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Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2018; 24(4): 445-460
Published online Jan 28, 2018. doi: 10.3748/wjg.v24.i4.445
Vitamin D deficiency and hepatitis viruses-associated liver diseases: A literature review
Nghiem Xuan Hoan, Hoang Van Tong, Le Huu Song, Christian G Meyer, Thirumalaisamy P Velavan
Nghiem Xuan Hoan, Le Huu Song, Institute of Clinical Infectious Diseases, 108 Military Central Hospital, Hanoi 10004, Vietnam
Nghiem Xuan Hoan, Christian G Meyer, Thirumalaisamy P Velavan, Molecular Genetics of Infectious Diseases, Institute of Tropical Medicine, University of Tübingen, Tübingen 72074, Germany
Nghiem Xuan Hoan, Hoang Van Tong, Le Huu Song, Christian G Meyer, Thirumalaisamy P Velavan, Vietnamese-German Center of Medical Research (VG-CARE), Hanoi 10004, Vietnam
Hoang Van Tong, Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, Hanoi 10004, Vietnam
Christian G Meyer, Thirumalaisamy P Velavan, Medical Faculty, Duy Tan University, Da Nang, Vietnam
ORCID number: Nghiem Xuan Hoan (0000-0002-6426-7818); Hoang Van Tong (0000-0002-7170-8810); Le Huu Song (0000-0003-2056-8499); Christian G Meyer (0000-0001-5561-2985); Thirumalaisamy P Velavan (0000-0002-9809-9883).
Author contributions: Meyer CG and Velavan TP shared senior authorship; Hoan NX, Tong HV, Song LH, Meyer CG and Velavan TP searched the publications, extracted data, summarized data in tables and discussed the literature and wrote the review; all authors approved the final version of this review.
Conflict-of-interest statement: We declare that we have no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Thirumalaisamy P Velavan, PhD, Professor, Molecular Genetics of Infectious Diseases, Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, Tübingen 72074, Germany.
Telephone: +49-7071-2985981 Fax: +49-7071-294684
Received: November 28, 2017
Peer-review started: November 29, 2017
First decision: December 13, 2017
Revised: January 8, 2018
Accepted: January 16, 2018
Article in press: January 16, 2018
Published online: January 28, 2018


The secosteroid hormone vitamin D has, in addition to its effects in bone metabolism also functions in the modulation of immune responses against infectious agents and in inhibiting tumorigenesis. Thus, deficiency of vitamin D is associated with several malignancies, but also with a plethora of infectious diseases. Among other communicable diseases, vitamin D deficiency is involved in the pathogenesis of chronic liver diseases caused by hepatitis B and C viruses (HBV, HCV) and high prevalence of vitamin D deficiency with serum levels below 20 mg/mL in patients with HBV and HCV infection are found worldwide. Several studies have assessed the effects of vitamin D supplementation on the sustained virological response (SVR) to interferon (IFN) plus ribavirin (RBV) therapy in HBV and HCV infection. In these studies, inconsistent results were reported. This review addresses general aspects of vitamin D deficiency and, in particular, the significance of vitamin D hypovitaminosis in the outcome of HBV- and HCV-related chronic liver diseases. Furthermore, current literature was reviewed in order to understand the effects of vitamin D supplementation in combination with IFN-based therapy on the virological response in HBV and HCV infected patients.

Key Words: Vitamin D, Vitamin D deficiency, Chronic liver disease, Hepatitis B virus infection, Hepatitis C virus infection, Liver cirrhosis, Hepatocellular carcinoma, Sustained virological response, Vitamin D supplementation

Core tip: Vitamin D deficiency is common and associated with chronic liver diseases. Several studies have ascribed a strong association of vitamin D insufficiency with unfavorable clinical courses and progression of liver disease in hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. However, any causal relation is so far not fully understood. In addition, there are inconsistent results with regard to the impact of vitamin D supplementation on the virological response to IFN-based therapy; this applies particularly to HCV infections. The present review addresses general aspects of vitamin D deficiency and focuses on its association with HBV and HCV infection. Furthermore, the effects of vitamin D supplementation in combination with IFN-based therapy on the virological response in HBV and HCV infected patients are reviewed.


