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D-livering the message: The importance of vitamin D status in chronic liver disease

Open AccessPublished:May 24, 2012DOI:https://doi.org/10.1016/j.jhep.2012.04.033

      Summary

      Vitamin D is synthesized predominantly in the liver and functions as an important secosteroid hormone with pleiotropic effects. While its key regulatory role in calcium and bone homeostasis is well established, recently there is increasing recognition that vitamin D also regulates cell proliferation and differentiation, and has immunomodulatory, anti-inflammatory and anti-fibrotic properties. These non-skeletal effects are relevant in the pathogenesis and treatment of many causes of chronic liver disease. Vitamin D deficiency is frequently present in chronic liver disease and may predict non-response to antiviral therapy in chronic hepatitis C. Small studies suggest that vitamin D supplementation improves sustained viral response rates, while 1α-hydroxylase polymorphisms and vitamin D-binding protein are also implicated in therapeutic outcomes. Vitamin D deficiency also closely relates to the severity of non-alcoholic fatty liver disease (NAFLD) and is implicated in the pathogenesis of insulin resistance, a key factor in the development of NAFLD. In preclinical studies, phototherapy and vitamin D supplementation ameliorate NAFLD histopathology, while vitamin D is a powerful anti-fibrotic against thioacetamide liver injury. In liver transplant recipients severe vitamin D deficiency predicts, and vitamin D supplementation prevents, acute cellular rejection. The role of vitamin D in the activation and regulation of both innate and adaptive immune systems may explain its importance in the above liver diseases. Further prospective studies are therefore warranted to investigate the therapeutic impact of vitamin D supplementation in chronic liver disease.

      Keywords

      Introduction

      Vitamin D is an important secosteroid hormone with pleiotropic effects (Table 1). While its role in the regulation of calcium and bone homeostasis is well established, recently there is increasing recognition that vitamin D has immunomodulatory, anti-inflammatory and anti-fibrotic properties and plays an important role in the regulation of cell proliferation and differentiation. These extraskeletal effects are relevant in the pathogenesis and treatment of many causes of chronic liver disease.
      Table 1Pleiotropic effects of vitamin D.

      Vitamin D synthesis and metabolism

      Vitamin D undergoes a 3-step activation process before it interacts with the vitamin D receptor. The majority of circulating vitamin D is synthesized in the skin as a result of exposure to sunlight. The initial step involves ultraviolet-B radiation (wavelength 290–315 nm) converting the cholesterol metabolite 7-dehydrocholesterol into previtamin D3 in the lower epidermis, which is rapidly converted to vitamin D3 in a heat-dependent process. However, excessive sunlight exposure does not cause vitamin D intoxication because excess vitamin D3 is destroyed by sunlight [
      • Holick M.F.
      • Garabedian M.
      Vitamin D: photobiology, metabolism, mechanism of action, and clinical applications.
      ]. Only a small proportion of vitamin D is obtained from dietary sources such as fatty fish, eggs, UV-irradiated mushrooms, supplements, and artificially fortified foods (Table 2). Dietary-derived vitamins D2 (ergocalciferol) and D3 (cholecalciferol) are absorbed via a bile-acid dependent process whereby vitamin D is incorporated into micelles in the intestinal lumen, then absorbed by enterocytes and packaged into chylomicrons that are then transported to the venous circulation via lymphatic drainage. Vitamin D from both skin synthesis and dietary sources can either be stored in adipocytes or undergo 25-hydroxylation in the liver. This process is mediated by the 25-hydroxylases, which are cytochrome P450 isoforms that include the important microsomal CYP2R1 and the mitochondrial CYP27A1 enzymes. This produces the main circulating, though biologically inactive, form 25-hydroxyvitamin D [25(OH)D], or calcidiol, which has a long half-life of 2–3 weeks and is therefore used to assess vitamin D status. The vast majority (88%) of serum 25(OH)D is bound to vitamin D-binding protein (DBP), which is also known as Gc or the group-specific component of globulin. DBP is a 58 kDa α-macroglobulin almost exclusively synthesized by the liver and a member of the albumin gene family located on chromosome 4, with high sequence homology to albumin and α-fetoprotein [
      • White P.
      • Cooke N.
      The multifunctional properties and characteristics of vitamin D-binding protein.
      ]. It is highly polymorphic, having three common isoforms, Gc1F, Gc1S, and Gc2, that display marked racial variation [
      • Kamboh M.I.
      • Ferrell R.E.
      Ethnic variation in vitamin D-binding protein (GC): a review of isoelectric focusing studies in human populations.
      ], with the Gc1F isoform having the highest affinity for vitamin D metabolites. DBP has anti-inflammatory and immunomodulatory functions independent of its role as the carrier of vitamin D [
      • Yamamoto N.
      • Homma S.
      Vitamin D3 binding protein (group-specific component) is a precursor for the macrophage-activating signal factor from lysophosphatidylcholine-treated lymphocytes.
      ,
      • Metcalf J.P.
      • Thompson A.B.
      • Gossman G.L.
      • Nelson K.J.
      • Koyama S.
      • Rennard S.I.
      • et al.
      Gc globulin functions as a cochemotaxin in the lower respiratory tract. A potential mechanism for lung neutrophil recruitment in cigarette smokers.
      ].
      Table 2Sources of vitamin D.
      The final step in the synthesis of vitamin D is 1α-hydroxylation that predominantly occurs in the proximal tubule of the kidney but also to a lesser extent in lymphocytes and parathyroid tissue. It is mediated by 1α-hydroxylase (CYP27B1) that produces the active form 1α,25-dihydroxyvitamin D [1α,25(OH)2D] or calcitriol, which is also highly bound to DBP (85%) [
      • White P.
      • Cooke N.
      The multifunctional properties and characteristics of vitamin D-binding protein.
      ] and has a half-life of only 4 h. 1α,25(OH)2D is the ligand that activates the vitamin D receptor (VDR). This then forms a heterodimer with the retinoid X receptor that acts as a transcription factor that binds to vitamin D response elements in the promoter region of target genes. 1α-hydroxylation is under the influence of factors such as serum phosphate and calcium concentration, parathyroid hormone (PTH), fibroblast growth factor 23 and genetic polymorphisms of CYP27B1. 1α,25(OH)2D acts in a negative feedback loop to decrease its own synthesis and increase the expression of 25-hydroxyvitamin D-24-hydoxylase (CYP24A1), which catabolizes 1α,25(OH)2D into calcitroic acid, a biologically inert agent excreted in the bile (Fig. 1).
      VDR is expressed in most tissues and cells of the human body, including liver, pancreas, and several immune cells including monocytes, macrophages, T lymphocytes, B lymphocytes, natural killer (NK) cells, and dendritic cells (DC), with expression most abundant on the epithelial cells of the gastrointestinal tract. As a transcription factor activated by 1α,25(OH)2D, VDR directly or indirectly regulates the expression of more than 200 genes that influence cell proliferation, differentiation and apoptosis, as well as immunomodulation and angiogenesis [
      • Holick M.F.
      • Vitamin D.
      Deficiency.
      ]. Studies in VDR null mice highlight the broad physiologic function of vitamin D [
      • Bouillon R.
      • Carmeliet G.
      • Verlinden L.
      • van Etten E.
      • Verstuyf A.
      • Luderer H.F.
      • et al.
      Vitamin D and human health: lessons from vitamin D receptor null mice.
      ].

      Vitamin D deficiency

      Vitamin D deficiency is broadly defined as a serum 25(OH)D level <50 nmol/L (<20 ng/ml). Levels between 75 and 125 nmol/L (30–50 ng/ml) are considered optimal as PTH levels rise when 25(OH)D is <75 nmol/L (30 ng/ml); hence, levels between 50 and 75 nmol/L (20–30 ng/ml) are increasingly recognized to represent vitamin D insufficiency [
      • Holick M.F.
      High prevalence of vitamin D inadequacy and implications for health.
      ,
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      ,
      • Malabanan A.
      • Veronikis I.E.
      • Holick M.F.
      Redefining vitamin D insufficiency.
      ,
      • Dawson-Hughes B.
      • Heaney R.P.
      • Holick M.F.
      • Lips P.
      • Meunier P.J.
      • Vieth R.
      Estimates of optimal vitamin D status.
      ]. Using these definitions, it is estimated that more than 1 billion people worldwide are either vitamin D deficient or insufficient [
      • Bouillon R.
      Genetic and environmental determinants of vitamin D status.
      ], with the elderly and those with chronic medical illness most at risk. However, even amongst healthy young people, vitamin D deficiency and insufficiency are still common [
      • Chapuy M.C.
      • Preziosi P.
      • Maamer M.
      • Arnaud S.
      • Galan P.
      • Hercberg S.
      • et al.
      Prevalence of vitamin D insufficiency in an adult normal population.
      ,
      • Tangpricha V.
      • Pearce E.N.
      • Chen T.C.
      • Holick M.F.
      Vitamin D insufficiency among free-living healthy young adults.
      ,
      • McGrath J.J.
      • Kimlin M.G.
      • Saha S.
      • Eyles D.W.
      • Parisi A.V.
      Vitamin D insufficiency in south-east Queensland.
      ]. A meta-analysis of 18 randomized-controlled trials involving 57,311 participants shows that subjects randomized to receive vitamin D supplementation, at a mean daily dose of 528 IU, have a statistically significant 7% reduction in all-cause mortality over a mean follow-up duration of 5.7 years [
      • Autier P.
      • Gandini S.
      Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.
      ]. Vitamin D deficiency has a deleterious clinical impact on a number of important medical conditions (Table 3).
      Table 3Clinical impact of vitamin D deficiency.

