Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial

• Published in: BMJ Vol. 330; no. 7497; pp. 932 - 935
• Main Authors: Bruno, Savino, Maisonneuve, Patrick, Castellana, Paola, Rotmensz, Nicole, Rossi, Sonia, Maggioni, Marco, Persico, Marcello, Colombo, Alberto, Monasterolo, Franco, Casadei-Giunchi, Donata, Desiderio, Franco, Stroffolini, Tommaso, Sacchini, Virgilio, Decensi, Andrea, Veronesi, Umberto
• Format: Journal Article
• Language: English
• Published: London British Medical Journal Publishing Group 23.04.2005; British Medical Association; BMJ Publishing Group LTD; BMJ Publishing Group; BMJ Publishing Group Ltd
• Edition: International edition
• Subjects: Adult; Aged; Antagonist drugs; Antineoplastic Agents, Hormonal - adverse effects; Biological and medical sciences; Biopsies; Biopsy - methods; Breast Neoplasms - prevention & control; Chemical and Drug Induced Liver Injury - etiology; Diabetes; Disease; Disease risk; Double-Blind Method; Fatty liver; Fatty Liver - chemically induced; Fatty Liver - epidemiology; Fatty Liver - pathology; Female; Follow-Up Studies; Gastroenterology. Liver. Pancreas. Abdomen; General aspects; Health risk assessment; Humans; Incidence; Italy - epidemiology; Liver; Liver - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Metabolic diseases; Middle Aged; Obesity; Other diseases. Semiology; Overweight; Placebos; Predisposing factors; Prospective Studies; Risk Factors; Tamoxifen - adverse effects; Women; Italy; Europe; Human; Antineoplastic agent; Antiestrogen; Hepatic disease; Antihormone; Epidemiology; Tamoxifene; Incidence; Medicine; Prospective; Prevention; Non alcoholic steatohepatitis; Risk factor; Digestive diseases; Clinical trial; Female; Woman; Non steroid compound; Public health
• ISSN: 0959-8138; 0959-8146; 1468-5833; 1756-1833
• DOI: 10.1136/bmj.38391.663287.E0

Abstract Objective To assess the incidence, cofactors, and excess risk of development of non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis, attributable to tamoxifen in women. Design Prospective, randomised, double blind, placebo controlled trial. Setting and participants 5408 healthy women who had had hysterectomies, recruited into the Italian tamoxifen chemoprevention trial from 58 centres in Italy. Intervention Women were randomly assigned to receive tamoxifen (20 mg daily) or placebo for five years. Main outcome measure Development of non-alcoholic fatty liver disease in all women with normal baseline liver function who showed at least two elevations of alanine aminotransferase (≥ 1.5 times upper limit of normal) over a six month period. Results During follow up, 64 women met the predefined criteria: 12 tested positive for hepatitis C virus, and the remaining 52 were suspected of having developed non-alcoholic fatty liver disease (34 tamoxifen, 18 placebo)—hazard ratio = 2.0 (95% confidence interval 1.1 to 3.5; P = 0.04). In all 52 women ultrasonography confirmed the presence of fatty liver. Other factors associated with the development of non-alcoholic fatty liver disease included overweight (2.4, 1.2 to 4.8), obesity (3.6, 1.7 to 7.6), hypercholesterolaemia (3.4, 1.4 to 7.8), and arterial hypertension (2.0, 1.0 to 3.8). Twenty women had liver biopsies: 15 were diagnosed as having mild to moderate steatohepatitis (12 tamoxifen, 3 placebo), and five had fatty liver alone (1 tamoxifen, 4 placebo). No clinical, biochemical, ultrasonic, or histological signs suggestive of progression to cirrhosis were observed after a median follow up of 8.7 years. Conclusions Tamoxifen was associated with higher risk of development of non-alcoholic steatohepatitis only in overweight and obese women with features of metabolic syndrome, but the disease, in both the tamoxifen and the placebo group, after 10 years of follow up seems to be indolent.