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

J Hepatol. 2021 Jul 2;S0168-8278(21)01883-3. doi: 10.1016/j.jhep.2021.06.034. Online ahead of print.

Abstract

Background & aims: Longitudinal data are scarce regarding the natural history and long-term risk of mortality, in children and young adults with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD).

Methods: 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). NAFLD patients 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 NAFLD patients to full-sibling comparators. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95%CIs.

Results: Over a median of 15.8 years, 59 NAFLD patients died (5.5/1000 person-years [PY]), compared to 36 population controls (0.7/1000PY; difference=4.8/1000PY; multivariable aHR=5.88 [95%CI=3.77-9.17]), corresponding to 1 additional death per each 15 patients with NAFLD, followed for 20 years. The 20-year absolute risk of overall mortality was 7.7% among NAFLD patients, and 1.1% among controls (difference=6.6%, 95%CI=4.0-9.2). Findings persisted after excluding subjects 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. 0.07/1000PY; aHR=15.60, 95%CI=4.97-48.93), liver disease (0.93 vs. 0.04/1000PY; aHR=16.46, 95%CI=2.75-98.43) and cardiometabolic disease (1.12 vs. 0.14/1000PY; aHR=4.32, 95%CI=1.73-10.79).

Conclusions: 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.

Lay summary: Currently, the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) is unknown. This nationwide cohort study evaluated the risk of all-cause and cause-specific mortality in pediatric and young adult patients in Sweden with biopsy-confirmed NAFLD, compared 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.

Keywords: adolescent; liver histology; pediatric NAFLD; steatohepatitis; survival.