Even mild fatty liver disease is linked to increased mortality

Non-alcoholic fatty liver disease, NAFLD, affects nearly one in four adults in Europe and the U.S. Earlier research has demonstrated an increased risk of death in patients with NAFLD and advanced fibrosis or cirrhosis. Now, researchers at Karolinska Institutet in Sweden and Massachusetts General Hospital in the U.S. show that mortality increases with disease severity, but even mild fatty liver disease is linked to higher mortality. The findings have been published in the scientific journal Gut.

Non-alcoholic fatty liver disease is often caused by obesity and affects nearly 25 percent of U.S. and European adults. It represents the most common cause of chronic liver disease in Western countries. Small clinical studies have demonstrated that among patients with NAFLD, advanced liver fibrosis is the most important histological predictor of mortality, but until now, population-level data have been missing from cohorts with liver histology.

All stages of fatty liver disease

A graph that shows the differences in mortality at different stages of fatty liver disease

The graph shows the differences in mortality at different stages of fatty liver disease and illustrates how the risk increases with disease severity. Credit: Gut, Simon et al, October 2020.

Given the growing burden of NAFLD, researchers at Karolinska Institutet and Massachusetts General Hospital matched 10,568 individuals with biopsy-confirmed NAFLD to general population controls through Sweden’s comprehensive, nationwide registers. They found that all stages of NAFLD were associated with excess mortality risk, even early stages of disease. This risk was driven primarily by deaths from extra-hepatic cancer and cirrhosis, while the risks of cardiovascular mortality or hepatocellular carcinoma (HCC) mortality were relatively modest.

Patients with NAFLD had a 93 percent increased risk of all-cause mortality, but the numbers varied with disease severity. The risk increased progressively from the mildest form of NAFLD (simple steatosis), to non-fibrotic steatohepatitis (NASH), to non-cirrhotic fibrosis and to severe NAFLD with liver cirrhosis.

Nationwide cohort study

Tracey Simon from Department of Epidemiology, Harvard T.H. Chan School of Public Health

Tracey G. Simon. Photo: Massachusetts General Hospital

“This is the first nationwide cohort study with detailed liver histology data to confirm that NAFLD contributes to an increased risk of all-cause mortality,” says first author, Tracey G. Simon, researcher and hepatologist at Massachusetts General Hospital. “These findings should be used to develop more targeted interventions designed to reduce mortality, in patients with NAFLD. We need public health strategies that prevent both extra-hepatic cancer and NAFLD progression to cirrhosis, for this rapidly growing population.”

The study builds on the ESPRESSO cohort (Epidemiology Strengthened by Histopathology Reports in Sweden). Histopathology data from more than two million people have been linked to nationwide Swedish registers such as the Patient Register, the Cause of Death Register, the Prescribed Drug Register and the Cancer Register.

Portrait photo of Professor Jonas Ludvigsson in front of Aula Medica at Karolinska Institutet

Jonas Ludvigsson. Photo: Alexander Donka

“Through contacting all pathology departments in Sweden, we have managed to construct a nationwide gastrointestinal histopathology cohort that allows us to examine a range of gastrointestinal diseases, including NAFLD,” says last author Jonas F. Ludvigsson, pediatrician at Örebro University Hospital and professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. “The current study on NAFLD and risk of death is the 17th study published this year that takes advantage of the ESPRESSO cohort.”

The research was supported by grants from NIH, Harvard University, Region Stockholm, Crohn’s and Colitis Foundation and Karolinska Institutet. Ludvigsson coordinates a study on behalf of the Swedish IBD quality register (SWIBREG). That study has received funding from the Janssen corporation. Simon has previously served as a consultant to Aetion, for work unrelated to this study.


“Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort.” Tracey G Simon, Bjorn Roelstraete, Hamed Khalili, Hannes Hagström, Jonas F Ludvigsson. Gut, online 9 October 2020, doi: 10.1136/gutjnl-2020-322786.

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