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

Abstract

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 biopsies to estimate the rates of fibrosis progression in patients with 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 biopsies 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 (CI), 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, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had 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 over14.3 years for patients with NAFL (95% CI, 9.1–50.0 years) and 7.1 years for patients with NASH (95% CI, 4.8–14.3 years). Conclusions Based a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with NAFL and NASH.

Time to Replace Assessment of Liver Histology With MR-Based Imaging Tests to Assess Efficacy of Interventions for Nonalcoholic Fatty Liver Disease

“…This conclusion has been further corroborated by the results of a recent meta-analysis looking at rates of fibrosis progression in 411 patients with NAFLD who had paired liver biopsies 13 .…”

“…Since the data discussed above [10][11][12][13] indicates that, contrary to popular belief, there is an important risk of progression with NAFL to more serious fibrotic liver disease over time, we suggest it is now an appropriate time to consider changing the focus of the primary endpoint used in therapeutic trials for NAFLD, be it pharmacologic, life-style 14 or surgical 15 . The aim of the primary care physician and the metabolic clinician at least, needs to focus on prevention or reversal of early disease.…”

Reply

“…We used an RIPK3 antibody from ProSci, which was validated using RIPK3-deficient liver tissues, and mouse embryonic fibroblasts. (2,3) Although Dara et al used the same antibody as we did, it is unclear why they failed to detect RIPK3 in the liver. Another finding from the study by Dara et al was that RIPK1 acted upstream of c-Jun N-terminal kinase (JNK).…”

“…(2) This is in line with the systematic review and meta-analysis of paired biopsy studies published by Singh and coworkers, where there was no association between baseline severity of necroinflammation and risk of progressive fibrosis. (3) With all this taken into account, we argue that NAS is not only imperfect as a predictor of mortality but probably also insignificant and that fibrosis stage is the most robust marker for prediction of overall mortality in NAFLD. What we need are larger clinical relevant cohort studies of NAFLD patients with liver histology to finally resolve what histopathological patterns actually predict outcome.…”

Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver

“…In contrast to previous notions that NAFL did not cause serious chronic liver disease, increasing evidence is now showing that NAFL is not harmless. Recently it has been shown that NAFL is an important risk factor for the development of clinically relevant liver fibrosis [8][9][10][11] and consequently it is now being realized that it is important to understand what interventions and treatments are effective for decreasing liver fat [12] within the spectrum of liver disease in NAFLD.…”