Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta‐analysis

Abstract

Background Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage-specific risk of all-cause and liver-related mortality in NAFLD. Methods Through a systematic review and meta-analysis, we identified 5 adult NAFLD cohort studies reporting fibrosis stage specific mortality (0–4). Using fibrosis stage 0 as a reference population, fibrosis stage-specific mortality rate ratios (MRR) with 95% confidence intervals (CI), for all-cause and liver-related mortality, were estimated. The study is reported according to the PRISMA statement. Results 1,495 NAFLD patients with 17,452 patient years of follow-up were included. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all-cause mortality and this risk increased with increase in the stage of fibrosis: stage 1, MRR, 1.58 (95% CI 1.19–2.11); stage 2, MRR, 2.52 (95% CI 1.85–3.42); stage 3, MRR, 3.48 (95% CI 2.51–4.83), and stage 4, MRR, 6.40 (95% CI 4.11–9.95). The results were more pronounced as the risk of liver-related mortality increased exponentially with increase in the stage of fibrosis: stage 1, MRR, 1.41 (95% CI 0.17–11.95); stage 2, MRR, 9.57 (95% CI 1.67–54.93); stage 3, MRR, 16.69 (95% CI 2.92–95.36); and stage 4, MRR, 42.30 (95% CI 3.51–510.34). Limitations Inability to adjust for co-morbid conditions or demographics known to impact fibrosis progression in NAFLD, and the inclusion of patients with simple steatosis and NASH without fibrosis in the reference comparison group. Conclusion The risk of liver-related mortality increases exponentially with increase in fibrosis stage. These data have important implications in assessing utility of each stage and benefits of regression of fibrosis from one stage to another.

Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030

“…NASH frequently progresses to liver fibrosis [7] that is the main risk factor for liver-related mortality [8]. Odds of progression to advanced liver disease, including hepatic decompensation and hepatocellular carcinoma (HCC), are higher among those with NASH compared to those with NAFL [7].…”

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…Liver-related mortality is not substantially affected by steatosis, while 10-25% of steatohepatitis will progress into cirrhosis over 8-14 years with an increased risk of developing portal hypertension (PHT), liver failure, and hepatocellular carcinoma [4]. While substantial evidence indicates that fibrosis is the ultimate predictor of longterm outcomes in patients with NAFLD [4][5][6], risk factors associated with disease progression are not fully identified.…”

The hedgehog pathway in nonalcoholic fatty liver disease

“…(Machado and Cortez-Pinto, 2014). Epidemiological studies of NAFLD have revealed that liver-related morbidity and mortality in individuals with NASH are predicted by the severity of liver fibrosis, rather than by the degree of obesity, insulin-resistance, or hepatic steatosis (Angulo et al, 2015; Ekstedt et al, 2015; Dulai et al, 2017). These findings suggest that dysregulated repair of fatty liver damage (NASH) might distinguish the NAFLD patients who are destined to suffer bad liver outcomes from those whose liver condition will follow a relatively indolent course.…”