      Vitamin D and chronic liver disease

      The liver is a pivotal organ in the synthesis of vitamin D. It is the site where 25-hydroxylation occurs and where the vast majority of DBP is synthesized. In those with chronic liver disease (CLD) the prevalence of vitamin D insufficiency (<75 nmol/L) is almost universal, with vitamin D deficiency (<50 nmol/L) present in around two-thirds of subjects. Even in the absence of cirrhosis, vitamin D deficiency is present in the majority of subjects. In those with cirrhosis, the prevalence of severe vitamin D deficiency (<25 nmol/L) increases with increasing severity of synthetic liver dysfunction [
      • Fisher L.
      • Fisher A.
      Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease.
      ,
      • Arteh J.
      • Narra S.
      • Nair S.
      Prevalence of vitamin D deficiency in chronic liver disease.
      ]. Notably, in those about to undergo liver transplantation, the frequency of 25(OH)D and 1α,25(OH)2D deficiency is 84% and 77%, respectively, with transplantation resulting in a marked increase in 25(OH)D, 1α,25(OH)2D, and DBP levels [

      Reese PP, Bloom RD, Feldman HI, Huverserian A, Thomasson A, Shults J, et al. Changes in vitamin D binding protein and vitamin D concentrations associated with liver transplantation. Liver Int 2011 Sep 9. doi: http://dx.doi.org/10.1111/j.1478-3231.2011.02638.x. [Epub ahead of print].

      ].
      The high prevalence of vitamin D deficiency in this population occurs regardless of the etiology of liver disease [
      • Rode A.
      • Fourlanos S.
      • Nicoll A.
      Oral vitamin D replacement is effective in chronic liver disease.
      ,
      • Malham M.
      • Jørgensen S.P.
      • Ott P.
      • Agnholt J.
      • Vilstrup H.
      • Borre M.
      • et al.
      Vitamin D deficiency in cirrhosis relates to liver dysfunction rather than Aetiology.
      ]. Synthetic liver dysfunction is not entirely responsible, as vitamin D deficiency is still highly prevalent in those with non-cirrhotic liver disease [
      • Fisher L.
      • Fisher A.
      Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease.
      ]. 25(OH)D levels normalize after oral or parenteral administration of vitamin D in patients with cirrhosis, indicating that 25-hydroxylation is preserved in this patient population [
      • Heaf J.G.
      Hepatic osteodystrophy.
      ,
      • Compston J.E.
      Hepatic osteodystrophy: vitamin D metabolism in patients with liver disease.
      ]. Serum DBP levels, which play a critical role in the transport and bioavailability of vitamin D, are moderately decreased in cirrhosis [
      • Masuda S.
      • Okano T.
      • Osawa K.
      • Shinjo M.
      • Suematsu T.
      • Kobayashi T.
      Concentrations of vitamin D-binding protein and vitamin D metabolites in plasma of patients with liver cirrhosis.
      ,
      • Schiødt F.V.
      Gc-globulin in liver disease.
      ]. However, as only 5% of DBP binding sites are occupied at any one time with vitamin D metabolites [
      • White P.
      • Cooke N.
      The multifunctional properties and characteristics of vitamin D-binding protein.
      ], profound liver dysfunction is required for low DBP levels to exert a significant contributing role to vitamin D deficiency in chronic liver disease.
      Vitamin D deficiency in CLD is likely to result from a number of mechanisms. In addition to those described above, those patients with a chronic medical illness such as liver disease are more likely to have lower levels of sunlight exposure and/or inadequate dietary intake of vitamin D. Moreover, luminal absorption of dietary sources of vitamin D may be hindered by intestinal edema complicating portal hypertension and/or impaired bile salt dependent micellar incorporation due to cholestasis.

      Vitamin D and chronic hepatitis C

      Around 170 million people worldwide have chronic hepatitis C (CHC) infection [

      World Health Organization. Fact sheet No164. http://www.who.int/mediacentre/factsheets/fs164/en/.

      ], causing a substantial burden of chronic liver disease globally [
      • Shepard C.W.
      • Finelli L.
      • Alter M.J.
      Global epidemiology of hepatitis C virus infection.
      ]. Vitamin D deficiency is more prevalent in CHC subjects than healthy controls, even in those with minimal liver fibrosis. The majority of subjects with CHC are vitamin D deficient (<50 nmol/L) with 25% having severe deficiency (<25 nmol/L) [
      • Petta S.
      • Cammà C.
      • Scazzone C.
      • Tripodo C.
      • Di Marco V.
      • Bono A.
      • et al.
      Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.
      ,
      • Lange C.M.
      • Bojunga J.
      • Ramos-Lopez E.
      • von Wagner M.
      • Hassler A.
      • Vermehren J.
      • et al.
      Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy.
      ]. Current understanding of the mechanisms underlying the high prevalence of vitamin D deficiency in CHC is incomplete.
      Nevertheless, recent evidence suggests that vitamin D may impact upon clinical outcomes and treatment response. Fundamental to this are several in vitro studies showing that vitamin D inhibits hepatitis C virus (HCV) replication in a dose-dependent manner [
      • Gal-Tanamy M.
      • Bachmetov L.
      • Ravid A.
      • Koren R.
      • Erman A.
      • Tur-Kaspa R.
      • et al.
      Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes.
      ,
      • Matsumura T.
      • Kato T.
      • Tasaka-Fujita M.
      • Murayama A.
      • Masaki T.
      • Wakita T.
      • et al.
      25-hydroxyvitamin D inhibits hepatitis C virus replication and production of the infectious viruses.
      ,
      • Yano M.
      • Ikeda M.
      • Abe K.
      • Dansako H.
      • Ohkoshi S.
      • Aoyagi Y.
      • et al.
      Comprehensive analysis of the effects of ordinary nutrients on hepatitis C virus RNA replication in cell culture.
      ]. Moreover, an association between baseline vitamin D status and treatment response to pegylated-interferon (PEG-IFN) and ribavirin (RBV) has recently been established (Fig. 2). Pre-treatment vitamin D deficiency is reportedly an independent predictor of failure to achieve a sustained virologic response (SVR) in HCV genotype 1 (HCV-1), [
      • Petta S.
      • Cammà C.
      • Scazzone C.
      • Tripodo C.
      • Di Marco V.
      • Bono A.
      • et al.
      Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.
      ,
      • Bitetto D.
      • Fattovich G.
      • Fabris C.
      • Ceriani E.
      • Falleti E.
      • Fornasiere E.
      • et al.
      Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C.
      ], and 2/3 infection [
      • Lange C.M.
      • Bojunga J.
      • Ramos-Lopez E.
      • von Wagner M.
      • Hassler A.
      • Vermehren J.
      • et al.
      Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy.
      ]. However, 25(OH)D level is not associated with SVR in HCV–HIV co-infection [
      • Terrier B.
      • Carrat F.
      • Geri G.
      • Pol S.
      • Piroth L.
      • Halfon P.
      • et al.
      Low 25-OH vitamin D serum levels correlate with severe fibrosis in HIV–HCV co-infected patients with chronic hepatitis.
      ]. In HCV-1 infection, the rs12979860 C/T polymorphism upstream of the interleukin-28B (IL28B) gene on chromosome 19 is the strongest pre-treatment predictor of SVR [
      • Ge D.
      • Fellay J.
      • Thompson A.J.
      • Simon J.S.
      • Shianna K.V.
      • Urban T.J.
      • et al.
      Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.
      ]. Baseline vitamin D status is independent of, but additive to, the IL28B genotype in predicting SVR in HCV-1. The highest SVR rate occurs in subjects who have the favorable CC genotype and 25(OH)D levels >50 nmol/L [
      • Bitetto D.
      • Fattovich G.
      • Fabris C.
      • Ceriani E.
      • Falleti E.
      • Fornasiere E.
      • et al.
      Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C.
      ].
      To date, there is limited data evaluating vitamin D supplementation in CHC treatment. Two small prospective randomized controlled studies from Israel showed that those subjects who received vitamin D3 supplementation of 2000 IU/day, targeting a 25(OH)D level >80 nmol/L in addition to PEG-IFN/RBV combination therapy, had higher rates of rapid virologic response (RVR; 44% vs. 17%, p <0.001), complete early virologic response (cEVR; 94% vs. 48%, p <0.001) and SVR (86% vs. 42%; OR 2.5, 95% CI 2.0-4.9, p <0.001) in HCV-1 [
      • Abu-Mouch S.
      • Fireman Z.
      • Jarchovsky J.
      • Zeina A.R.
      • Assy N.
      Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients.
      ] and SVR (95% vs. 77%, p <0.001) in HCV-2/3 infection [
      • Nimer A.
      • Mouch A.
      Vitamin D improves viral response in hepatitis C genotype 2–3 naïve patients.
      ] compared to subjects treated with standard therapy. Moreover, recipients of vitamin D3 supplementation were less likely to be relapsers or non-responders to antiviral therapy, and had improved insulin resistance indices [
      • Abu-Mouch S.
      • Fireman Z.
      • Jarchovsky J.
      • Zeina A.R.
      • Assy N.
      Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients.
      ]. Similarly, a small retrospective Italian study showed vitamin D3 supplementation improved SVR rate in the treatment of recurrent hepatitis C post liver transplantation (53.3% vs. 18.5%, p = 0.02) [
      • Bitetto D.
      • Fabris C.
      • Fornasiere E.
      • Pipan C.
      • Fumolo E.
      • Cussigh A.
      • et al.
      Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C.
      ]. It remains unclear whether these improvements in the clearance of HCV with vitamin D supplementation are the result of an alteration in innate and/or adaptive immune function, or are mediated via improvement in insulin resistance. Large, prospective, placebo-controlled studies are thus required to assess the impact of vitamin D supplementation on viral response in CHC treatment. However, these studies now seem unlikely to occur in the new and rapidly evolving era of direct acting viral therapy.
      Vitamin D status also reportedly correlates with liver histology in CHC. Patients with vitamin D deficiency have a higher grade of hepatic necroinflammation [
      • Petta S.
      • Cammà C.
      • Scazzone C.
      • Tripodo C.
      • Di Marco V.
      • Bono A.
      • et al.
      Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.
      ,
      • Bitetto D.
      • Fattovich G.
      • Fabris C.
      • Ceriani E.
      • Falleti E.
      • Fornasiere E.
      • et al.
      Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C.
      ], more advanced fibrosis stage [
      • Petta S.
      • Cammà C.
      • Scazzone C.
      • Tripodo C.
      • Di Marco V.
      • Bono A.
      • et al.
      Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.
      ,
      • Lange C.M.
      • Bojunga J.
      • Ramos-Lopez E.
      • von Wagner M.
      • Hassler A.
      • Vermehren J.
      • et al.
      Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy.
      ,
      • Terrier B.
      • Carrat F.
      • Geri G.
      • Pol S.
      • Piroth L.
      • Halfon P.
      • et al.
      Low 25-OH vitamin D serum levels correlate with severe fibrosis in HIV–HCV co-infected patients with chronic hepatitis.
      ] and may possibly have more rapid fibrosis progression [

