Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
OBJECTIVE
Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD.


METHODS
We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination.


RESULTS
Over a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05-1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis.


CONCLUSIONS
In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.
Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, Kentucky.
Paul
P
Angulo
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland. Electronic address: kleinerd@mail.nih.gov.
David E
DE
Kleiner
Department of Medicine, Koege University Hospital, Koege, Denmark.
Sanne
S
Dam-Larsen
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
Leon A
LA
Adams
Faculty of Medicine, University of Iceland, Section of Gastroenterology and Hepatology, National University Hospital, Reykjavik, Iceland.
Einar S
ES
Bjornsson
Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Phunchai
P
Charatcharoenwitthaya
Gartnavel General Hospital, Glasgow, United Kingdom.
Peter R
PR
Mills
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
Jill C
JC
Keach
Gartnavel General Hospital, Glasgow, United Kingdom.
Heather D
HD
Lafferty
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
Alisha
A
Stahler
Department of Pediatrics, Rikshospitalet, Oslo University Hospital, Oslo, Norway.
Svanhildur
S
Haflidadottir
Department of Gastroenterology, Hvidovre Hospital and Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
Flemming
F
Bendtsen
D000328:Adult; D000367:Age Factors; D001706:Biopsy; D003920:Diabetes Mellitus / Q000453:epidemiology; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000453:epidemiology* / Q000473:pathology*; D016031:Liver Transplantation / Q000401:mortality*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D012907:Smoking / Q000453:epidemiology; D013785:Thailand; D013997:Time Factors; D014481:United States
NASH; PRELHIN Study; Prediction; Prognosis