Non-alcoholic fatty liver disease in children and young adults is associated with increased long-term mortality

Abstract

Longitudinal data are scarce regarding the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD). This nationwide, matched cohort study included all Swedish children and young adults (≤25 years) with biopsy-confirmed NAFLD (1966-2017; n= 718). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden's 28 pathology departments, and further categorized as simple steatosis or steatohepatitis (NASH). Patients with NAFLD were matched to ≤5 general population controls by age, sex, calendar year and county (n= 3,457). To account for shared genetic and early-life factors, we also matched patients with NAFLD to full-sibling comparators. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% CIs. Over a median of 15.8 years, 59 patients with NAFLD died (5.5/1,000 person-years [PY]) compared to 36 population controls (0.7/1,000 PY; difference= 4.8/1,000 PY; multivariable aHR 5.88; 95% CI 3.77-9.17), corresponding to 1 additional death per 15 patients with NAFLD, followed for 20 years. The 20-year absolute risk of overall mortality was 7.7% among patients with NAFLD, and 1.1% among controls (difference= 6.6%; 95% CI 4.0-9.2). Findings persisted after excluding those who died within the first 6 months (aHR 4.65; 95% CI 2.92-7.42), and after using full-sibling comparators (aHR 11.72; 95% CI 3.18-43.23). Simple steatosis was associated with a 5.26-fold higher adjusted rate of mortality compared to controls (95% CI 3.05-9.07), and this was amplified with NASH (aHR 11.51, 95% CI 4.77-27.79). Most of the excess mortality was from cancer (1.67 vs. 0.07/1,000PY; aHR 15.60; 95% CI 4.97-48.93), liver disease (0.93 vs. 0.04/1,000PY; aHR 16.46; 95% CI 2.75-98.43) and cardiometabolic disease (1.12 vs. 0.14/1,000PY; aHR 4.32, 95% CI 1.73-10.79). Swedish children and young adults with biopsy-confirmed NAFLD have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality compared to matched general population controls. Currently, the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD) is unknown. This nationwide cohort study compared the risk of all-cause and cause-specific mortality in pediatric and young adult patients in Sweden with biopsy-confirmed NAFLD to matched general population controls. We found that compared to controls, children and young adults with biopsy-confirmed NAFLD and NASH have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality.