Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort

Abstract

ObjectivePopulation-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).DesignThis 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.ResultsOver 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).ConclusionAll 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.

Natural History of NAFLD

“…This risk increased in a dose-dependent manner with the spectrum of the histological severity in NAFLD: 10.7% higher in patients with simple steatosis, 18.5% higher in patients with NASH without fibrosis, 25% higher in patients with NASH and advanced fibrosis without cirrhosis and 49% higher in patients with NASH cirrhosis. In particular, when compared with patients with simple steatosis, patients with non-fibrotic NASH had an excess mortality rate of 5.1 per 1000 person-year, which means that, over 20 years of follow-up, 1 out of 10 persons with NASH without significant fibrosis will die [ 127 ]. The excess mortality risk in NAFLD is mainly related to extra-hepatic cancers and cirrhosis [ 54 , 118 , 128 ] as already emphasized in this review.…”

Prevalence and Risk Factors of Metabolic Associated Fatty Liver Disease in China: A Cross-Sectional Study

“…In males, the prevalence rises steeply between the age of 18-39, then rose slowly after 40 years and reached peak at the age of 50-54, revealing that MAFLD is more prevalent in men in their middle ages and they were at an increasing risk of having MALFD while in a younger age which need to be paid special attention. We observed that older men had a lower prevalence of MAFLD than middle-aged men, the possible reasons might be as follows: Some people died of other disease in their older age as fatty liver can signi cantly increase overall mortality [15], hence these people cannot be counted in; Compared with old men who usually retire, middle-aged men who are at peak of their careers have much more social engagement like dinner and party to take part in, which might increase their risk of having metabolic disorders. Whereas in females, the prevalence of MAFLD is relatively low before the age of 50, however, it rose sharply between the age of 50-69 and reached peak at the age of 65-69.…”

Individualized Polygenic Risk Score Identifies NASH in the Eastern Asia Region: A Derivation and Validation Study

“…Because NAFLD affects up to a quarter of the general population worldwide ( 1 ), millions of patients worldwide, who are at risk of NAFLD progression, would benefit from treatment that is focused on effecting regression of NASH. Recently, a nationwide matched cohort study in Sweden showed that all histological stages of NAFLD were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLD histology ( 36 )—compared with matched controls, significant excess mortality risk was observed with simple steatosis (8.3/1,000 person-year [PY]) and NASH (13.4/1,000 PY); compared with those with simple steatosis, the multivariable-adjusted hazard ratio for overall mortality was increased in patients with NASH (hazard ratio 1.14; 95% CI 1.03–1.26) ( 36 ). Moreover, compared with matched controls, the mortality rate from cardiovascular causes was increased in those with NASH (absolute rate difference 2.7/1,000 PY), and compared with those with simple steatosis, the 20-year absolute excess risk of cardiovascular mortality was higher in patients with NASH (4.4%, P < 0.05) ( 36 ).…”