Liver fibrosis as an independent cardiovascular risk factor in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) stands as a prominent liver disorder globally, with its incidence surging from 25.26% in 1990–2006 to 38.00% in 2016–2019. NAFLD characterizes the accumulation of fat in hepatocytes of ≥5% in patients without alcohol abuse, presenting as simple steatosis without liver fibrosis (LF) or progressing to nonalcoholic steatohepatitis (NASH), characterized by inflammation, hepatocyte ballooning, and various stages of LF.

NAFLD's link to cardiovascular diseases (CVDs) is well-established, with increased frequencies of coronary artery disease, hypertension, atherosclerosis, myocardial infarction, ischemic stroke, atrial fibrillation, and heart failure observed. As NAFLD progresses, particularly with advanced LF, the risk of CVDs escalates making CVDs the primary cause of death in NAFLD patients. Furthermore, conventional cardiovascular risk assessment tools, such as the Framingham risk score, may underestimate the risk associated with NAFLD.

Given this context, this review aims to summarize the current evidence underscoring the significance of LF as an independent cardiovascular risk factor in NAFLD. By delving into the pathophysiological mechanisms, noninvasive LF assessment methods, and the clinical impact of LF on CVDs in NAFLD, we hope to highlight the urgent need for early LF diagnosis and stratified management.

Pathophysiological Mechanisms of Cardiovascular Disorders in NAFLD

The predisposition to CVDs in NAFLD stems from a complex interplay of factors. These include atherogenic dyslipidemia, impaired glucose metabolism and liver insulin resistance, low-grade systemic inflammation, endothelial dysfunction, and gut dysbiosis, all modulated by genetic and epigenetic factors. In advanced LF/cirrhosis, portal hypertension-induced hyperdynamic circulatory changes contribute to cardiovascular remodeling, a key predictor of unfavorable outcomes. Additionally, systemic inflammation in NAFLD amplifies CVD risk through interactions with various organs and systems.

Noninvasive Tests of Liver Fibrosis to Assess Cardiovascular Risk in NAFLD

Owing to the limitations of liver biopsy, noninvasive tests have emerged as vital tools for assessing LF and its impact on CVD risk in NAFLD. Key methods include the Fibrosis-4 (FIB-4) score, NAFLD fibrosis score (NFS), BARD score, AST to Platelet Ratio Index (APRI), Forns index, and transient elastography. Each method employs different parameters and has varying accuracy for mild to moderate LF assessment. For instance, a FIB-4 score ≥2.67 or NFS >0.675 indicate a high risk of significant LF. Although noninvasive tests offer practical advantages, their limitations, such as inadequate differentiation between LF stages and subclinical features, warrant continued research.

Impact of Liver Fibrosis on Cardiovascular Risk in NAFLD

Numerous studies confirm that advanced LF independently increases the risk of CVDs in NAFLD, beyond established metabolic risk factors. Patients with NASH or advanced LF demonstrate higher atherosclerotic CVD risk than those without LF. Studies have demonstrated that noninvasive LF markers predict major adverse cardiovascular events, regardless of metabolic syndrome. In the Framingham Heart Study, LF severity correlated strongly with obesity-related comorbidities, such as hypertension, low HDL cholesterol, and type 2 diabetes mellitus (T2DM), reinforcing the link between LF and cardiometabolic disorders.

Impact of Liver Fibrosis on the Cardiovascular Outcome in NAFLD

CVDs account for at least 40% of deaths in NAFLD patients, 53 with advanced LF contributing significantly to this burden. In a meta-analysis, the pooled CVD-related mortality rate in NAFLD patients was 4.2 per 1,000 person-years.1 Hence, NAFLD patients with NASH and progressive LF represent a high-risk group for CVDs. Early diagnosis of LF and targeted interventions could help mitigate this risk.

Conclusions

In conclusion, liver fibrosis emerges as a formidable independent cardiovascular risk factor in NAFLD. The understanding of its pathophysiological underpinnings, combined with the development of noninvasive diagnostic tools, provides critical insights into stratifying NAFLD patients and guiding tailored management strategies. Given the significant contribution of CVDs to NAFLD-related mortality, prioritizing LF detection and timely intervention becomes imperative to improve patient outcomes.

Full text

https://www.xiahepublishing.com/2994-8754/JTG-2023-00071

The study was recently published in the Journal of Translational Gastroenterology.

Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.

Follow us on X: @xiahepublishing

Follow us on LinkedIn: Xia & He Publishing Inc.