      Baur K, Mertens JC, Schmitt J, Iwata R, Stieger B, Eloranta JJ, et al. Combined effect of 25-OH vitamin D plasma levels and genetic Vitamin D Receptor (NR 1|1) variants on fibrosis progression rate in HCV patients. Liver Int 2011 Dec 8. doi: http://dx.doi.org/10.1111/j.1478-3231.2011.02674.x. [Epub ahead of print].

      ]. At a cellular level, vitamin D deficiency is associated with downregulation of the 25-hydroxylase enzyme CYP27A1 in liver tissue. This may have pathogenetic relevance, given the established inverse relationship between CYP27A1 expression and the severity of necroinflammatory activity [
      • Petta S.
      • Cammà C.
      • Scazzone C.
      • Tripodo C.
      • Di Marco V.
      • Bono A.
      • et al.
      Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.
      ].
      The above findings highlight the potential role that proteins and enzymes involved in the synthesis and metabolism of vitamin D may have in liver inflammation and response to anti-viral therapy. Genetic variation in the rs10877012 A/C polymorphism in the promoter region of the 1α-hydroxylase enzyme CYP27B1, but not the rs10735810 FokI VDR polymorphism, is associated with SVR in HCV-1 infection. Subjects with the AA genotype have higher SVR rate and 1α,25(OH)2D level than those with the AC or CC genotype [
      • Lange C.M.
      • Bojunga J.
      • Ramos-Lopez E.
      • von Wagner M.
      • Hassler A.
      • Vermehren J.
      • et al.
      Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy.
      ], suggesting a key role of vitamin D in CHC infection. Moreover, a recently published proteomic study has shown vitamin DBP to be one of three metaproteins associated with SVR [
      • Patel K.
      • Lucas J.E.
      • Thompson J.W.
      • Dubois L.G.
      • Tillmann H.L.
      • Thompson A.J.
      • et al.
      High predictive accuracy of an unbiased proteomic profile for sustained virologic response in chronic hepatitis C patients.
      ]. DBP levels are significantly lower in subjects with significant or advanced fibrosis (METAVIR F2-4) compared with those with absent or minimal fibrosis (F0/1) and healthy controls [
      • Ho A.S.
      • Cheng C.C.
      • Lee S.C.
      • Liu M.L.
      • Lee J.Y.
      • Wang W.M.
      • et al.
      Novel biomarkers predict liver fibrosis in hepatitis C patients: alpha 2 macroglobulin, vitamin D binding protein and apolipoprotein A1.
      ,
      • Gressner O.A.
      • Gao C.
      • Siluschek M.
      • Kim P.
      • Gressner A.M.
      Inverse association between serum concentrations of actin-free vitamin D-binding protein and the histopathological extent of fibrogenic liver disease or hepatocellular carcinoma.
      ].
      Thus, vitamin D deficiency appears to be common in CHC and may be associated with adverse outcomes such as lower treatment response, more advanced fibrosis stage and increased severity of necroinflammation. It remains, however, uncertain as to whether vitamin D supplementation improves the SVR rate in patients receiving combination anti-viral therapy with PEG-IFN and RBV. Still, the findings of a significant association between the CYP27B1 rs10877012 A/C polymorphism, higher 1α,25(OH)2D levels, and SVR rate, as well as the association between vitamin D-binding protein and SVR suggest that higher 25(OH)D and 1α,25(OH)2D levels directly improve the virologic response to PEG-IFN and RBV therapy, presumably by impacting on the downstream regulation of vitamin D target gene transcription. DBP determines how much free 25(OH)D substrate is available for 1α-hydroxylase as well as the amount of free 1α,25(OH)2D ligand available to activate the VDR and influences downstream gene transcription. Hepatic 1α-hydroxylase activity levels therefore represent a major additional factor regulating 1α,25(OH)2D concentration in the liver.