Vitamin D deficiency affects almost one billion people globally[1]. Further to its crucial role in bone metabolism by supporting enteric absorption of calcium, magnesium, phosphate, iron and zinc, vitamin D has important non-skeletal effects which are involved in many biological processes. In addition to insufficient sun exposure, seasonality, place of residence, diet and the extent of skin pigmentation, which all affect vitamin D bioavailability, hepatitis B and C, the major causes of liver cirrhosis (LC) and hepatocellular carcinoma (HCC), may also contribute to vitamin D deficiency. Low vitamin D serum levels are associated with many human diseases[2,3] and frequently observed in chronic liver diseases; vitamin D constraints contribute to disease progression in chronic hepatitis B[4,5], chronic hepatitis C[6,7], but also to non-alcoholic fatty liver disease (NAFLD)[8-10]. Protective properties of vitamin D in preventing HBV and HCV replication and in retarding clinical progression of HBV/HCV-related liver diseases have been reported[11-14].

The prevalence of vitamin D insufficiency in patients with HBV and HCV infection covers the broad range from 16% up to 100%[5,15,16]. Several studies have demonstrated a strong association between vitamin D insufficiency and the clinical outcome and disease progression of HBV and HCV infections. This applies in particular to the onset of LC. However, the causal relation and applying pathophysiological mechanisms are not fully understood. Although increasing numbers of studies describe the influence of vitamin D deficiency on either the outcome of HBV/HCV-related liver disease or on the virological response to interferon (IFN)/ribavirin (RBV) treatment, the findings are still inconsistent[6,17-23] (Ref. 19:; identifier NCT01277601). Conflicting observations and conclusions apply also to several randomized clinical trials in which the effects of vitamin D supplementation were evaluated[24-29].

Here, we address general aspects of vitamin D deficiency and, in particular, focus on its association with HBV and HCV-related chronic liver disease. We also review the effects of vitamin D supplementation in combination with IFN-based therapy on the virological response in HBV and HCV infected patients.


A systematic literature search was conducted using PubMed, MEDLINE and (identifiers given where applicable). Search terms used in various combinations were “vitamin D”, “vitamin D deficiency”, “hepatitis B virus infection”, “hepatitis C virus infection”, “chronic liver disease”, “liver cirrhosis” and “hepatocellular carcinoma”. We did not restrict the search to a certain period of time. Thus, articles written in English and published in peer-reviewed journals describing associations of vitamin D deficiency with clinical outcomes or the effects of vitamin D in combination with IFN-based therapy on the virological response in HBV and HCV infected patients were included. Abstracts, letters and posters presented in conferences were not considered.


Vitamin D was first identified as a prohormone early in the 20th century. It is a fat-soluble secosteroid and regulates skeletal and non-skeletal functions[30]. Adequate vitamin D levels are required for bone growth and remodeling of osseous structures by osteoblasts and osteoclasts, thus protecting from osteoporosis[30,31]. Vitamin D promotes the absorption of calcium, magnesium, phosphate, iron and zinc from the gut and maintains essential serum calcium and phosphate concentrations to warrant normal bone mineralization and to prevent hypocalcaemia.

Since the discovery of the vitamin D receptor (VDR) the non-skeletal functions of vitamin D have gained attention. VDR is a member of the nuclear receptor family of transcription factors and is expressed on more than 35 types of solid tissues[32], but also on macrophages as well as on T and B cells[33,34]. Vitamin D is involved in physiological processes through VDR activation, including the regulation of immune responses, cell growth and cell differentiation[35,36]. Therefore, vitamin D is considered a powerful modulator of pathophysiological mechanisms in several infectious diseases, cancers and metabolic disorders[6,37-39].

