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

Disclosures

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

In This Article

Discussion

In this systematic review and meta-analysis of approximately 5000 NAFLD cases and 8000 controls, we found lower vitamin D levels in NAFLD subjects compared with controls (SMD 0.36 ng/mL, 95% CI: 0.32, 0.40). Moreover, NAFLD subjects were 26% more likely to be vitamin D deficient (OR 1.26; 95% CI: 1.17, 1.35). These differences were higher when we stratified the analyses in Western vs. Eastern participants (Figures 2 and 3). Our results suggest that vitamin D levels are indeed low in patients with NAFLD and might be part of the pathogenesis of NAFLD.

Insulin resistance, a key risk factor in the pathogenesis of NAFLD, is linked to the development of oxidative stress and lipotoxicity.[36–38] It is now recognised that pro-inflammatory cytokines such as TNF-α, IL-6 and adipokines such as leptin and adiponectin play a major role in the progression from steatosis to steatohepatitis.[39] Moreover, the nuclear factor κ-B (NF-κB) pathway appears to be an important mediator between insulin resistance and hepatic inflammation.[40]

As already mentioned above, recent years have witnessed a significant scientific interest into the potential role played by vitamin D in the pathophysiology of insulin resistance and diabetes. A recent systematic review found that vitamin D levels >25 ng/mL were associated with a 43% lower risk of type 2 diabetes compared to vitamin D levels <14 ng/mL (95% CI 24, 57%).[41] In the same study, vitamin D treatment improved insulin resistance among patients with baseline glucose intolerance.[41] Similarly, another meta-analysis showed that vitamin D supplementation improved insulin resistance by 0.25 standard deviation (95% confidence interval 0.03–0.48, P = 0.03) compared to placebo.[42] The underlying mechanisms by which vitamin D may preserve glucose tolerance are thought to be related to effects on insulin secretion and sensitivity via the regulation of insulin receptor expression in pancreatic beta cells[43,44] and in peripheral target tissues (including the liver)[45,46] as well as via improvement in systemic inflammation seen in insulin resistance.[47,48]

Additional evidence from animal studies further supports the notion of an immunomodulatory role of vitamin D in NAFLD. In a recent study, rats fed a vitamin D-deficient Westernised diet had a higher NAFLD activity score on liver histology compared with those on the nonvitamin D-deficient Westernised diet; in addition, they had increased hepatic mRNA levels for resistin, IL-4, IL-6 and TNFα – markers known to be implicated in oxidative stress and hepatic inflammation.[12] Accordingly, in another rat NASH model, phototherapy elevated 25(OH)D and 1,25(OH)2D3 levels while reducing hepatocyte inflammation, fibrosis and apoptosis compared with controls. Phototherapy also improved insulin resistance and increased serum adiponectin in association with reduced hepatic expression of inflammatory genes TNF-α and TGF-β as well as α-smooth muscle actin (α-SMA) known to be a marker of hepatic stellate cell activation.[49] Furthermore, vitamin D significantly reduced free radical liver peroxidation substances and increased hepatic glucose uptake in a streptozotocin-induced diabetic rat model.[11] These findings suggest that vitamin D deficiency may exacerbate NAFLD at least in part via an inflammatory-mediated pathway.

Vitamin D mediates its intracellular signals via its receptor VDR, which is constitutively expressed in the liver.[50–52] VDR expression on cholangiocytes and hepatocytes from NAFLD subjects was inversely correlated with non-alcoholic fatty liver activity score.[53] In the same study, liver VDR expression was strongly associated with a diagnosis of NASH independently from other metabolic determinants such as BMI, insulin resistance or adiponectin; additionally, CYP27A1 and CYP2R1 expression – enzymes that catalyse the 25-hydroxylation of vitamin D – was preserved in NASH patients.[53] These observations therefore question the hypothesis of a loss of hydroxylation capacity of hepatocytes as a cause of NASH. Conversely, the finding of a direct inverse association of 25(OH)D3 levels with intra-hepatic ballooning in this study favours a possible hepatoprotective role of vitamin D.

The role of vitamin D in liver fibrosis has also been examined. In rat models of liver fibrosis, 1,25(OH)2D3 – the active form of vitamin D – had protective antifibrotic effects and prevented the development of cirrhosis by thioacetamide (TAA).[54] Similarly, in another in vitro study of human hepatic stellate cells, 1,25(OH)2D3 inhibited type I collagen formation, suggesting that correction of vitamin D deficiency could be a pathway to prevent fibrosis in chronic liver disease, including NAFLD.[14]

To our knowledge, this is the first meta-analysis to investigate the association of vitamin D levels with NAFLD. Our search method had no language or date restrictions and, by including EMBASE, we also incorporated grey literature accepted for scientific meetings, thus adding strength to our study. However, our study had several limitations. First, the method of NAFLD diagnosis varied across studies. Only a few studies used liver biopsy, which is considered the gold standard, while some studies used imaging techniques or elevated ALT levels as to identify NAFLD cases. However, based on results from a recent meta-analysis, ultrasound has been proven to be an accurate and reliable imaging technique for the detection of fatty liver disease with an overall sensitivity and specificity of 85% and 94% respectively.[55] Elevated ALT levels are also strongly associated with NAFLD in subjects with the metabolic syndrome,[56] and have been used in clinical and population studies as surrogate markers of NAFLD. The use of imaging and particularly of biochemical methods to assess NAFLD may also be associated with considerable measurement error and may substantially underestimate the association between vitamin D and NAFLD. Second, the cut-off level for defining vitamin D deficiency varied across studies, probably contributing to the heterogeneity in our findings. The normal range of vitamin D remains a controversial area of research and has been the subject of debate over the past several years. While some investigators recommend using 30 ng/mL as the cut-off level,[57] the most recent Institute of Medicine (IOM) committee report endorses the use of 20 ng/mL.[58] Third, many of the original studies did not adjust for potentially important confounders, such as BMI, presence of diabetes or season. Finally, there was evidence of statistical heterogeneity in our analysis, but the current studies suggest no major clinical heterogeneity and, therefore, we thought appropriate to provide the pooled analyses.

In conclusion, we have demonstrated that vitamin D deficiency is prevalent in NAFLD subjects, suggesting that vitamin D may play a role in the development of the disease. The anti-inflammatory and immune-modulatory properties of vitamin D provide plausible mechanisms by which vitamin D may impact on disease progression and severity in NAFLD. Due to the nature of the abstracted cross-sectional studies in our review, directionality of our results cannot be ascertained. Future research should focus on investigating prospectively the association between vitamin D and NAFLD as well as on randomised controlled trials of vitamin D supplementation in NAFLD subjects. Vitamin D is an inexpensive intervention, well tolerated and widely available with minimal side effects. Hence, vitamin D supplementation may prove to be beneficial in the treatment of NASH in addition to vitamin E.

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