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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 (<10ng/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. [ABSTRACT FROM AUTHOR]

Background & Aims: A recent genome-wide association study identified genetic polymorphism (rs738409 C>G) in the PNPLA3/adiponutrin gene associated with liver steatosis. This variant has also been linked to increased risk of alcoholic liver disease (ALD) and cirrhosis in Mestizo Mexicans with excessive alcohol intake. Our aim was to study the influence of this polymorphism on European Caucasian patients with histologically suggestive ALD. Methods: Three-hundred-and-twenty-eight healthy controls and 330 ALD patients, among whom 265 had cirrhosis, were genotyped for the rs738409 polymorphism. We studied the impact of rs738409 on clinical and biological parameters, together with histological staging of steatosis and fibrosis. PNPLA3 messenger RNA (mRNA) levels were measured by quantitative real-time PCR according to the patient’s phenotype. Results: The G-allele was significantly more frequent in ALD patients than in controls (odds ratio [OR]=1.54, 95% confidence interval [CI]=1.12–2.11 p =0.008) and was, among ALD patients, significantly associated with steatosis (p =0.048), fibrosis (p =0.001), and greater risk of cirrhosis (p =0.001). In multivariate analysis, rs738409 remained the strongest independent factor associated with risk of cirrhosis (OR=2.08; 95% CI=1.15–3.77; p =0.02). Furthermore, the PNPLA3 mRNA liver expression level was significantly lower in patients with more advanced fibrosis (p =0.03) and negatively correlated with the hepatic venous pressure gradient (r =−0.41, p =0.006). Conclusions: In European Caucasians, the rs738409 variant is associated with increased risk of ALD, liver damage, and cirrhosis. Further prospective studies are required to confirm these results and to evaluate the potential of PNPLA3 as both a predictor and a therapeutic target in ALD. [Copyright &y& Elsevier]