Objective Population-based data are lacking regarding the risk of overall and cause-specific mortality across the complete histological spectrum of non-alcoholic fatty liver disease (NAFLD).
Design This nationwide, matched cohort study included all individuals in Sweden with biopsy-confirmed NAFLD (1966 to 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 categorised 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 HRs (aHRs) and 95% CIs.
Results Over a median of 14.2 years, 4,338 NAFLD patients died. Compared with controls, NAFLD patients had significantly increased overall mortality (16.9 vs 28.6/1000 PY; difference=11.7/1000 PY; aHR=1.93, 95% CI=1.86 to 2.00). Compared with controls, significant excess mortality risk was observed with simple steatosis (8.3/1000 PY, aHR=1.71, 95% CI=1.64 to 1.79), non-fibrotic NASH (13.4/1000 PY, aHR=2.14, 95% CI=1.93 to 2.38), non-cirrhotic fibrosis (18.4/1000 PY, aHR=2.44, 95% CI=2.22 to 2.69) and cirrhosis (53.6/1000 PY, aHR=3.79, 95% CI=3.34 to 4.30)(ptrend <0.01). This dose-dependent gradient was similar when simple steatosis was the reference (ptrend <0.01). The excess mortality associated with NAFLD was primarily from extrahepatic cancer (4.5/1000 PY, aHR=2.16, 95% CI=2.03 to 2.30), followed by cirrhosis (2.7/1000 PY, aHR=18.15, 95% CI=14.78 to 22.30), cardiovascular disease (1.4/1000 PY, aHR=1.35, 95% CI=1.26 to 1.44) and hepatocellular carcinoma (HCC) (1.2/1000 PY, aHR=11.12, 95% CI=8.65 to 14.30).
Conclusion 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 extrahepatic cancer and cirrhosis, while in contrast, the contributions of cardiovascular disease and HCC were modest.
- fatty liver
- hepatocellular carcinoma
- liver cirrhosis
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Correction notice This article has been corrected since it published Online First. Figure 1 has been amended.
Contributors Guarantor: The corresponding author (JFL) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All co-authors. Acquisition of data: JFL. Analysis: BR. Interpretation of data: All co-authors. Writing first draft of the manuscript: TS and JFL. Critical revision of the manuscript for important intellectual content and approval of final version: All co-authors.
Funding TS was supported by NIH K23 DK122104. TS was supported by the Harvard University Center for AIDS Research (CFAR). HH was supported by grants from Region Stockholm (postdoctoral appointment). HK was supported by the Crohns and Colitis Foundation Senior Research Award. JFL was funded by the Karolinska Institutet (institutional award).
Competing interests JFL coordinates a study on behalf of the Swedish Inflammatory Bowel Disease quality register (SWIBREG), that has received funding from Janssen Corporation. HH reports research grants to his institution from AstraZeneca, Intercept and Gilead, and board advisory for Bristol Myers Squibb and Gilead. TS has served as a consultant to Aetion for work unrelated to this manuscript.
Patient consent for publication Not required.
Ethics approval This study was approved by the Regional Ethics Committee, Stockholm, Sweden (Protocol number: 2014/1287-31/4).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No additional data are available due to Swedish regulations.
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