Genetic predeterminants and recent advancements in steatotic liver disease: A roadmap toward precision hepatology

Steatotic liver disease (SLD) encompasses a group of disorders characterized by the excessive accumulation of fat in the liver. It is classified into four categories based on clinical manifestations: Metabolic dysfunction-associated SLD (MASLD), metabolic-alcohol-associated liver disease (ALD), ALD, and cryptogenic SLD. In the United States, its prevalence stands at 34.2%, making it the most common cause of cirrhosis and hepatocellular carcinoma (HCC). In addition to factors related to endocrine, nutrition, and medications, several genetic markers have been implicated in the disease's pathogenesis. Notable genes include PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13. These genetic polymorphisms can significantly impact prognosis and disease outcomes. For example, PNPLA3 is the most frequently associated gene with MASLD, increasing the risk of HCC by 12-fold and liver-related mortality by 18-fold. Furthermore, certain genetic markers are more prevalent in specific ethnic groups; for instance, PNPLA3 is common among Hispanics, while TM6SF2 is linked to higher fat content in African Americans. With a better understanding of the genetic factors involved in the pathogenesis of SLD, significant advancements have been made in diagnostics and therapeutics. This review explores the role of genetic factors in the disease's development, discusses current advancements in non-invasive diagnostic modalities, and examines therapeutic improvements based on these genetic insights to achieve better outcomes.