1 Institute of Health and Well Being, University of Glasgow, United Kingdom. Electronic address: email@example.com.
2 R2 Consultancy, Glasgow, United Kingdom.
3 Institute of Applied Health Research, University of Birmingham, United Kingdom.
4 Unit of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.
5 Department of Gastroenterology and Hepatology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
6 University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany.
7 Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
8 Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.
9 Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
10 Department of Gastroenterology and Hepatology, Rabin Medical Center, Beilinson hospital, Petach-Tikva; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
11 Department of Medicine D, Rabin Medical Center, Beilinson hospital, Petach-Tikva; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
12 Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
13 Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
14 Institute of Applied Health Research, University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, United Kingdom.
15 Department of Medicine, Inova Fairfax Hospital, Falls Church, Virginia, United States.
16 Institute of Clinical & Translational Research, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre & Liver Transplant Unit, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom.
17 Liver Transplant Unit, The Newcastle upon Tyne Hospitals NHS Foundation Trust; Institute of Clinical and Translational Research, Newcastle University, & Newcastle NIHR Biomedical Research Centre, Newcastle-upon-Tyne, United Kingdom.
18 National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, UK. Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK. Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
BACKGROUND & AIMS: Biopsy-confirmed liver fibrosis is a prognostic factor for patients with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review to quantify the prognostic value of fibrosis stage in patients with NAFLD and the subgroup of patients with non-alcoholic steatohepatitis (NASH) and to assess the evidence that change in fibrosis stage is a surrogate endpoint.
METHODS: We searched the MEDLINE, EMBASE, Cochrane Library, and trial registry databases through August 2018 for prospective or retrospective cohort studies of liver-related clinical events and outcomes in adults with NAFLD or NASH. We collected data on mortality (all-cause and liver-related) and morbidity (cirrhosis, liver cancer, and all liver-related events) by stage of fibrosis, determined by biopsy, for patients with NAFLD or NASH. Using fibrosis stage 0 as a reference population, we calculated fibrosis stage-specific relative risk (RR) and 95% CI values for mortality and morbidities. We performed fixed-effect and random-effect model meta-analyses. Meta-regression was used to examine associations among study design (prospective vs retrospective cohort), overall risk of bias (medium or high), and mean duration of follow up (in years).
RESULTS: Our meta-analysis included 13 studies, comprising 4428 patients with NAFLD; 2875 of these were reported to have NASH. Compared to no fibrosis (stage 0), unadjusted risk increased with increasing stage of fibrosis (stage 0 vs 4): all-cause mortality RR, 3.42 (95% CI, 2.63-4.46); liver-related mortality RR, 11.13 (95% CI, 4.15-29.84); livertransplantation RR, 5.42 (95% CI, 1.05-27.89), and liver-related events RR, 12.78 (95% CI, 6.85-23.85). The magnitude of RR did not differ significantly following adjustment for confounders including age or sex in the subgroup of NAFLD patients with NASH. Three studies examined the effects of increasing fibrosis on quality of life had inconsistent findings.
CONCLUSIONS: In a systematic review and meta-analysis, we found biopsy-confirmed fibrosis to be associated with risk of mortality and liver-related morbidity in patients with NAFLD, with and without adjustment for confounding factors and in patients with reported NASH. Further studies are needed to assess the association between fibrosis stage and patient quality of life and establish that change in liver fibrosis stage is a valid endpoint for use in clinical trials.