Should the Cardiologist Bother About Fatty Liver?

The nonalcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is defined as the presence of more than 5% of fat in hepatocytes and is nothing but a hepatic manifestation of a multi-system metabolic disorder, in the absence of causes like alcohol consumption, medications, diseases, or hereditary causes. For precise diagnosis, staging, and grading of MASLD, liver biopsy is the gold standard. However, non-invasive evaluation is done based on various tests and indices that include FIB-4, NAFLD fibrosis score, enhanced liver fibrosis (ELF), vibration-controlled transient elastography (VCTE/FibroScan), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) proton density fat fraction. Metabolic dysfunction-associated steatohepatitis, previously called nonalcoholic steatohepatitis (NASH), is an advanced stage of MASLD. ¹

Metabolic dysfunction-associated steatotic liver disease has rapidly grown over the last few years to become the most prevalent chronic liver disease globally. Among the Indian population, the prevalence is reported in 9%-32%; it is more often associated with type 2 diabetics, obesity, and metabolic syndrome. Post-menopausal women may be particularly vulnerable. In an interesting study of 345 information technology (IT) professionals at Hyderabad, MASLD was detected by vibration-controlled transient electrography FibroScan in 84%. The mean age was 38 years, with an average body mass index (BMI) of 24.4. All had a sedentary lifestyle with long hours of sitting at work, sleep deprivation, stress, and unregulated diet habits. The authors called for an urgent need for lifestyle modification and appropriate workplace management to prevent MASLD. ²

The basic understanding of the MASLD-cardiovascular disease (CVD) interface is gradually evolving. The link between MASLD and CVDs lies in the presence of several molecular and inflammatory markers in both conditions. Adipocytokines (leptin and adiponectin), C-reactive protein, tumor necrosis factor (TNF)-alpha, hepatokines such as fetuin and fibroblast growth factor-21, have been shown to influence endothelial function, hepatic steatosis, and vascular inflammation. Metabolic dysfunction-associated steatotic liver disease is proven to make dyslipidemia more atherogenic, increase inflammation and oxidative stress, disrupt endothelial function, increase visceral adiposity and insulin resistance, increase thrombogenicity, and cause gut dysbiosis; thus, enhancing cardiovascular events like myocardial infarction, ischemic stroke, heart failure, arrhythmias, and cardiovascular mortality. In such a dysregulated metabolic milieu, both hepatic fibrosis and vascular injury can develop over the years. This interplay could be influenced by genetic polymorphisms such as PNPLA3 and TM6SF2.^3–5

The cardiovascular implications of this new cardiometabolic epidemic are not yet fully appreciated, despite several studies pouring in. There is a fundamental need to understand that MASLD is a systemic metabolic risk factor rather than an isolated chronic hepatic disease. Many studies have provided robust evidence of an increased cardiovascular risk. In a large cohort from a national analysis of 7 million adults, it was calculated that the hazard ratio for CVD events was 1.39, independent of the influence of age, sex, diabetes, hypertension, and obesity.^{6, 7} A meta-analysis of 129 studies yielded a hazard ratio of 1.43 for cardiovascular events in MASLD patients. ⁸ The CV manifestations can occur even before the hepatic events manifest. Similarly, sub-clinical manifestations of atherosclerosis, like increased coronary artery calcium (CAC) and carotid intima–media thickness (CIMT), are more frequent in MASLD. In the study by Bhardwaj and Sharma, published in this issue, the authors assessed the occurrence of coronary artery disease (CAD) among 321 patients with NAFLD and the incidence of NAFLD among 405 patients with angiographically proven CAD. ⁹ Angiographic CAD was strongly associated with NAFLD in a grade-dependent manner in their observation. It is a commendable study that attempted to fill in the gaps in the knowledge.

There are gaps in understanding the true value of non-invasive diagnostic methods like elastography, MRE, and MRI-derived proton density fat fraction in the diagnosis and staging of MASLD and in estimating the cardiovascular risk. Therapeutic options are few and limited to molecules like ursodeoxycholic acid, high-dose vitamin E, resmetirom, saroglitazar, pioglitazone, SGLT2 inhibitors, and GLP1 agonists. A few weeks back, semaglutide received accelerated Food and Drug Administration (FDA) approval for treating metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced fibrosis based on the results of the ESSENCE trial. ¹⁰ It is also important to highlight that MASLD is not a contraindication for the use of statins when indicated by the conventional cardiovascular risk assessment. Full metabolic evaluation and CV risk reduction are the prudent strategies for the management of fatty liver in light of the current knowledge.