Can Hep C Cause Vitamin D Deficiency

Can Hep C Cause Vitamin D Deficiency

Summary

Vitamin D is increasingly becoming recognized as an important physiological regulator with pleiotropic functions outside of its classical role in skeletal homeostasis. A growing body of clinical evidence highlights the prevalence and risks of vitamin D deficiency in patients suffering from chronic hepatitis C infection, and vitamin D supplementation has been proposed as an adjunct to current standards of care. This review considers the experimental evidence for the anti-inflammatory, antifibrotic and antiviral effects of vitamin D, and discusses the therapeutic potential of vitamin D supplementation to protect against liver disease progression and improve responses to treatment.

Abbreviations:

HCV (hepatitis C virus), SVR (sustained virological response), 25(OH)D (25-hydroxyvitamin D), 1,25(OH)2D (1,25-dihydroxyvitamin D), VDR (vitamin D receptor), RXR (retinoid X receptor), VDREs (vitamin D response elements), PTH (parathyroid hormone), TLR (toll-like receptor), TNFR (tumor necrosis factor receptor)

Keywords

• Hepatitis C
• Vitamin D
• 25(OH)D
• 1,25(OH)2D
• Inflammation

Introduction

Advances in hepatitis C virus (HCV) pharmaceutical development are being made at a blistering pace; however, highly effective, non-toxic therapies remain a hope for the future. This leaves an immediate need for interventions that can minimize disease progression and/or improve sustained virological response (SVR) rates in the short term. The aging of the HCV-positive population is creating an epidemic of end stage liver disease. Many patients cannot wait for second and third generation direct acting antiviral drugs to reach the clinic. As an interim measure, vitamin D supplements have been proposed as an adjunct to pegylated-interferon and ribavirin. This review integrates the known biological effects of the vitamin D system with recent clinical findings and discusses the therapeutic potential of vitamin D supplementation in HCV-positive patients.

Vitamin D metabolism

Unlike most vitamins, vitamin D is neither an enzyme co-factor nor an essential nutrient that must be obtained from food. Rather, it is a precursor of a seco-steroid hormone. Vitamin D can be manufactured endogenously from 7-dehydrocholesterol when skin is exposed to ultraviolet B radiation (Fig. 1). Historically, sun exposure was the main source of vitamin D, but food and supplements are now important sources, especially among urban populations and people who work indoors. During its conversion from a precursor to an active hormone, vitamin D is first modified in the liver by microsomal vitamin D 25-hydroxylases, which form 25-hydroxyvitamin D [25(OH)D], a stable metabolite that is the best single indicator of vitamin D status [

]. A second hydroxylation step, mediated by the mitochondrial cytochrome P450 oxidase, CYP27B1, produces the most biologically active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)₂D]. In individuals with adequate renal function, most of the circulating 1,25(OH)₂D is produced by the kidney; however, CYP27B1 activity occurs in many extra-renal tissues, including innate immune cells, such as macrophages and dendritic cells. The local metabolism of 25(OH)D by these cells is likely to be an important factor in generating the high local concentrations of 1,25(OH)₂D needed for its paracrine and autocrine activities.

Fig. 1 Vitamin D is obtained from dietary sources and through the photochemical conversion of 7-dehydrocholesterol in the skin. It binds to vitamin D-binding protein and is transported to the liver, where it is hydroxylated by 25-hydroxylases to form 25(OH)D, a stable metabolite that is the best single indicator of vitamin D status. A second hydroxylation step, mediated by the 1a-hydroxylase CYP27B1 in the kidneys and other extrarenal tissues, produces the most active metabolite 1,25(OH)₂D, which signals primarily through the VDR, resulting in pleiotropic physiological effects, as highlighted in the Fig. 1,25(OH)₂D is catabolized by CPY24A1 to its inactive metabolite, calcitroic acid.