      Vitamin D and non-alcoholic fatty liver disease

      Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. It is the most common liver disease in the developed world, with a prevalence of 20–30% [
      • Lazo M.
      • Hernaez R.
      • Bonekamp S.
      • Kamel I.R.
      • Brancati F.L.
      • Guallar E.
      • et al.
      Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study.
      ]. Thirty percent of subjects with NAFLD have histologic evidence of non-alcoholic steatohepatitis (NASH) [
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • Torres D.M.
      • Shaw J.
      • Contreras M.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      ] and are at risk of disease progression and development of cirrhosis. The pathogenesis of NAFLD is yet to be fully elucidated, but insulin resistance (IR) is implicated as the key mechanism leading to hepatic steatosis. Apart from lifestyle modification that results in significant weight loss [
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • Jackvony E.
      • Kearns M.
      • Wands J.R.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      ], there is currently no safe, effective therapy for NASH.
      Vitamin D levels decrease by 1.3 nmol/L with each 1 kg/m2 increase in body mass index (BMI) [
      • Stein E.M.
      • Strain G.
      • Sinha N.
      • Ortiz D.
      • Pomp A.
      • Dakin G.
      • et al.
      Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study.
      ]. Normal vitamin D status is associated with a two-thirds lower prevalence of metabolic syndrome compared to those with reduced levels [
      • Hyppönen E.
      • Boucher B.J.
      • Berry D.J.
      • Power C.
      25-hydroxy vitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort.
      ]. In non-diabetic Caucasians low vitamin D levels are independently associated with insulin resistance [
      • Liu E.
      • Meigs J.B.
      • Pittas A.G.
      • McKeown N.M.
      • Economos C.D.
      • Booth S.L.
      • et al.
      Plasma 25-hydroxyvitamin D is associated with markers of the insulin resistant phenotype in nondiabetic adults.
      ] and are a predictor of increased 10-year risk of developing hyperglycemia and insulin resistance [
      • Forouhi N.G.
      • Luan J.
      • Cooper A.
      • Boucher B.J.
      • Wareham N.J.
      Baseline serum 25-hydroxyvitamin D is predictive of future glycaemic status and insulin resistance. the Medical Research Council Ely Prospective Study 1990–2000.
      ]. A vitamin D response element is present in the insulin gene promoter region, and 1α,25(OH)2D activates transcription of the insulin gene [
      • Pittas A.G.
      • Lau J.
      • Hu F.B.
      • Dawson-Hughes B.
      The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis.
      ]. Both 1α-hydroxylase and the vitamin D receptor are expressed on pancreatic β cells, with an association between low vitamin D levels and impaired β cell function having been suggested [
      • Pittas A.G.
      • Lau J.
      • Hu F.B.
      • Dawson-Hughes B.
      The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis.
      ,
      • Chiu K.C.
      • Chu A.
      • Go V.L.
      • Saad M.F.
      Hypovitaminosis D is associated with insulin resistance and β cell dysfunction.
      ]. Two randomized placebo-controlled trials have shown that high dose vitamin D supplementation improved insulin sensitivity in non-diabetic South Asians [
      • Nagpal J.
      • Pande J.N.
      • Bhartia A.
      A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men.
      ,
      • von Hurst P.R.
      • Stonehouse W.
      • Coad J.
      Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient – a randomised, placebo-controlled trial.
      ]. A large prospective cohort study of women demonstrated that those who received vitamin D supplementation had a significantly lower risk of developing type 2 diabetes [
      • Pittas A.G.
      • Dawson-Hughes B.
      • Li T.
      • Van Dam R.M.
      • Willett W.C.
      • Manson J.E.
      • et al.
      Vitamin D and calcium intake in relation to type 2 diabetes in women.
      ].
      Subjects with NAFLD have lower vitamin D levels when compared with controls. Low vitamin D levels are closely associated with histologic severity of steatosis, necroinflammation, and fibrosis in NAFLD, independent of age, gender, BMI, Homeostatic Model Assessment (HOMA)-IR score and presence of metabolic syndrome [
      • Targher G.
      • Bertolini L.
      • Scala L.
      • Cigolini M.
      • Zenari L.
      • Falezza G.
      • et al.
      Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease.
      ,
      • Barchetta I.
      • Angelico F.
      • Del Ben M.
      • Baroni M.G.
      • Pozzilli P.
      • Morini S.
      • et al.
      Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes.
      ]. These findings have been confirmed in children with NAFLD [
      • Manco M.
      • Ciampalini P.
      • Nobili V.
      Low levels of 25-hydroxyvitamin D3 in children with biopsy-proven nonalcoholic fatty liver disease.
      ].
      In a recent study of Lewis rats with diet-induced (choline-deficient and iron-supplemented l-amino acid or CDAA) NASH, phototherapy elevated 25(OH)D, and 1α,25(OH)2D levels while reducing hepatocyte inflammation, fibrosis, and apoptosis when compared to controls. Phototherapy also improved insulin resistance and increased serum adiponectin in association with reduced hepatic expression of the profibrotic transforming growth factor (TGF)-β and α-smooth muscle actin (α-SMA), a marker of hepatic stellate cell activation. In addition, oral vitamin D3 supplementation reportedly improved liver histology in a dose-dependent manner [
      • Nakano T.
      • Cheng Y.F.
      • Lai C.Y.
      • Hsu L.W.
      • Chang Y.C.
      • Deng J.Y.
      • et al.
      Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats.
      ]. Furthermore, in a rodent high fat diet model of NAFLD, vitamin D deficiency exacerbated histologic features of NAFLD, increased insulin resistance, and upregulated liver tissue expression of genes involved in hepatic inflammation and oxidative stress [

      Roth CL, Elfers CT, Figlewicz DP, Melhorn SJ, Morton GJ, Hoofnagle A, et al. Vitamin D deficiency in obese rats exacerbates NAFLD and increases hepatic resistin and toll-like receptor activation. Hepatology 2011 Oct 12. doi: http://dx.doi.org/10.1002/hep.24737. [Epub ahead of print].

      ]. Given the above findings, prospective studies that assess the impact of vitamin D supplementation on the histologic features of NASH are warranted as a priority, given the lack of an effective therapy for this condition.

      Vitamin D and liver fibrosis

      1α,25(OH)2D has anti-fibrotic effects in lung fibroblasts and mesenchymal multipotent cells in vitro [
      • Ramirez A.M.
      • Wongtrakool C.
      • Welch T.
      • Steinmeyer A.
      • Zügel U.
      • Roman J.
      Vitamin D inhibition of pro-fibrotic effects of transforming growth factor beta1 in lung fibroblasts and epithelial cells.
      ,
      • Artaza J.N.
      • Norris J.C.
      Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells.
      ], as well as anti-proliferative and anti-fibrotic effects in both in vitro and in vivo rat models of liver fibrosis. VDR is expressed by hepatic stellate cells (HSC) and this expression is upregulated by 1α,25(OH)2D. In addition, 1α,25(OH)2D suppresses HSC proliferation, and expression of cyclin D1, tissue inhibitor of metalloproteinase 1 and collagen Iα1 in vitro. In vivo, 1α,25(OH)2D decreases α-SMA expression and collagen levels, and prevents the development of cirrhosis by thioacetamide (TAA) [
      • Abramovitch S.
      • Dahan-Bachar L.
      • Sharvit E.
      • Weisman Y.
      • Tov A.B.
      • Brazowski E.
      • et al.
      Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats.
      ,
      • Reif S.
      • Betov A.
      • Sharvit E.
      • Brazowski E.
      • Weisman Y.
      • Abramovitch S.
      Vitamin D has a protective antifibrotic effect in rat model of liver fibrosis.
      ]. A vitamin D level >50 nmol/L may be associated with a decreased frequency of rapid fibrosis progression in CHC [

      Baur K, Mertens JC, Schmitt J, Iwata R, Stieger B, Eloranta JJ, et al. Combined effect of 25-OH vitamin D plasma levels and genetic Vitamin D Receptor (NR 1|1) variants on fibrosis progression rate in HCV patients. Liver Int 2011 Dec 8. doi: http://dx.doi.org/10.1111/j.1478-3231.2011.02674.x. [Epub ahead of print].

      ]. However, the clinical importance of vitamin D as an anti-fibrotic agent remains to be determined.

      Vitamin D receptor polymorphisms and liver disease

      The vitamin D receptor (VDR) gene is located on chromosome 12. It encodes a 48 kDa soluble protein that is a member of the nuclear receptor family of ligand-activated transcription factors. Common single nucleotide polymorphisms (SNP) of the VDR gene include FokI (rs10735810), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236). There is a marked racial variation in the allele frequency of these VDR polymorphisms [
      • Fan L.
      • Tu X.
      • Zhu Y.
      • Zhou L.
      • Pfeiffer T.
      • Feltens R.
      • et al.
      Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese.
      ], but their influence on VDR function and signaling is unknown [
      • Adorini L.
      • Vitamin D.
      Receptor polymorphisms in primary biliary cirrhosis: a functional connection?.
      ]. The BsmI, ApaI, and TaqI SNPs are all in the 3′ region of the VDR gene and are in linkage disequilibrium with each other [
      • Falleti E.
      • Bitetto D.
      • Fabris C.
      • Cussigh A.
      • Fontanini E.
      • Fornasiere E.
      • et al.
      Vitamin D receptor gene polymorphisms and hepatocellular carcinoma in alcoholic cirrhosis.
      ].
      In CHC infection, the bAt [CCA]-haplotype of the BsmI, ApaI, and TaqI alleles, and the CC genotype of the ApaI allele are associated with rapid fibrosis progression, cirrhosis and increased intrahepatic expression of the fibrosis marker gene MMP-9 [

      Baur K, Mertens JC, Schmitt J, Iwata R, Stieger B, Eloranta JJ, et al. Combined effect of 25-OH vitamin D plasma levels and genetic Vitamin D Receptor (NR 1|1) variants on fibrosis progression rate in HCV patients. Liver Int 2011 Dec 8. doi: http://dx.doi.org/10.1111/j.1478-3231.2011.02674.x. [Epub ahead of print].

