Meta-analysis: Vitamin D and Non-alcoholic Fatty Liver Disease

M. Eliades; E. Spyrou; N. Agrawal; M. Lazo; F. L. Brancati; J. J. Potter; A. A. Koteish; J. M. Clark; E. Guallar; R. Hernaez


Aliment Pharmacol Ther. 2013;38(3):246-254. 

In This Article

Abstract and Introduction


Background Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition. Emerging evidence suggests that vitamin D may play a role in the pathogenesis of NAFLD.

Aim To review systematically the association between vitamin D levels, measured as serum 25-hydroxy vitamin D [25(OH)D], and NAFLD.

Methods We used PubMed and EMBASE databases to identify all studies that assessed the association between vitamin D and NAFLD up until 22 April 2013, without language restrictions. We included studies that compared vitamin D levels between NAFLD cases and controls and also those that compared the odds of vitamin D deficiency by NAFLD status. Pooled standardised differences and odds ratios were calculated using an inverse variance method.

Results Seventeen cross-sectional and case–control studies have evaluated the association between vitamin D and NAFLD. NAFLD was diagnosed using biopsy (4 studies), ultrasound or CT (10 studies) and liver enzymes (3 studies). Nine studies provided data for a quantitative meta-analysis. Compared to controls, NAFLD patients had 0.36 ng/mL (95% CI: 0.32, 0.40 ng/mL) lower levels of 25(OH)D and were 1.26 times more likely to be vitamin D deficient (OR 1.26, 95% CI: 1.17, 1.35).

Conclusions NAFLD patients have decreased serum 25(OH)D concentrations, suggesting that vitamin D may play a role in the development of NAFLD. The directionality of this association cannot be determined from cross-sectional studies. Demonstration of a causal role of hypovitaminosis D in NAFLD development in future studies could have important therapeutic implications.


Non-alcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease in Western countries with a prevalence as high as 30%, already exceeding viral hepatitis and alcoholic fatty liver disease.[1] NAFLD comprises of a wide spectrum of liver damage ranging from simple steatosis to steatohepatitis (NASH), to fibrosis and cirrhosis that can progress to liver failure and hepatocellular carcinoma.[2] Although NAFLD is strongly associated with obesity, insulin resistance, diabetes and the metabolic syndrome, its pathogenesis is incompletely understood. Currently, the pathogenesis of NAFLD and NASH is framed in the 'multiple-hits hypothesis' where a number of diverse parallel processes involving extrahepatic factors (genetic and nutritional) may contribute to the development and progression of liver inflammation.[3]

Vitamin D is a fat-soluble vitamin formed in the skin from 7-dehydrocholesterol during exposure to solar ultraviolet B (UVB) radiation.[4] Although vitamin D can be derived from the diet, few foods naturally contain vitamin D, such as oily fish. Vitamin D from the skin or from diet is metabolised in the liver to 25-hydroxyvitamin D [25(OH)D], which is the major circulating metabolite and the most widely used indicator of vitamin D stores.[5] 25(OH)D is metabolised in the kidneys to the biologically active form 1,25(OH)2D, which exerts its functions through binding to its nuclear receptor (vitamin D receptor, VDR). Within the last two decades, VDR has been shown to be present not only in primary target tissues such as bone, kidney and intestine, but also in many other tissues, including the immune and endocrine systems, muscles, brain and liver, therefore expanding the role of vitamin D beyond the skeletal system.[6]

Numerous publications propose that low levels of vitamin D may contribute to the development of insulin resistance, the metabolic syndrome and more recently NAFLD.[7–9] Accordingly, there are reports to suggest increasing prevalence of vitamin D deficiency in parallel to the prevalence of obesity.[10] Although the mechanisms underlying the association of vitamin D with NAFLD are not yet fully understood, recent animal studies have shown that vitamin D has an important role in the regulation of oxidative stress, the production of pro-inflammatory cytokines,[11,12] hepatocyte apoptosis[13] and even liver fibrosis.[14] As both diseases – NAFLD and vitamin D deficiency – are associated with insulin resistance, type 2 diabetes and cardiovascular disease, many studies have emerged over the past few years examining the relationship of vitamin D status, reflected by 25(OH) vitamin D level, with the development of NAFLD. To this end, we aimed to systematically review and quantify the association between vitamin D levels and NAFLD. We hypothesised that low vitamin D levels were associated with higher prevalence of NAFLD.