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1,25(OH)₂D mediates most of its biological effects by binding to the vitamin D receptor (VDR), which is expressed at some level in almost all human tissues. In the absence of its ligand, the VDR largely exists as an inactive homodimer. Upon binding 1,25(OH)₂D, the VDR is phosphorylated and forms a heterodimer with its preferred binding partner, the retinoid X receptor (RXR), forming a nuclear transcription factor. This VDR/RXR heterodimer binds vitamin D response elements (VDREs) in DNA and recruits co-regulatory protein complexes to modulate the expression of hundreds of genes. In addition to acting as a ligand-activated transcription factor, the VDR is also thought to activate cell signaling pathways independent of its genomic effects [

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The multiple steps in vitamin D bioactivation are controlled by intricate regulatory pathways [

]. CYP27B1 expression in the renal proximal tubule is stimulated by the parathyroid hormone (PTH), which is regulated by free serum calcium levels. 1,25(OH)₂D itself can directly and indirectly inhibit CYP27B1 expression, thereby providing a tight negative feedback loop. CYP27B1 expression in keratinocytes is stimulated by both PTH and inflammatory cytokines such as TNFα and IFNγ. 1,25(OH)₂D negatively regulates its own activity in these cells by inducing the expression of the 1,25(OH)₂D catabolic enzyme, CYP24A1. The functional expression of CYP27B1 and intracellular synthesis of 1,25(OH)₂D in macrophages are induced by both inflammatory cytokines, such as IFNγ, and toll-like receptor (TLR) ligands, such as lipopolysaccharide. Because vitamin D metabolism is controlled by multiple factors, the amount of vitamin D consumed in the diet is only one of many variables that determine the local activity of the vitamin D system. The levels of vitamin D binding protein and VDR are additional variables that strongly influence the magnitude of the biological effects of vitamin D.

VDR activation by 1,25(OH)₂D has long been known to increase intestinal calcium and phosphate absorption, fostering healthy bones. A growing number of recent studies reveal pleiotropic roles of 1,25(OH)₂D beyond bone and calcium metabolism, including the induction of antimicrobial genes and the reduction of inflammation and fibrogenesis [

]. Given the prevalence of bone disease, inflammation, and fibrosis in HCV-positive patients, both classical and newly-discovered effects of vitamin D may be relevant to disease management.

Vitamin D deficiency in patients with liver disease

Knowledge of the widespread physiological importance of vitamin D raises concern about the risks of vitamin D deficiency. Focusing on bone, several groups have attempted to identify markers that can be used to determine whether a patient's vitamin D status is optimal. A panel assembled by the Institute of Medicine (IOM) determined that a serum 25(OH)D concentration of 20 ng/ml is sufficient for the majority of healthy adults, but also determined that a concentration of 16 ng/ml is insufficient for about 50% of healthy adults, suggesting that there is very little margin of error at a 25(OH)D level of 20 ng/ml [

]. A panel from the Endocrine Society concluded that 32 ng/ml should be used as the threshold of 25(OH)D sufficiency in patients with various disease conditions [

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]. It is not clear whether the optimal level of 25(OH)D is the same for adults of all racial groups, which may be an important issue when considering these guidelines.

While serum levels of 25(OH)D are the best single surrogate marker of vitamin D status, PTH levels provide a second useful marker, and skeletal homeostasis is influenced by the combined effect of these two hormones. There is high inter-individual variability in the relationship between 25(OH)D and PTH levels. With serial testing, a patient's vitamin D status can be optimized by increasing vitamin D supplements until a 25(OH)D level is reached that maximally suppresses PTH. This approach is time consuming and costly, and the financial burden of widespread vitamin D testing is becoming recognized as an increasingly significant issue [

]. Some have advocated that screening efforts should be focused on specific high risk individuals; however, a recent study has shown that 25% of a group of young physicians had 25(OH) D levels below 20 ng/ml, despite their lack of established risk factors [

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It is important to keep in mind that the estimates of the 25(OH)D levels needed for optimal health are based exclusively on skeletal outcomes. The levels required for the non-classical functions of vitamin D have yet to be established and are under dispute [

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A large number of studies have examined the relationship between the vitamin D status of patients with chronic hepatitis C and disease outcome [