      ]. In chronic hepatitis B (HBV) infection, the variation in allele frequency of BsmI, ApaI, and TaqI is associated with HBeAg positivity and HBV flare [
      • Huang Y.W.
      • Liao Y.T.
      • Chen W.
      • Chen C.L.
      • Hu J.T.
      • Liu C.J.
      • et al.
      Vitamin D receptor gene polymorphisms and distinct clinical phenotypes of hepatitis B carriers in Taiwan.
      ]. Variation in ApaI, and to a lesser extent TaqI, is also associated with a higher HBV viral load and more severe fibrosis and necroinflammation [
      • Suneetha P.V.
      • Sarin S.K.
      • Goyal A.
      • Kumar G.T.
      • Shukla D.K.
      • Hissar S.
      Association between vitamin D receptor, CCR5, TNF-α and TNF-β gene polymorphisms and HBV infection and severity of liver disease.
      ]. Variation in the TaqI VDR polymorphism is also associated with both chronic HBV infection [
      • Bellamy R.
      • Ruwende C.
      • Corrah T.
      • McAdam K.P.
      • Thursz M.
      • Whittle H.C.
      • et al.
      Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene.
      ] and occult HBV infection [
      • Arababadi M.K.
      • Pourfathollah A.A.
      • Jafarzadeh A.
      • Hassanshahi G.
      • Rezvani M.E.
      Association of exon 9 but not intron 8 VDR polymorphisms with occult HBV infection in south-eastern Iranian patients.
      ], in which there is a low degree of HBV replication present in HBsAg negative subjects.
      In hepatocellular carcinoma (HCC), complicating cirrhosis variation in the allele frequency of the BsmI, ApaI, and TaqI, but not FokI VDR polymorphisms is associated with HCC development when compared to cirrhotic patients without HCC. This association is most marked in subjects with alcohol-related cirrhosis, where carriage of the BsmIApaITaqI A–T–C and G–T–T haplotypes is independently associated with an increased risk of HCC. Furthermore, there is a significant difference in allele frequency of these VDR polymorphisms in alcohol-related cirrhosis compared to cirrhosis complicating chronic viral hepatitis [
      • Falleti E.
      • Bitetto D.
      • Fabris C.
      • Cussigh A.
      • Fontanini E.
      • Fornasiere E.
      • et al.
      Vitamin D receptor gene polymorphisms and hepatocellular carcinoma in alcoholic cirrhosis.
      ].
      Multiple studies have confirmed an association between VDR polymorphisms and autoimmune liver disease in both European and Asian populations. Variation in the allele frequency of the BsmI polymorphism is associated with primary biliary cirrhosis [
      • Halmos B.
      • Szalay F.
      • Cserniczky T.
      • Nemesanszky E.
      • Lakatos P.
      • Barlage S.
      • et al.
      Association of primary biliary cirrhosis with vitamin D receptor BsmI genotype polymorphism in a Hungarian population.
      ,
      • Tanaka A.
      • Nezu S.
      • Uegaki S.
      • Kikuchi K.
      • Shibuya A.
      • Miyakawa H.
      • et al.
      Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations.
      ], while variation of the FokI polymorphism is associated with autoimmune hepatitis [
      • Fan L.
      • Tu X.
      • Zhu Y.
      • Zhou L.
      • Pfeiffer T.
      • Feltens R.
      • et al.
      Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese.
      ,
      • Vogel A.
      • Strassburg C.P.
      • Manns M.P.
      Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis.
      ]. Furthermore, carriage of the VDR BsmITaqI G–T/G–T diplotype is an independent predictor of acute cellular rejection post-liver transplantation [
      • Bitetto D.
      • Cussigh A.
      • Fornasiere E.
      • Cmet S.
      • Fontanini E.
      • Bignulin E.
      • et al.
      Recipient vitamin D receptor BsmI–TaqI G–T/G–T diplotype predicts acute cellular rejection in liver transplanted patients.
      ]. Similarly, VDR polymorphisms are associated with a variety of other autoimmune and immune-mediated diseases, including type 1 diabetes [
      • McDermott M.F.
      • Ramachandran A.
      • Ogunkolade B.W.
      • Aganna E.
      • Curtis D.
      • Boucher B.J.
      • et al.
      Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians.
      ], leprosy [
      • Roy S.
      • Frodsham A.
      • Saha B.
      • Hazra S.K.
      • Mascie-Taylor C.G.
      • Hill A.V.
      Association of vitamin D receptor genotype with leprosy type.
      ], Crohn’s disease [
      • Simmons J.D.
      • Mullighan C.
      • Welsh K.I.
      • Jewell D.P.
      Vitamin D receptor gene polymorphism: association with Crohn’s disease susceptibility.
      ], tuberculosis [
      • Bellamy R.
      • Ruwende C.
      • Corrah T.
      • McAdam K.P.
      • Thursz M.
      • Whittle H.C.
      • et al.
      Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene.
      ,
      • Wilkinson R.J.
      • Llewelyn M.
      • Toossi Z.
      • Patel P.
      • Pasvol G.
      • Lalvani A.
      • et al.
      Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study.
      ], psoriasis [
      • Park B.S.
      • Park J.S.
      • Lee D.Y.
      • Youn J.I.
      • Kim I.G.
      Vitamin D receptor polymorphism is associated with psoriasis.
      ], multiple sclerosis [
      • Fukazawa T.
      • Yabe I.
      • Kikuchi S.
      • Sasaki H.
      • Hamada T.
      • Miyasaka K.
      • et al.
      Association of vitamin D receptor gene polymorphism with multiple sclerosis in Japanese.
      ], and Graves’ disease [
      • Ban Y.
      • Taniyama M.
      • Ban Y.
      Vitamin D receptor gene polymorphism is associated with Graves’ disease in the Japanese population.
      ] (Table 4).
      Table 4Genetic variation in vitamin D and disease.

      Vitamin D, the immune system, and the liver

      There is an increased incidence and prevalence of autoimmune diseases such as type I diabetes, multiple sclerosis (MS) and Crohn’s disease in geographic regions at higher latitude [
      • Cantorna M.T.
      • Zhu Y.
      • Froicu M.
      • Wittke A.
      Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system.
      ,
      • Ponsonby A.L.
      • McMichael A.
      • van der Mei I.
      Ultraviolet radiation and autoimmune disease: insights from epidemiological research.
      ]. This phenomenon is suggested to be related to lower 25(OH)D levels resulting from decreased ultraviolet sunlight exposure. In support of this hypothesis, the incidence of MS decreases with increasing 25(OH)D levels [
      • Munger K.L.
      • Levin L.I.
      • Hollis B.W.
      • Howard N.S.
      • Ascherio A.
      Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.
      ] and vitamin D supplementation decreases the risk of developing both MS in women [
      • Munger K.L.
      • Zhang S.M.
      • O’Reilly E.
      • Hernán M.A.
      • Olek M.J.
      • Willett W.C.
      • et al.
      Vitamin D intake and incidence of multiple sclerosis.
      ] and type 1 diabetes in children by 80% [
      • Hyppönen E.
      • Läärä E.
      • Reunanen A.
      • Järvelin M.R.
      • Virtanen S.M.
      Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study.
      ]. In this context, vitamin D has an important role in both the innate and adaptive immune system [
      • Bikle D.D.
      Vitamin D and the immune system: role in protection against bacterial infection.
      ]. Macrophages, T cells, and DCs express both 1α-hydroxylase and vitamin D receptor, and are thus direct targets of 25(OH)D and 1,25(OH)2D [
      • Adams S.
      • Sharma O.P.
      • Gacad M.A.
      • Singer F.R.
      Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis.
      ,
      • Baeke F.
      • Korf H.
      • Overbergh L.
      • van Etten E.
      • Verstuyf A.
      • Gysemans C.
      • et al.
      Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system.
      ,
      • Sigmundsdottir H.
      • Pan J.
      • Debes G.F.
      • Alt C.
      • Habtezion A.
      • Soler D.
      • et al.
      DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27.
      ].

