Rethinking metabolic risk in primary biliary cholangitis: The prognostic impact of lean type 2 diabetes mellitus

Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by progressive immune-mediated destruction of the intrahepatic bile ducts and lymphocytic cholangitis. It can progress to cirrhosis and hepatic failure and increase mortality risk. Emerging evidence highlights the role of metabolic abnormalities in the progression of chronic liver diseases, with glucose metabolism disorders and insulin resistance contributing to hepatic inflammation and fibrosis. Notably, lean type 2 diabetes mellitus (T2DM) represents a distinct phenotype characterized by β-cell dysfunction and increased cardiometabolic risk despite a normal body mass index (BMI). We read with great interest the study by Yin et al, which demonstrated that lean T2DM is an independent predictor of mortality in patients with PBC, with a synergistic adverse effect observed in patients with both low BMI and diabetes. These findings challenge the assumption that a normal BMI confers metabolic protection. Mechanistically, metabolic dysfunction may promote disease progression through insulin resistance, inflammation, and oxidative stress, independent of body weight. However, reverse causality related to sarcopenia and advanced disease should be considered. This opinion review examines the role of lean T2DM as a prognostic modifier in PBC and highlights the need to incorporate metabolic assessment into current risk stratification strategies.

Keywords: Type 2 diabetes mellitus; Primary biliary cholangitis; Body mass index; Mortality; Metabolic dysfunction

Core Tip: Primary biliary cholangitis presents marked clinical heterogeneity that is not fully explained by the current prognostic models. These models are primarily based on the biochemical response to ursodeoxycholic acid and the fibrosis stage. Emerging evidence suggests that metabolic dysfunction, particularly type 2 diabetes mellitus in lean individuals, is an underrecognized modifier of disease progression and mortality. Recent findings indicate synergistic adverse effects between the thin phenotype and diabetes, which challenges traditional body mass index-based assumptions regarding metabolic risk in patients with primary biliary cholangitis. Thus, beyond weight, comprehensive metabolic assessment should be incorporated into risk stratification strategies. In addition, future prospective studies should evaluate whether integrating lean type 2 diabetes mellitus into existing prognostic models can improve individualized patient management.