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Vitamin D as a down-modulator of inflammation

Chronic HCV infection is associated with intrahepatic inflammation and enhanced circulating levels of multiple inflammatory cytokines including members of the TNF superfamily, a complex group of ligands and receptors that are involved in cell survival, death and differentiation. Circulating TNFα and soluble TNF receptor (TNFR) levels are elevated in patients with chronic HCV relative to controls, and serum TNFR levels correlate with the grade of liver inflammation [

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Hepatic TNFα expression is highly correlated with hepatic toll-like receptor (TLR)2 and TLR4 expression in HCV-infected patients [

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Another proinflammatory factor that is strongly associated with HCV infection is the chemokine CXCL10 (a.k.a., interferon gamma-inducible protein 10), which exhibits strong chemotactic effects on effector T cells. CXCL10 levels are elevated in HCV-positive patients compared with healthy controls and correlate with viral load, ALT elevations, and the extent of hepatic inflammation [

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If proinflammatory cytokines and chemokines promote HCV persistence and disease progression, vitamin D's anti-inflammatory effects may be beneficial. These effects are illustrated by studies showing that treatment of human monocytes, macrophages and myeloid dendritic cells with 1,25(OH)₂D downregulates TLR expression, reduces the production of multiple inflammatory factors, including TNFα and CXCL10, and promotes a more tolerogenic phenotype [

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Vitamin D as a downregulator of fibrogenesis

Progressive liver fibrosis is a dreaded consequence of HCV infection. Advanced fibrosis/cirrhosis is associated with reduced virologic response rates [

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Vitamin D and the response to antiviral treatment

The anti-inflammatory and anti-fibrotic roles of vitamin D indicate that vitamin D has the potential to reduce HCV-mediated liver disease and, perhaps, to positively contribute to treatment outcome. It is well established that vitamin D plays an important antibacterial role by regulating cathelicidin expression in human monocytes [

]. A number of studies now suggest that vitamin D may also have analogous effects, as evidenced by the fact that vitamin D and its metabolites can synergize with IFN treatment to directly inhibit HCV RNA replication in vitro [

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Conclusions

Vitamin D is increasingly becoming recognized as an important physiological regulator with pleiotropic effects. A growing body of experimental and clinical evidence suggests that vitamin D deficiency is a risk factor in HCV-infected patients and that vitamin D supplementation might protect against liver disease progression and improve responses to treatment. There is still a lack of consensus on optimal 25(OH)D target levels and dosing strategies. The existing evidence highlights the need for additional well-designed clinical trials to evaluate the effects of vitamin D supplementation. The outcomes should include effects on the fibrosis progression rate (in patients with ongoing HCV replication and in patients who achieve a SVR), the incidence of hepatocellular carcinoma, and the incidence of bone fractures. In light of data showing protective effects of vitamin D supplementation in preventing influenza virus infection [

], studies of vitamin D supplementation in HCV patients should also examine vaccine responses and susceptibility to infectious diseases. Given that the relationships between vitamin D and chronic inflammation and progressive hepatic fibrosis are not unique to HCV infection, and that vitamin D deficiency may also be a factor in other liver diseases [

], clinical trials to study the effects of vitamin D supplementation in HCV patients are likely to be broadly relevant to the field of hepatology. Although dose-response data are limited, many liver disease patients will likely require relatively high doses of nutritional vitamin D to achieve 25(OH)D levels above 20 ng/ml. Until clinical data are available, 4000 IU/day is a reasonable daily dose for patients with baseline 25(OH)D levels below 10 ng/ml and 2000 IU/day is an appropriate starting dose for patients with levels between 10 and 20 ng/ml.

Conflict of interest

The authors do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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Article Info

Publication History

Published online: August 06, 2012

Accepted: July 31, 2012

Received in revised form: July 30, 2012

Received: April 18, 2012

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DOI: https://doi.org/10.1016/j.jhep.2012.07.026

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© 2012 European Association for the Study of the Liver. Published by Elsevier Inc.

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