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

Abstract

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. Through a systematic review and meta-analysis, we identified five 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 (MRRs) with 95% confidence intervals (CIs) for all-cause and liver-related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow-up. 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 increases 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 each 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 of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis 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 the utility of each stage and benefits of regression of fibrosis from one stage to another. (Hepatology 2017;65:1557-1565).

Figure 1. Incidence Rate of All-cause Mortality in NAFLD by Fibrosis Stage (vs. Stage 0 Fibrosis)

No heterogeneity for Fibrosis stages 1–3 vs. 0 (I²=0); for stage 4 vs. stage 0 = 52%; P-value for difference between groups=0.001, i.e. statistically different between groups

Figure 2. Fibrosis Stage Specific All-Cause Mortality Rate and Mortality Rate Ratio

Panel A: Crude All-Cause Mortality Rate by Fibrosis Stage. Panel B: All-Cause Mortality Rate Ratio with 95% Confidence Intervals by Fibrosis Stage. PYF – patient years follow-up.

Figure 3. Incidence Rate of Liver-related Mortality in NAFLD by Fibrosis Stage (vs. Stage 0 Fibrosis)

No heterogeneity for Fibrosis stages 1–4 vs. 0 (I²=0); P-value for difference between groups p=0.02, i.e. statistically different between groups. After including Angulo et al. which included liver-related events, instead of only liver-related mortality, estimates were similar: stage 1, MRR, 1.70 (95% CI 0.56–5.21); stage 2, MRR, 5.75 (95% CI 2.15–15.35); stage 3, MRR, 10.43 (95% CI 4.0–27.19); and stage 4, MRR, 18.12 (95% CI 5.67–57.97).

Figure 4. Fibrosis Stage Specific Liver-Related Mortality Rate and Mortality Rate Ratio

Panel A: Crude Liver-Related Mortality Rate by Fibrosis Stage. Panel B: Liver-Related Mortality Rate Ratio with 95% Confidence Intervals by Fibrosis Stage. PYF – patient years follow-up.