Advanced Fibrosis Is Associated With Incident Cardiovascular Disease in Patients With Non-alcoholic Fatty Liver Disease

Jacqueline B. Henson; Tracey G. Simon; Alyson Kaplan; Stephanie Osganian; Ricard Masia; Kathleen E. Corey


Aliment Pharmacol Ther. 2020;51(7):728-736. 

In This Article

Abstract and Introduction


Background: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease. It is not well understood, however, which individuals with NAFLD are at highest risk for cardiovascular disease.

Aims: To determine the factors associated with incident cardiovascular events in a prospective cohort of individuals with biopsy-proven NAFLD without pre-existing cardiovascular disease.

Methods: From 2011 to 2018, adults with biopsy-proven NAFLD without cardiovascular disease were enrolled in a tissue repository and were followed prospectively to the first recorded date of incident cardiovascular disease, death or the end of follow-up (11/1/2018). Competing risks analysis was performed to identify predictors of incident cardiovascular disease.

Results: After a median follow-up time of 5.2 years, 26/285 (9.1%) individuals experienced an incident cardiovascular event. Advanced fibrosis (stage 3–4) on biopsy was a significant predictor of incident cardiovascular disease, and this persisted on multivariable analysis (SHR 2.86, 95% CI 1.36–6.04) after considering relevant covariates, including cardiovascular risk scores, which were not independent predictors. Of the non-invasive indicators of fibrosis, the NAFLD fibrosis score was the only independent predictor of cardiovascular disease. Other histologic features, including steatohepatitis, were not associated with incident cardiovascular disease.

Conclusions: In adults with biopsy-proven NAFLD, advanced fibrosis on biopsy and higher NAFLD fibrosis score were significant and independent predictors of incident cardiovascular disease, even after considering traditional risk factors and cardiovascular risk scores. These findings should be considered when evaluating NAFLD patients for primary prevention of cardiovascular disease, and further evaluation into the link between advanced fibrosis and cardiovascular disease is needed.


Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, affecting an estimated 25% of the population, and its prevalence continues to grow.[1] NAFLD is characterised by the accumulation of fat in the liver in the absence of excessive alcohol intake, and it encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) to liver fibrosis and cirrhosis.

Beyond its hepatic manifestations, NAFLD is closely linked with cardiovascular disease (CVD), which confers significant morbidity and mortality in this population. More individuals with NAFLD die from CVD than from liver-related complications, and NAFLD has been identified as an independent risk factor for CVD.[2–5] It is therefore important to identify and modify the cardiovascular risk in these patients; however, it is not well understood which patients with NAFLD are at highest risk for cardiovascular events or whether cardiovascular risk varies across the spectrum of NAFLD.

Cardiovascular risk stratification has important clinical implications, including the decision to implement primary prevention with statins and other agents. In the general population, risk scores such as the Framingham Risk Score (FRS) or the Atherosclerotic Cardiovascular Disease (ASCVD) Pooled Cohort Equations Risk Score help guide these decisions.[6,7] The FRS for Coronary Heart Disease was validated for use in NAFLD patients in one study, although this study lacked liver histology, thus it remains unknown whether NAFLD-specific features such as the presence of steatohepatitis or fibrosis influence cardiovascular risk.[8]

Existing data regarding the impact of NAFLD severity on cardiovascular risk are both conflicting and limited. A recent meta-analysis found that more severe NAFLD was associated with a higher risk of CVD, but only one of the included studies used histologic data.[5] Few studies examining the link between NAFLD and CVD have been performed in biopsy-characterised cohorts. Some of these have suggested that only histologic evidence of NASH confers increased cardiovascular mortality, while others have not demonstrated this relationship.[9–12] Other studies, like the one in the aforementioned meta-analysis, have identified fibrosis as the best predictor of long-term survival, with increased cardiovascular mortality in patients with advanced fibrosis.[2,3,5] Yet, data on the relationship between fibrosis and CVD have also been inconsistent, and many of these prior studies were limited by either a retrospective design, a small number with advanced fibrosis, or inclusion of individuals with pre-existing CVD.[13,14] Furthermore, nearly all of these studies assessed cardiovascular mortality; few evaluated the development of incident fatal and nonfatal CVD as an outcome.

Therefore, to better understand the determinants of cardiovascular risk in patients with NAFLD, we conducted this study of a prospective, biopsy-characterised cohort of individuals with NAFLD without pre-existing CVD and with long-term clinical follow-up. We aimed to identify predictors of incident CVD and to examine whether histologic or clinical features are NAFLD-specific risk factors for incident cardiovascular events.