Vitamin D occurs as vitamin D3 (25(OH)D3; cholecalciferol) and vitamin D2 (25(OH)D2; ergocalciferol). More than 90% of vitamin D3, the prevailing form of vitamin D, are produced in the skin by means of sunlight exposure, while the remainder is retrieved from dietary components[3,30]. Vitamin D2 does not depend on sunlight and only minute amounts of vitamin D2 are derived from plants[40]. Both vitamin D3 and D2 are inert. To become biologically active they need to be sequentially converted to their intermediate metabolite [calcidiol, 25(OH)D] and the final active form [calcitriol, 1,25(OH)2D] by hydroxylation in the liver and the kidney[1]. Hydroxylation of vitamin D is a process that introduces a hydroxyl group (-OH) into vitamin D2 and D3 in the liver to form 25-hydroxyvitamin D [25(OH)D]. The metabolites are further hydroxylated in the kidney to produce the active form calcitriol. The active form circulates as a hormone in the blood stream to regulate the concentrations of calcium and phosphate and to promote healthy growth and remodeling of bones[41].

Precise quantification of calcitriol is problematic due to its short half-life and the serum concentrations that are 1000 times less compared to those of 25(OH)D. In contrast, 25(OH)D has a half-life of approximately three weeks, making it an appropriate and largely reliable indicator of the individual vitamin D status[1,42].

An appropriate duration of exposure to ultraviolet B (UVB) radiation is crucial in cutaneous vitamin D production[1,43], and a strong correlation exists between vitamin D serum levels, UVB exposure and geographical residence[1,44,45]. As latitudes increase, disposable amounts of vitamin D decrease[44]. At latitudes > 37°N and < 37°S, sunlight does not sufficiently induce vitamin D synthesis in the skin, in particular during the winter months[46]. Latitude and UVB exposure are, however, not exclusive indicators of vitamin D deficiency. Other factors are age, nutritional components and skin pigmentation as well as certain chronic pathological conditions[1,43,45].


A standard definition of vitamin D deficiency does not exist. Formerly, the vitamin D status was assessed empirically, e.g., through overt diagnoses of childhood rickets and osteomalacia in adults[47,48]. Today, the recognition of deficiency relies on quantification of vitamin D serum levels, representing the current supply rather than functional activity and, thus, not sufficiently supporting a standard definition of vitamin D deficiency.

Serum 25(OH)D levels are inversely correlated with parathyroid hormone (PTH) levels. Low levels of vitamin D stimulate PTH production and, consequently, PTH may be considered a surrogate marker in the diagnosis of vitamin D deficiency. However, high vitamin D levels do not always lead to decreased PTH levels. If vitamin D values are above approximately 30 ng/mL, serum PTH levels will be at a low steady level[49,50]. Thus, current and widely accepted definitions of vitamin D levels include deficiency (< 20 ng/mL), insufficiency (20-30 ng/mL), and sufficiency (> 30 ng/mL)[1].

Vitamin D deficiency is associated with a wide spectrum of diseases including not only bone disorders, but also several autoimmune and infectious diseases, asthma and malignancies as well as psychiatric conditions[1,51,52]. Vitamin D inadequacy involves both deficiency and insufficiency and constitutes an underestimated health factor in many populations[53]. In developed countries, vitamin D deficiency is very common, with almost half of the population affected[1]. Moreover, global assessment of the vitamin D status in postmenopausal women with osteoporosis showed that 24% had severe deficiency (< 10 ng/mL), with the highest prevalences reported in central and southern Europe[42]. A similar trend was reported in a cross-sectional, observational study conducted at 61 sites across the United States, indicating that 52% and 18% among 1536 postmenopausal women receiving osteoporosis treatment had 25(OH)D levels of less than 30 ng/mL and 20 ng/mL[49], respectively.

Vitamin D deficiency is common in western and northern countries, but also in Africa and Asia[4,54-58]. Serum levels in Asian populations were assessed in three large cross-sectional studies in China (n = 3262)[56], South Korea (n = 6925)[55], and in Thailand (n = 2641)[54]. These studies defined deficiency as levels of < 20 ng/mL and indicated highest prevalences of deficiency in China (69%) and in South Korea (males 47%; females 65%)[55]. In contrast, a significantly lower prevalence of deficiency of 6% only was observed in Thailand[54]. This results most likely from its geographical location close to the equator. In Vietnam, recent studies with, however, smaller sample sizes found that vitamin D deficiency prevalences range from 16 to 63%[4,59,60].

