Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease

Abstract

Background & aims: Vitamin D deficiency has been frequently reported in advanced liver disease. However, its influence on alcoholic liver disease (ALD) has been poorly elucidated. We investigated the association of vitamin D with clinical, biological, and histological parameters and survival in ALD patients. Furthermore, we explored the effect of vitamin D treatment on ALD patient peripheral blood mononuclear cells (PBMCs), and in a murine experimental model of ALD.

Methods: Serum levels of 25-hydroxyvitamin D [25(OH)D] were determined in 324 Caucasian ALD patients and 201 healthy controls. In vitro experiments on vitamin D pre-treated PBMCs evaluated TNFα production by ELISA in culture supernatants. Mice were submitted to an ethanol-fed diet and some of them were orally supplemented three times per week with 1,25(OH)2D.

Results: Severe deficiency in 25(OH)D (<10 ng/ml) was significantly associated with higher aspartate aminotransferase levels (p=1.00 × 10(-3)), increased hepatic venous pressure gradient (p=5.80 × 10(-6)), MELD (p=2.50 × 10(-4)), and Child-Pugh scores (p=8.50 × 10(-7)). Furthermore, in multivariable analysis, a low 25(OH)D concentration was associated with cirrhosis (OR=2.13, 95% CI=1.18-3.84, p=0.013) and mortality (HR=4.33, 95% CI=1.47-12.78, p=7.94 × 10(-3)) at one year. In addition, in vitro, 1,25(OH)2D pretreatment decreased TNFα production by stimulated PBMCs of ALD patients (p=3.00 × 10(-3)), while in vivo, it decreased hepatic TNFα expression in ethanol-fed mice (p=0.04).

Conclusions: Low 25(OH)D levels are associated with increased liver damage and mortality in ALD. Our results suggest that vitamin D might be both a biomarker of severity and a potential therapeutic target in ALD.

Keywords: 1,25(OH)(2)D; 1,25-dihydroxyvitamin D; 25(OH)D; 25-hydroxyvitamin D; AC; AH; ALD; ALT; AST; Alcoholic liver disease; BMI; CHC; CI; ConA; Ctrl; ELISA; EtOH; GGT; GWAS; Genetic factors; HCC; HPRT; HR; HRS; HS; HVPG; Inflammation; MELD; NAFLD; OR; PBMCs; RT-PCR; SBP; SNP; TNFα; Vitamin D; alanine aminotransferase; alcoholic cirrhosis; alcoholic hepatitis; alcoholic liver disease; aspartate aminotransferase; body mass index; chronic hepatitis C; concanavalin A; confidence interval; control; enzyme-linked immunosorbent assay; ethanol; gamma-glutamyl transferase; genome-wide association studies; hazards ratio; healthy subjects; hepatic venous pressure gradient; hepatocellular carcinoma; hepatorenal syndrome; hypoxanthine-guanine phosphoribosyltransferase; model for end-stage liver disease; non-alcoholic fatty liver disease; odds ratio; peripheral blood mononuclear cells; reverse transcriptase polymerase chain reaction; single nucleotide polymorphism; spontaneous bacterial peritonitis; tumor necrosis factor-α.