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


METHODS
Prospective, randomised, double blind, placebo controlled trial.


METHODS
5408 healthy women who had had hysterectomies, recruited into the Italian tamoxifen chemoprevention trial from 58 centres in Italy.


METHODS
Women were randomly assigned to receive tamoxifen (20 mg daily) or placebo for five years.


METHODS
Development of non-alcoholic fatty liver disease in all women with normal baseline liver function who showed at least two elevations of alanine aminotransferase (> or = 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.
Bruno
Savino
S
Liver Unit, Azienda Ospedaliera Fatebenefratelli e Oftalmico, Corso di Porta Nuova 23, 20121 Milan, Italy. savino.bruno@fbf.milano.it
Maisonneuve
Patrick
P
Castellana
Paola
P
Rotmensz
Nicole
N
Rossi
Sonia
S
Maggioni
Marco
M
Persico
Marcello
M
Colombo
Alberto
A
Monasterolo
Franco
F
Casadei-Giunchi
Donata
D
Desiderio
Franco
F
Stroffolini
Tommaso
T
Sacchini
Virgilio
V
Decensi
Andrea
A
Veronesi
Umberto
U
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D001706:Biopsy / Q000379:methods; D001943:Breast Neoplasms / Q000517:prevention & control*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004311:Double-Blind Method; D005234:Fatty Liver / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007558:Italy / Q000453:epidemiology; D008099:Liver / Q000473:pathology; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D013629:Tamoxifen / Q000009:adverse effects*
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen
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