Vitamin D deficiency in African populations may be attributed to the skin pigmentation, traditional full-length clothing, and the occurrence of infectious diseases (tuberculosis, HIV/AIDS, malaria) which are associated with deficiency[61-65]. A cross-sectional analysis of adults in a National Health and Nutrition Examination Survey (n = 8415) conducted in the United States reported that vitamin D insufficiency among African Americans was as high as 81%, but only 28% in individuals of European descent[66]. Other studies also consistently indicate that vitamin D deficiency is more prevalent in immigrants from Africa to the United States and to Europe[67,68]. These reports underline that skin pigmentation is an important factor in reducing vitamin D production.

Sub-Saharan Africa and several parts of Asia bear a heavy burden of communicable diseases, which may affect the vitamin D status. Several studies investigated the causal effect of vitamin D deficiency on the severity and progression of infectious diseases, in particular of tuberculosis[69-71] and respiratory tract infections[72-74]. Recently, vitamin D deficiency has also been implicated in susceptibility to viral hepatitis and the severity and progression of viral hepatitis-associated chronic liver diseases[4,12,75-77].


Whether low vitamin D levels are the cause or the result of certain diseases, including chronic viral liver diseases, is not clear. Based on 290 prospective and intervention studies, a systematic review has recently concluded that vitamin D deficiency might be a result and a biological marker of deteriorating health, driving 25(OH)D to low concentrations, rather than a cause of disease[2]. Vitamin D deficiency may contribute to liver damage through increased inflammation and fibrosis[6,39]. Other studies have shown that vitamin D deficiency is clearly associated with unfavorable clinical outcomes and accelerated progression of chronic liver diseases due to viral hepatitis, alcohol consumption and NAFLD[4,8,10,12,60,78-82]. Although vitamin D is associated with NAFLD, a recent study showed that vitamin D insufficiency was not associated with the presence of NAFLD[83]. Relationship between vitamin D deficiency and the pathogenesis of NAFLD has been systematically reviewed[10], and that vitamin D could be used as a supplement in the management of NAFLD. However, clinical trials concluded that vitamin D supplementation has a less impact on the NAFLD pathogenesis such as hepatic fat, injury, and hepatic steatosis[84,85]. Notably, vitamin D deficiency may also contribute to reduced antiviral responses in IFN/RBV treatment of hepatitis B and C[6,19,28,86]. Comparable studies with regard to more recent treatment regimens such as IFN-free and direct-acting antiviral agents are not available so far.

Worldwide, approximately 257 and 130-150 million people are affected by chronic hepatitis B and C, respectively, making it a significant cause of viral infection-related fatality[87,88]. A high prevalence of vitamin D deficiency occurs in almost all chronic liver diseases and their progression, irrespective of their etiology[9,19,78]. Based on results of studies on vitamin D insufficiency and deficiency in chronic hepatitis B and C, serum vitamin D levels of < 20 ng/mL range from 16%-100%[5,15,16] (Tables 1 and 2). Although high prevalences of vitamin D insufficiency/deficiency are observed both in healthy populations and in patients with viral hepatitis, significantly higher rates of deficiency were found in hepatitis patients compared to controls in several studies[4,6,80].

