Original article
Systematic reviews and meta-analyses
Fibrosis Progression in Nonalcoholic Fatty Liver vs Nonalcoholic Steatohepatitis: A Systematic Review and Meta-analysis of Paired-Biopsy Studies

https://doi.org/10.1016/j.cgh.2014.04.014Get rights and content

Background & Aims

Little is known about differences in rates of fibrosis progression between patients with nonalcoholic fatty liver (NAFL) vs nonalcoholic steatohepatitis (NASH). We conducted a systematic review and meta-analysis of all studies that assessed paired liver biopsy specimens to estimate the rates of fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD) including NAFL and NASH.

Methods

Through a systematic search of multiple databases and author contact, up to June 2013, we identified studies of adults with NAFLD that collected paired liver biopsy specimens at least 1 year apart. From these, we calculated a pooled-weighted annual fibrosis progression rate (number of stages changed between the 2 biopsy samples) with 95% confidence intervals (CIs), and identified clinical risk factors associated with progression.

Results

We identified 11 cohort studies including 411 patients with biopsy-proven NAFLD (150 with NAFL and 261 with NASH). At baseline, the distribution of fibrosis for stages 0, 1, 2, 3, and 4 was 35.8%, 32.5%, 16.7%, 9.3%, and 5.7%, respectively. Over 2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had an improvement in fibrosis stage. The annual fibrosis progression rate in patients with NAFL who had stage 0 fibrosis at baseline was 0.07 stages (95% CI, 0.02–0.11 stages), compared with 0.14 stages in patients with NASH (95% CI, 0.07–0.21 stages). These findings correspond to 1 stage of progression over 14.3 years for patients with NAFL (95% CI, 9.1–50.0 y) and 7.1 years for patients with NASH (95% CI, 4.8–14.3 y).

Conclusions

Based on a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with NAFL and NASH.

Section snippets

Methods

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the process followed an a priori established protocol.14

Results

From a total of 1994 unique studies identified using the prespecified systematic search strategy, 11 observational studies were included in this analysis.7, 8, 12, 13, 22, 23, 24, 25, 26, 27, 28 Six studies were excluded owing to a lack of sufficient information to calculate the FPR despite the availability of paired liver biopsies. We were able to obtain additional information (which was not available in the published article) that was required to calculate the FPR by the presence of baseline

Discussion

Based on evidence derived from this systematic review and meta-analysis of paired liver biopsy studies, we show that both patients with NAFL and NASH may develop progressive liver fibrosis. The annual FPR in patients with NAFL vs NASH, with baseline stage 0 fibrosis, was 0.07 stages vs 0.14 stages, respectively, corresponding to an average progression of 1 stage over 14.3 vs 7.1 years, respectively. Among patients who developed progressive liver fibrosis on follow-up liver biopsy, we identified

Acknowledgments

The authors sincerely thank the following investigators for kindly sharing additional data from their cohort, which enabled this meta-analysis to be performed: Manel Abdelmalek, MD, MPH (Division of Gastroenterology/Hepatology, Duke University Medical Center, Durham, North Carolina); Henry Chan, MD (Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China); Stergio Kechagias, MD, PhD (Division of Gastroenterology and Hepatology, Linköping University,

References (50)

  • P.J. Easterbrook et al.

    Publication bias in clinical research

    Lancet

    (1991)
  • V. Ratziu et al.

    Liver fibrosis in overweight patients

    Gastroenterology

    (2000)
  • G.P. Aithal et al.

    Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis

    Gastroenterology

    (2008)
  • L.B. Van Wagner et al.

    Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial

    Ann Hepatol

    (2011)
  • E.M. Brunt et al.

    Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions

    Am J Gastroenterol

    (1999)
  • N. Rafiq et al.

    Long-term follow-up of patients with nonalcoholic fatty liver

    Clin Gastroenterol Hepatol

    (2009)
  • H. Huang et al.

    Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C

    Gastroenterology

    (2006)
  • T. Poynard et al.

    Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C

    J Hepatol

    (2001)
  • S.A. Harrison et al.

    The natural history of nonalcoholic fatty liver disease: a clinical histopathological study

    Am J Gastroenterol

    (2003)
  • Q.M. Anstee et al.

    Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis

    Nat Rev Gastroenterol Hepatol

    (2013)
  • N. Chalasani et al.

    The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

    Hepatology

    (2012)
  • L.A. Adams et al.

    Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study

    Am J Gastroenterol

    (2010)
  • C. Soderberg et al.

    Decreased survival of subjects with elevated liver function tests during a 28-year follow-up

    Hepatology

    (2010)
  • R. Loomba et al.

    The global NAFLD epidemic

    Nat Rev Gastroenterol Hepatol

    (2013)
  • M. Ekstedt et al.

    Long-term follow-up of patients with NAFLD and elevated liver enzymes

    Hepatology

    (2006)
  • Cited by (1021)

    • Implementation of a liver health check in people with type 2 diabetes

      2024, The Lancet Gastroenterology and Hepatology
    • The Origin and Fate of Liver Myofibroblasts

      2024, Cellular and Molecular Gastroenterology and Hepatology
    View all citing articles on Scopus

    This article has an accompanying continuing medical education activity on page e40. Learning Objective–Upon completion of this activity, successful learners will be able to estimate rate of progression of fibrosis in patients with non-alcoholic fatty liver disease.

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported in part by the American Gastroenterological Association Foundation–Sucampo–Association of Specialty Professors Designated Research Award in Geriatric Gastroenterology, a T. Franklin Williams Scholarship Award, Atlantic Philanthropies, Inc, the John A. Hartford Foundation, the Association of Specialty Professors, and National Institute of Health grants P30CA23100-28 and K23DK090303 (R.L.).

    View full text