Beyond bones: Revisiting the role of vitamin D in chronic liver disease

Abstract

Beyond its traditional role in calcium and bone metabolism, vitamin D has emerged as a critical regulator of liver health. Its active form, calcitriol [1α,25(OH)₂D], signals through the vitamin D receptor (VDR), which is expressed in hepatic stellate cells, Kupffer cells, and cholangiocytes. Through this pathway, vitamin D modulates fibrosis, inflammation, oxidative stress, bile acid homeostasis, and immune responses. This review explores the growing body of evidence linking vitamin D deficiency to chronic liver diseases, including autoimmune hepatitis, primary biliary cholangitis, alcoholic liver disease, viral hepatitis B and C, and metabolic-associated steatotic liver disease. Low vitamin D levels are frequently observed in these conditions and are associated with disease severity, complications (such as spontaneous bacterial peritonitis, sarcopenia, and hepatic encephalopathy), and increased mortality. Mechanistically, vitamin D-VDR signaling inhibits profibrotic TGF-β1/SMAD pathways, downregulates proinflammatory cytokines, enhances regulatory T cell differentiation, and improves insulin sensitivity. Although preclinical studies support its protective effects, clinical trials of vitamin D supplementation have produced mixed results. Overall, vitamin D appears to influence multiple pathways in liver disease pathophysiology, and correcting its deficiency may offer clinical benefits. However, its integration into clinical care will depend on identifying responsive patient subgroups and defining optimal dosing strategies to maximize therapeutic benefit.

Keywords: Vitamin D; Vitamin D receptor; Fibrosis; Inflammation; Immune response; Vitamin D deficiency; Chronic liver diseases

Core Tip: Vitamin D plays diverse roles in chronic liver disease beyond bone health, including modulation of fibrosis, immune responses, bile acid metabolism, and oxidative stress via vitamin D receptor signaling. Deficiency is common across liver disease etiologies and linked to worse outcomes. Although preclinical data are promising, clinical trials have yielded inconsistent results. This review summarizes the mechanistic and clinical evidence for vitamin D in autoimmune, viral, alcoholic, and metabolic liver diseases, emphasizing its potential as a modifiable factor and the need to define patient subgroups most likely to benefit from supplementation.