Table 1 Representative studies on vitamin D deficiency in chronic hepatitis B virus patients.
Study populationDiagnosisSample size (n)Study designLength of follow-upVitamin D cutoff (ng/mL)(%)Main resultsRef.
China CHB (n = 560)Multicenter, randomized, controlled104 wk from initiation of antiviral treatment< 20: deficiency < 30: insufficiency ≥ 30: sufficiency21 55 24Vitamin D insufficiency highly prevalent in treatment-naïve patients with chronic hepatitis B Baseline levels predict virologic response at week 104 after treatment initiation (67% in the insufficiency group vs 82% in the sufficient group)Yu et al[29], 2017
China CHB (n = 133)Cross-sectionalNA< 14: severe deficiency ≥ 14: deficiency < 30 sufficiency27 66 7Vitamin D deficiency significantly associated with HBV genotype BZhu et al[93], 2016
Vietnam CHB (n = 165) LC (n = 127) HCC (n = 108)Cross-sectionalNA< 10: severe deficiency < 20: deficiency < 30: insufficiency ≥ 30: sufficiency10.4 41.5 32.4 15.7Vitamin D insufficiency frequent among HBV patients Reduced vitamin D levels significantly associated with clinical progression of LC Vitamin D levels and HBV DNA loads strongly and inversely correlatedHoan et al[4], 2016
China CHB (n = 115) LC ( = 115) HC ( = 115)Cross-sectionalNA< 10: deficiency < 20: insufficiency ≥ 20: sufficiency83 17 0Vitamin D levels significantly lower in LC compared to CHB and HC groups (P < 0.001) Child-Pugh score independently associated with vitamin D deficiency (cutoff < 10  ng/mL)Zhao et al[5], 2016
South Korea CHB (n = 110) Other CLD (n = 97)Cross-sectionalNA< 10: deficiency < 20: insufficiency ≥ 20: sufficiency34.8 45.4 19.8Vitamin D deficiency independently associated with advanced liver fibrosisKo et al[154], 2016
Iran CHB (n = 84)Cross-sectionalNA< 10: deficiency < 20: insufficiency ≥ 20: sufficiency17.9 34.5 47.6No significant association of vitamin D levels in treated and treatment-naïve patientsSali et al[155], 2016
Multicenter in Europe, Asia and North America CHB (n = 737)Randomized, open-label, active-controlled clinical trial48 wk of TDF + PegIFN 16 wk of TDF + PegIFN followed by 32 wk of TDF 48 wk PegIFN or 120 wk of TDF< 20: deficiency < 30: insufficiency ≥ 30: sufficiency58 35 7Reduced vitamin D levels highly prevalent among untreated CHB patients Low baseline levels of vitamin D associated with high HBV DNA loads, abnormal ALT at week 48 independent of treatment groups Baseline vitamin D levels not associated with treatment outcomesChan et al[19], 2015
China CHB (n = 426)Cross-sectionalNA< 32 insufficiency ≥ 32 sufficiency82 18Vitamin D deficiency common among patients with CHB and associated with adverse clinical outcomesWong et al[78], 2015
China CHB (n = 242)Cross-sectionalNA< 20: deficiency < 30: insufficiency ≥ 30: sufficiency8.7 31.4 60Higher prevalence of vitamin D insufficiency in HBV genotype B patients than in genotype C patients Vitamin D levels not associated with HBV DNA levels or the stage of fibrosis in CHB patientsYu et al[23], 2015
China CHB (n = 133)Cross-sectionalNA< 14: deficiency < 30: insufficiency ≥ 30: sufficiency27 66.2 6.8Higher prevalence of vitamin D insufficiency in HBV genotype B patients than in genotype C patients Vitamin D levels not associated with other clinical parametersZhu et al[93], 2016
Germany CHB (n = 203)Cross-sectionalNA< 10: deficiency < 20: insufficiency ≥ 20: sufficiency34 47 19HBV DNA viral loads as strong predictor of low vitamin D levels in CHB patientsFarnik et al[12], 2013
Egypt OBI (n = 16) CHB (n = 52)Cross-sectionalNA< 10: deficiency < 30: insufficiency ≥ 30: sufficiencyOBI: 12.5 CHB: 40.4 OBI: 62.5 CHB: 59.6 OBI: 25 CHB: 0Vitamin D levels significantly higher in OBI than in CHB patients Serum level of vitamin D inversely correlated with HBV DNA loadsMashaly et al[156], 2016
