Mortality in Biopsy-Confirmed Nonalcoholic Fatty Liver Disease: Results From A Nationwide Cohort

OBJECTIVE: Population-based data are lacking regarding the risk of overall and cause-specific mortality across the complete histological spectrum of nonalcoholic fatty liver disease (NAFLD). DESIGN: This nationwide, matched cohort study included all individuals in Sweden with biopsy-confirmed NAFLD (1966–2017; n=10,568). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden’s 28 pathology departments, after excluding other etiologies of liver disease, and further categorized as, simple steatosis, non-fibrotic steatohepatitis (NASH), non-cirrhotic fibrosis and cirrhosis. NAFLD cases were matched to ≤5 general population comparators by age, sex, calendar year and county (n=49,925). Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95%CIs. RESULTS: Over a median of 14.2 years, 4,338 NAFLD patients died. Compared to controls, NAFLD patients had significantly increased overall mortality (16.9 vs. 28.6/1000 person-years [PY]; difference=11.7/1000PY; aHR=1.93, 95%CI=1.86–2.00). Compared to controls, significant excess mortality risk was observed with simple steatosis (8.3/1000PY, aHR=1.71, 95%CI=1.64–1.79), non-fibrotic NASH (13.4/1000PY, aHR=2.14, 95%CI=1.93–2.38), non-cirrhotic fibrosis (18.4/1000PY, aHR=2.44, 95%CI=2.22–2.69) and cirrhosis (53.6/1000PY, aHR=3.79, 95%CI=3.34–4.30)(P(trend)<0.01). This dose-dependent gradient was similar when simple steatosis was the reference (P(trend)<0.01). The excess mortality associated with NAFLD was primarily from extra-hepatic cancer (4.5/1000PY; aHR=2.16, 95%CI=2.03–2.30), followed by cirrhosis (2.7/1000PY; aHR=18.15, 95%CI=14.78–22.30), cardiovascular disease (1.4/1000PY; aHR=1.35, 95%CI=1.26–1.44) and hepatocellular carcinoma (HCC)(1.2/1000PY; aHR=11.12, 95%CI=8.65–14.30). CONCLUSIONS: All NAFLD histological stages were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLD histology. Most of this excess mortality was from extra-hepatic cancer and cirrhosis, while in contrast, the contributions of cardiovascular disease and HCC were modest.