      Innate immunity

      The innate immune response is mediated by pattern-recognition receptors (PRR). Toll-like receptors (TLR) are a family of transmembrane PRRs with broad specificity, expressed on immune cells such as polymorphonuclear cells, monocytes, and macrophages. They interact with pathogen-associated molecular patterns such as viral nucleic acids, and bacterial and fungal products, to trigger an inflammatory (TNF, IL-1β, and IL-6) or antimicrobial response in the host [
      • Medzhitov R.
      Recognition of microorganisms and activation of the immune response.
      ]. Several data from studies focusing on the immunology of mycobacterial infection suggest vitamin D and DBP play a significant part in the activation of the innate immune response. The risk of Mycobacterium tuberculosis (TB) infection is increased in subjects with vitamin D deficiency, with the greatest risk observed in subjects with the lowest 25(OH)D levels [
      • Wilkinson R.J.
      • Llewelyn M.
      • Toossi Z.
      • Patel P.
      • Pasvol G.
      • Lalvani A.
      • et al.
      Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study.
      ,
      • Ustianowski A.
      • Shaffer R.
      • Collin S.
      • Wilkinson R.J.
      • Davidson R.N.
      Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London.
      ,
      • Nnoaham K.E.
      • Clarke A.
      Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis.
      ,
      • Gibney K.B.
      • MacGregor L.
      • Leder K.
      • Torresi J.
      • Marshall C.
      • Ebeling P.R.
      • et al.
      Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa.
      ]. At a cellular level, macrophages infected with M. tuberculosis initiate a TLR2/1 response that enhances 1α-hydroxylase and VDR expression and induction of the anti-microbial peptide cathelicidin. The anti-microbial activity of macrophages occurs via a vitamin D-dependent process. Addition of 1α,25(OH)2D to M. tuberculosis-infected macrophages reduces the number of viable bacilli, while both vitamin D and TLR2/1 are required for cathelicidin production [
      • Liu P.T.
      • Stenger S.
      • Li H.
      • Wenzel L.
      • Tan B.H.
      • Krutzik S.R.
      • et al.
      Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
      ]. DBP plays a key role in modulating monocyte responses to 25(OH)D and 1α,25(OH)2D, that varies according to the DBP genotype. Notably, monocytes cultured in serum from DBP null mice, and in human serum with the lower affinity Gc1S and Gc2 DBP isoforms, have more potent induction of cathelicidin than monocytes cultured in serum from DBP+/− mice or human serum with the high affinity Gc1F isoform [
      • Chun R.F.
      • Lauridsen A.L.
      • Suon L.
      • Zella L.A.
      • Pike J.W.
      • Modlin R.L.
      • et al.
      Vitamin D-binding protein directs monocyte response to 25-hydroxy- and 1,25-dihydroxyvitamin D.
      ]. The Gc2 isoform is associated with lower 25(OH)D levels [
      • Lauridsen A.L.
      • Vestergaard P.
      • Hermann A.P.
      • Brot C.
      • Heickendorff L.
      • Mosekilde L.
      • et al.
      Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women.
      ,
      • Abbas S.
      • Linseisen J.
      • Slanger T.
      • Kropp S.
      • Mutschelknauss E.J.
      • Flesch-Janys D.
      • et al.
      The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status.
      ], and carriers of this allele have an increased susceptibility to active TB in the presence of severe vitamin D deficiency (<20 nmol/L) [
      • Martineau A.R.
      • Leandro A.C.
      • Anderson S.T.
      • Newton S.M.
      • Wilkinson K.A.
      • Nicol M.P.
      • et al.
      Association between Gc genotype and suspectibility to TB is dependent on vitamin D status.
      ]. The Gc2 isoform is less able to be converted into macrophage activating factor, resulting in reduced macrophage function [
      • Yamamoto N.
      • Homma S.
      Vitamin D3 binding protein (group-specific component) is a precursor for the macrophage-activating signal factor from lysophosphatidylcholine-treated lymphocytes.
      ]. These data indicate that vitamin D-dependent antimicrobial responses may be strongly influenced by genetic polymorphisms in DBP, especially in the presence of vitamin D deficiency. Moreover, adjunctive high-dose vitamin D significantly hastens the time to sputum culture conversion during intensive-phase antimicrobial treatment of pulmonary TB in the subset of patients with the tt genotype of the TaqI VDR polymorphism [
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • Hanifa Y.
      • Islam K.
      • Claxton A.P.
      • et al.
      High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomized controlled trial.
      ]. In addition, variation in allele frequency of the FokI and TaqI VDR polymorphisms in the presence of vitamin D deficiency is associated with increased risk of TB [
      • Bellamy R.
      • Ruwende C.
      • Corrah T.
      • McAdam K.P.
      • Thursz M.
      • Whittle H.C.
      • et al.
      Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene.
      ,
      • Wilkinson R.J.
      • Llewelyn M.
      • Toossi Z.
      • Patel P.
      • Pasvol G.
      • Lalvani A.
      • et al.
      Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study.
      ].
      The role of vitamin D in innate immunity has implications on liver disease. Chronic liver disease is characterized by ongoing increased exposure of the liver via the portal circulation to bacterial products such as lipopolysaccharide (LPS). Contributing factors include increased intestinal mucosal permeability, alcohol ingestion, and small bowel bacterial overgrowth [
      • Mencin A.
      • Kluwe J.
      • Schwabe R.F.
      Toll-like receptors as targets in chronic liver disease.
      ,
      • Fukui H.
      • Brauner B.
      • Bode J.C.
      • Bode C.
      Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay.
      ,
      • Parlesak A.
      • Schäfer C.
      • Schütz T.
      • Bode J.C.
      • Bode C.
      Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease.
      ]. Dietary factors, such as a high-fat diet that predisposes to NAFLD, may also contribute to increased intestinal permeability and result in increased hepatic exposure to LPS [
      • Cani P.D.
      • Amar J.
      • Iglesias M.A.
      • Poggi M.
      • Knauf C.
      • Bastelica D.
      • et al.
      Metabolic endotoxemia initiates obesity and insulin resistance.
      ]. Kupffer cells, the resident macrophages of the liver, represent 80–90% of the macrophages in the body [
      • Baffy G.
      Kupffer cells in non-alcoholic fatty liver disease: the emerging view.
      ], and their innate immune vitamin D-dependent antimicrobial response is also likely to be influenced by the vitamin D status and genetic polymorphisms in DBP. They also express TLR2, TLR4, and TLR9, and are responsive to LPS, the main ligand of TLR4. Hepatocytes, hepatic stellate cells, sinusoidal epithelial cells, biliary epithelial cells, and hepatic DCs also express TLR4 and are responsive to LPS. The interaction of LPS with TLR4 in the liver is crucial during hepatic fibrogenesis [
      • Mencin A.
      • Kluwe J.
      • Schwabe R.F.
      Toll-like receptors as targets in chronic liver disease.
      ,
      • Guo J.
      • Friedman S.L.
      Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis.
      ]. Serum vitamin D levels are inversely proportional to TLR2 and TLR4 expression in monocytes, with administration of 1α,25(OH)2D downregulating expression of TLR2, TLR4, and TLR9 [
      • Sadeghi K.
      • Wessner B.
      • Laggner U.
      • Ploder M.
      • Tamandl D.
      • Friedl J.
      • et al.
      Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns.
      ,
      • Do J.E.
      • Kwon S.Y.
      • Park S.
      • Lee E.S.
      Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet’s disease.
      ,
      • Murillo G.
      • Nagpal V.
      • Tiwari N.
      • Benya R.V.
      • Mehta R.G.
      Actions of vitamin D are mediated by the TLR4 pathway in inflammation-induced colon cancer.
      ,
      • Dickie L.J.
      • Church L.D.
      • Coulthard L.R.
      • Mathews R.J.
      • Emery P.
      • McDermott M.F.
      Vitamin D3 down-regulates intracellular Toll-like receptor 9-induced IL-6 production in human monocytes.
      ]. Intestinal microbiota play an essential role in hepatic fat accumulation. TLR2, TLR4, and TLR9 are implicated in the pathogenesis of NAFLD, with TLR4 and TLR9 signaling associated with worsening steatosis, inflammation and fibrosis [
      • Li L.
      • Chen L.
      • Hu L.
      • Liu Y.
      • Sun H.Y.
      • Tang J.
      • et al.
      Nuclear factor high-mobility group box1 mediating the activation of toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice.
      ,
      • Miura K.
      • Seki E.
      • Ohnishi H.
      • Brenner D.A.
      Role of toll-like receptors and their downstream molecules in the development of nonalcoholic fatty liver disease.
      ]. In obese rats, vitamin D deficiency increases hepatic mRNA levels of TLR2, TLR4, and TLR9, and the endotoxin receptor CD14, which is implicated in worsening histologic features of NAFLD [

      Roth CL, Elfers CT, Figlewicz DP, Melhorn SJ, Morton GJ, Hoofnagle A, et al. Vitamin D deficiency in obese rats exacerbates NAFLD and increases hepatic resistin and toll-like receptor activation. Hepatology 2011 Oct 12. doi: http://dx.doi.org/10.1002/hep.24737. [Epub ahead of print].

