement, arrhythmias, and osteoarthropathy, although a postmortem examination revealed a giant pituitary (1). In 1881, Brigidi reported a description clinically consistent with acromegaly from the autopsy of the Italian actor Ghirlenzoni 102 Colao et al. • Acromegaly Complications Endocrine Reviews, February 2004, 25(1):102–152 (2). This man had visceromegaly and enlarged hypertrophic pituitary. However, both Verga and Brigidi misinterpreted the pathogenesis of the syndrome, which was attributed to early menopause in the former and to primary bone disease in the latter case. Five years after Brigidi’s description, Pierre Marie (3) indicated with acromegaly his observation of two patients he had treated at the Salpetrière Hospital in Paris. At autopsy, Marie observed visceromegaly and enlarged pituitaries but was uncertain whether pituitary overgrowth was the cause etiology of such syndrome or whether it reflected the general process of organomegaly observed in these patients (3). Afterward, a progressively increasing number of similar descriptions were provided. Massalongo in 1892 and Benda in 1900 both indicated the cause of the disease as originating in the pituitary (2). However, it was only in 1909 that Harvey Cushing (4) reported the remission of clinical symptoms of acromegaly after partial hypophysectomy, thus indicating the etiology of the disease and its potential treatment as well. Acromegaly is known to be characterized by progressive somatic disfigurement and a wide range of systemic manifestations (5, 6). At diagnosis, patients generally exhibit coarsened facial features, exaggerated growth of hands and feet, and soft tissue hypertrophy (Table 1). Other characteristics may include hyperhidrosis, goiter, osteoarthritis, carpal tunnel syndrome, fatigue, visual abnormalities, increased number of skin tags, colon polyps, sleep apnea and daytime somnolence, reproductive disorders, and cardio- vascular disease, which most commonly includes cardiac hypertrophy, hypertension, and moderate arrhythmias, although congestive heart failure occurs more rarely (5–7). Improvement of surgical procedures, radiotherapy tools, and the availability of pharmacological compounds active on somatotroph pituitary cells greatly changed the approach to this disease that is an extraordinary model to investigate the pathophysiology of GH and IGF-I actions on virtually all body organs and systems; several systemic consequences developing in the course of (...truncated)