      ]. In CHC infection, increasing hepatic necroinflammatory activity correlates with increasing hepatic mRNA expression of TLR2 and TLR4, and hepatic TNFα mRNA is also closely correlated with TLR2 and TLR4 mRNA expression [
      • Berzsenyi M.D.
      • Roberts S.K.
      • Preiss S.
      • Woollard D.J.
      • Beard M.R.
      • Skinner N.A.
      • et al.
      Hepatic TLR2 & TLR4 expression correlates with hepatic inflammation and TNF-α in HCV & HCV/HIV infection.
      ]. Furthermore, the antiviral effect of vitamin D on hepatitis C inoculated HuH7.5 hepatoma cells is mediated by innate immune system activation of the interferon-mediated signaling pathways [
      • Gal-Tanamy M.
      • Bachmetov L.
      • Ravid A.
      • Koren R.
      • Erman A.
      • Tur-Kaspa R.
      • et al.
      Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes.
      ].
      NK cells and DCs are both important innate immune effector cells. Studies in VDR knockout mice have shown that expression of VDR is necessary for NK cell development and function [
      • Yu S.
      • Cantorna M.T.
      The vitamin D receptor is required for iNKT cell development.
      ]. 1α,25(OH)2D enhances NK cell cytotoxicity [
      • Lee J.H.
      • Park S.
      • Cheon S.
      • Lee J.H.
      • Kim S.
      • Hur D.Y.
      • et al.
      1,25-Dihydroxyvitamin D3 enhances NK susceptibility of human melanoma cells via Hsp60-mediated FAS expression.
      ] and suppresses DC maturation, inducing a more tolerant DC phenotype which, at the interface of the innate and adaptive immune systems, promotes T regulatory (Treg, CD4+CD25+) cell activity [
      • Hewison M.
      Vitamin D and immune function: an overview.
      ].

      Adaptive immunity

      Vitamin D is an important modulator of T cell response to pathogens, which is a key component of adaptive immunity. In particular, activation of naïve T cells is a vitamin D-dependent process. In the inactivated state, naïve T cells do not express VDR and express almost no phospholipase C-γ1 (PLCγ1), which is a key molecule required for subsequent classical T cell receptor signaling and T cell activation. Following stimulus exposure, VDR is expressed on T cells through T cell receptor signaling via the alternative mitogen-activated kinase p38 pathway. The VDR complex, activated by binding of 1α,25(OH)2D, upregulates transcription of the gene encoding PLCγ1 and results in a 75-fold increase in PLCγ1 expression, enabling activation of naïve T cells. T cells in patients with lower 25(OH)D and 1α,25(OH)2D levels have a lower proliferation index after stimulation than T cells from patients with normal 25(OH)D and 1α,25(OH)2D levels; this pattern is overcome by exogenous administration of 1α,25(OH)2D [
      • von Essen M.R.
      • Kongsbak M.
      • Schjerling P.
      • Olgaard K.
      • Odum N.
      • Geisler C.
      Vitamin D controls T cell antigen receptor signaling and activation of human T cells.
      ].
      1α,25(OH)2D also has an anti-proliferative effect on adaptive immunity. It inhibits proliferation of T helper type 1 (Th1) lymphocytes, which produce interferon (IFN)-γ, interleukin (IL)-2, and activate macrophages [
      • Lemire J.M.
      • Archer D.C.
      • Beck L.
      • Spiegelberg H.L.
      Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions.
      ], and shifts the balance to a T helper type 2 (Th2) phenotype with increased production of IL-4, IL-5, and IL-10 [
      • Boonstra A.
      • Barrat F.J.
      • Crain C.
      • Heath V.L.
      • Savelkoul H.F.
      • O’Garra A.
      1α,25-dihydroxyvitamin D3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells.
      ]. 1α,25(OH)2D increases Treg cells [
      • Penna G.
      • Adorini L.
      1α,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation.
      ,
      • Daniel C.
      • Sartory N.A.
      • Zahn N.
      • Radeke H.H.
      • Stein J.M.
      Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile.
      ], enhances DC secretion of IL-10, decreases DC secretion of IL-12, a critical cytokine in Th1 development [
      • D’Ambrosio D.
      • Cippitelli M.
      • Cocciolo M.G.
      • Mazzeo D.
      • Di Lucia P.
      • Lang R.
      • et al.
      Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene.
      ], and inhibits Th17 development via inhibition of IL-6 and IL-23 production [
      • Daniel C.
      • Sartory N.A.
      • Zahn N.
      • Radeke H.H.
      • Stein J.M.
      Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile.
      ]. In patients with MS, 25(OH)D, but not 1α,25(OH)2D, levels correlate with the ability of Treg cells to suppress the proliferation of activated T responder cells and inversely correlated with Th1/Th2 ratio [
      • Smolders J.
      • Menheere P.
      • Thewissen M.
      • Peelen E.
      • Tervaert J.W.
      • Hupperts R.
      • et al.
      Regulatory T cell function correlates with serum 25-hydroxyvitamin D, but not with 1,25-dihydroxyvitamin D, parathyroid hormone and calcium levels in patients with relapsing remitting multiple sclerosis.
      ]. IL-2, IL-10, and IL-12 genes in T cells have regions which bind to VDR and 1α,25(OH)2D may directly play a role in the transcription of these cytokines in T cells [
      • Matilainen J.M.
      • Räsänen A.
      • Gynther P.
      • Väisänen S.
      The genes encoding cytokines IL-2, IL-10 and IL-12B are primary 1α,25(OH)2D3 target genes.
      ]. The ability of 1α,25(OH)2D to modulate the adaptive immune system may explain the association of vitamin D supplementation and higher 25(OH)D levels with a lower risk of multiple autoimmune diseases.
      In orthotopic liver transplant recipients, severe 25(OH)D deficiency (<12.5 nmol/L) and VDR BsmITaqI G–T/G–T diplotype are independent predictors of moderate-severe acute cellular rejection, whilst vitamin D3 supplementation decreases the risk of acute rejection by 60% [
      • Bitetto D.
      • Cussigh A.
      • Fornasiere E.
      • Cmet S.
      • Fontanini E.
      • Bignulin E.
      • et al.
      Recipient vitamin D receptor BsmI–TaqI G–T/G–T diplotype predicts acute cellular rejection in liver transplanted patients.
      ,
      • Bitetto D.
      • Fabris C.
      • Falleti E.
      • Fornasiere E.
      • Fumolo E.
      • Fontanini E.
      • et al.
      Vitamin D and the risk of acute allograft rejection following human liver transplantation.
      ]. These findings highlight the importance of optimizing the vitamin D status in liver transplant recipients, not only to prevent bone loss, but also to reduce the risk of T cell-mediated acute rejection. A lower Th1/Th2 ratio is an independent predictor of SVR in treatment of HCV-1 [
      • Shirakawa H.
      • Matsumoto A.
      • Joshita S.
      • Komatsu M.
      • Tanaka N.
      • Umemura T.
      • et al.
      Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors.
      ], which possibly explains why vitamin D supplementation may improve therapeutic outcomes with PEG-IFN plus RBV. The immune tolerant phenotype promoted by vitamin D may also be of therapeutic benefit in NASH, where activation of both innate and adaptive immunity is implicated in its pathogenesis.

      Genome wide association studies of vitamin D

      Only about a quarter of vitamin D variability between individuals is explained by factors such as reported dietary intake, latitude and season of measurement [
      • Livs hits G.
      • Karasik D.
      • Seibel M.J.
      Statistical genetic analysis of plasma levels of vitamin D: familial study.
      ,
      • Shea M.K.
      • Benjamin E.J.
      • Dupuis J.
      • Massaro J.M.
      • Jacques P.F.
      • D’Agostino Sr., R.B.
      • et al.
      Genetic and non-genetic correlates of vitamins K and D.
      ]. Twin and family studies suggest that genetic factors play a significant role in the wide variation of vitamin D levels observed within and between populations [
      • Hunter D.
      • De Lange M.
      • Snieder H.
      • MacGregor A.J.
      • Swaminathan R.
      • Thakker R.V.
      • et al.
      Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation.
      ]. Polymorphisms of the hydroxylases, DBP, and VDR may have a profound influence on serum vitamin D levels and the efficacy of vitamin D as a hormone. Two large genome wide association studies (GWAS), involving patients of European ancestry [
      • Wang T.J.
      • Zhang F.
      • Richards J.B.
      • Kestenbaum B.
      • van Meurs J.B.
      • Berry D.
      • et al.
      Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
      ,
      • Ahn J.
      • Yu K.
      • Stolzenberg-Solomon R.
      • Simon K.C.
      • McCullough M.L.
      • Gallicchio L.
      • et al.
      Genome-wide association study of circulating vitamin D levels.
      ], of SNPs and their association with 25(OH)D levels have revealed important information about genetic variation in the enzymes and carrier proteins which are integral to the synthesis and metabolism of vitamin D.
      The NADSYN1/DHCR7 locus is closely related to the de novo synthesis of vitamin D3 in the skin from the precursor 7-dehydrocholesterol. There is an association between 25(OH)D levels and several SNPs including rs12785878, rs12800438, rs3794060, rs4945008, and rs4944957 of this locus [
      • Matilainen J.M.
      • Räsänen A.
      • Gynther P.
      • Väisänen S.
      The genes encoding cytokines IL-2, IL-10 and IL-12B are primary 1α,25(OH)2D3 target genes.
      ]. SNPs in the 25-hydroxylase CYP2R1 locus rs10741657, rs2060793, rs12794714, rs10500804, and rs7116978 are also significantly associated with 25(OH)D levels [
      • Shea M.K.
      • Benjamin E.J.
      • Dupuis J.
      • Massaro J.M.
      • Jacques P.F.
      • D’Agostino Sr., R.B.
      • et al.
      Genetic and non-genetic correlates of vitamins K and D.
      ,
      • Hunter D.
      • De Lange M.
      • Snieder H.
      • MacGregor A.J.
      • Swaminathan R.
      • Thakker R.V.
      • et al.
      Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation.
      ].
      The highly polymorphic vitamin D-binding protein binds the majority of 25(OH)D and 1α,25(OH)2D. DBP is predominantly produced in the liver, but also in kidney, gonads, fat, and neutrophils. SNPs in the DBP locus associated with 25(OH)D levels are rs2282679, rs7041, rs3755967, rs17467825, rs2298850, and rs1155563 [
      • Matilainen J.M.
      • Räsänen A.
      • Gynther P.
      • Väisänen S.
      The genes encoding cytokines IL-2, IL-10 and IL-12B are primary 1α,25(OH)2D3 target genes.
      ,
      • Bitetto D.
      • Fabris C.
      • Falleti E.
      • Fornasiere E.
      • Fumolo E.
      • Fontanini E.
      • et al.
      Vitamin D and the risk of acute allograft rejection following human liver transplantation.
      ,
      • Shirakawa H.
      • Matsumoto A.
      • Joshita S.
      • Komatsu M.
      • Tanaka N.
      • Umemura T.
      • et al.
      Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors.
      ]. Response to vitamin D supplementation may vary with differing genotypes of DBP [
      • Fu L.
      • Yun F.
      • Oczak M.
      • Wong B.Y.
      • Vieth R.
      • Cole D.E.
      Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation.
      ,
      • Chun R.F.
      • Peercy B.E.
      • Adams J.S.
      • Hewison M.
      Vitamin D binding protein and monocyte response to 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D: analysis by mathematical modeling.
      ]. In addition to the three common isoforms Gc1F, Gc1S, and Gc2, there are >120 rare variants of DBP. Haplotypes of the SNPs rs4588 and rs7041 in exon 11 of the gene result in the Gc1F, Gc1S, and Gc2 isoforms, which have differing affinities for vitamin D [
      • Chishimba L.
      • Thickett D.R.
      • Stockley R.A.
      • Wood A.M.
      The vitamin D axis in the lung: a key role for vitamin D-binding protein.
      ]. The DBP SNP rs2282679, which has the strongest association with vitamin D levels, lies in intron 12 near the actin subdomain III and may affect DBP binding of 25(OH)D [
      • Ahn J.
      • Yu K.
      • Stolzenberg-Solomon R.
      • Simon K.C.
      • McCullough M.L.
      • Gallicchio L.
      • et al.
      Genome-wide association study of circulating vitamin D levels.
      ].
      24-hydroxylase (CYP24A1) is primarily responsible for the inactivation of 25(OH)D and 1α,25(OH)2D. The SNP rs6013897 from this locus is also associated with vitamin D levels [
      • Wang T.J.
      • Zhang F.
      • Richards J.B.
      • Kestenbaum B.
      • van Meurs J.B.
      • Berry D.
      • et al.
      Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
      ].
      These studies highlight the importance of genetic variation in vitamin D status and may explain in part the varying response seen to vitamin D supplementation. Polymorphisms in four specific loci involved in vitamin D synthesis and metabolism have a significant impact on circulating 25(OH)D levels in patients of European ancestry. Further GWAS that include patients of more diverse racial backgrounds may reveal more genetic associations with the vitamin D status.

      Vitamin D and cancer

      Vitamin D is also associated with the development of neoplasia. Higher 25(OH)D levels are associated with a lower risk of incident left-sided colorectal adenomas [
      • Yin L.
      • Grandi N.
      • Raum E.
      • Haug U.
      • Arndt V.
      • Brenner H.
      Meta-analysis: serum vitamin D and colorectal adenoma risk.
      ]. Multiple meta-analyses, and large prospective and retrospective observational studies have established that vitamin D deficiency is associated with an increased risk of colon [
      • Feskanich D.
      • Ma J.
      • Fuchs C.S.
      • Kirkner G.J.
      • Hankinson S.E.
      • Hollis B.W.
      • et al.
      Plasma vitamin D metabolites and risk of colorectal cancer in women.
      ,
      • Gorham E.D.
      • Garland C.F.
      • Garland F.C.
      • Grant W.B.
      • Mohr S.B.
      • Lipkin M.
      • et al.
      Optimal vitamin D status for colorectal cancer prevention.
      ,
      • Yin L.
      • Grandi N.
      • Raum E.
      • Haug U.
      • Arndt V.
      • Brenner H.
      Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk.
      ,
      • Giovannucci E.
      Epidemiology of vitamin D and colorectal cancer: casual or causal link?.
      ], breast [
      • Garland C.F.
      • Garland F.C.
      • Gorham E.D.
      • Lipkin M.
      • Newmark H.
      • Mohr S.B.
      • et al.
      The role of vitamin D in cancer prevention.
      ,
      • Abbas S.
      • Linseisen J.
      • Slanger T.
      • Kropp S.
      • Mutschelknauss E.J.
      • Flesch-Janys D.
      • et al.
      Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer – results of a large case–control study.
      ,
      • Yin L.
      • Grandi N.
      • Raum E.
      • Haug U.
      • Arndt V.
      • Brenner H.
      Meta-analysis: serum vitamin D and breast cancer risk.
      ], and prostate cancer [
      • Ahonen M.H.
      • Tenkanen L.
      • Teppo L.
      • Hakama M.
      • Tuohimaa P.
      Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland).
      ,
      • Ahn J.
      • Albanes D.
      • Berndt S.I.
      • Peters U.
      • Chatterjee N.
      • Freedman N.D.
      • et al.
      Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk.
      ]. Furthermore, increased sunlight exposure is associated with a reduced risk of non-Hodgkin’s lymphoma [
      • Chang E.T.
      • Smedby K.E.
      • Hjalgrim H.
      • Porwit-MacDonald A.
      • Roos G.
      • Glimelius B.
      • et al.
      Family history of hematopoietic malignancy and risk of lymphoma.
      ] and VDR polymorphisms are associated with adenocarcinoma in the colon [
      • Touvier M.
      • Chan D.S.
      • Lau R.
      • Aune D.
      • Vieira R.
      • Greenwood D.C.
      • et al.
      Meta-analyses of vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms, and colorectal cancer risk.
      ], ovary [
      • Lurie G.
      • Wilkens L.R.
      • Thompson P.J.
      • Carney M.E.
      • Palmieri R.T.
      • Pharaoh P.D.
      • et al.
      Vitamin D receptor rs2228570 polymorphism and invasive ovarian carcinoma risk: pooled analysis in five studies within the Ovarian Cancer Association Consortium.
      ], breast, prostate, renal cell carcinoma, and melanoma [
      • Köstner K.
      • Denzer N.
      • Müller C.S.
      • Klein R.
      • Tilgen W.
      • Reichrath J.
      The relevance of vitamin D receptor (VDR) gene polymorphisms for cancer: a review of the literature.
      ]. With respect to the liver, a variety of VDR polymorphisms are associated with the development of HCC in at-risk patients as detailed above. However, it remains unclear as to whether vitamin D deficiency is associated with an increased risk of HCC.

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