China CHB (n = 128)Cross-sectionalNA< 10: deficiency < 20: insufficiency ≥ 20: sufficiency13.3 61.7 25Vitamin D levels negatively correlated with HBV DNA loads Effective antiviral therapy might increase the level of vitamin D in CHB patientsChen et al[11], 2015
Iran CHB (n = 173)Cross-sectionalNA< 10: deficiency < 20: insufficiency ≥ 20: sufficiency58 39 3Vitamin D levels inversely correlated with HBV DNA levelsMohamadkhani et al[89], 2015
Table 2 Representative studies regarding vitamin D status in chronic hepatitis C virus patients.
Study populationDiagnosisSample size (n)Study objectiveStudy designLength of follow-upVitamin D cutoff (ng/mL)(%)Main resultsRef.
Italy CHC (n = 197) HCV genotype 1 controls (n = 49)Cross-sectionalNA< 30: deficiency ≥ 30: sufficiency73 27Low vitamin D linked to severe fibrosis and low SVR in IFN-based treatmentPetta et al[6], 2010
United States CHC (n = 218) LC (n = 123) Non-LC (n = 95)Prospective12 wk after cessation of antiviral therapy SVR12: defined as a viral load undetectable or below the level of detection at week 12 after cessation of antiviral treatment< 20: deficiency < 30: insufficiency ≥ 30: sufficiency43 33 24Vitamin D deficiency associated with HCV–related LC and with hepatic function No significant association between SVR12 and serum vitamin D levels at baselineBackstedt et al[18], 2017
Switzerland CHC (n = 269) HCV genotypes 1-4Case-controlNA< 30: deficiency ≥ 30: sufficiency74 26No significant association between SVR and serum vitamin D levels irrespective of genotypesLange et al[20], 2012
Spain CHC genotypes 1-4 (n = 182)Cross-sectionalNA< 20: deficiency < 30: insufficiency ≥ 30: sufficiency36 41 23Vitamin D deficiency not related to biochemical and virological variables or to the stage of fibrosis stageLadero et al[157], 2013
Northern Italy CHC ( = 211) HCV genotypes 1-5Prospective24 wk after cessation of antiviral therapy SVR24: defined as a viral load undetectable or below the level of detection at week 24 after cessation of antiviral treatment< 20: deficiency ≥ 20: sufficiency46.4 53.6SVR24 rates to IFNα therapy were 50%, 61%, and 69% in CHC patients with baseline vitamin D levels of ≤ 10 ng/mL, 10-20 ng/mL, and > 20 ng/mL, respectivelyBitetto et al[25], 2011
Multicenter study, United States Cases (histological progression or clinical decompensation; ( = 129), controls (n = 129)Nested case-control studyOver 4 yrAt baseline: cases: 44.8 controls, 44.0Not statedNo difference in vitamin D levels in patients with and without progression of HCV-associated liver diseaseCorey et al[158], 2012
Multicenter study, Japan CHC (n = 247) HCV genotype 1bCase-controlNA< 20: deficiency < 30: insufficiency ≥ 30: sufficiency At baseline: 22(6–64)Not statedNS5A Y93H and L31M resistance-associated variants associated with vitamin D deficiencyOkubo et al[159], 2016
Multicenter study, France HCV-HIV coinfection (n = 189)Cross-sectionalNA< 30: deficiency ≥ 30: sufficiency85 15Low serum vitamin D levels correlated with liver fibrosis as assessed by FibroTest No association between SVR rate to IFN-based therapy and baseline vitamin D levelsTerrier et al[7], 2011
Japan CHC (n = 619)Cross-sectionalNA< 20: deficiency < 30: insufficiency ≥ 30: sufficiency47 36.7 16.3Vitamin D levels influenced by gender, age, hemoglobin level, albumin and seasonalityAtsukawa et al[160], 2015
Egypt CHC (n = 70) controls (n = 50)Cross-sectionalNAAt baseline Cases: 18.6 Control: 56NAVitamin D decreased in HCV patientsReda et al.[161], 2015
Australia CHC (n = 274) HCV genotype 1Case-controlNA< 20: deficiency < 30: insufficiency ≥ 30: sufficiency16 48 36Baseline vitamin D levels not associated with SVR or fibrosis stage in HCV genotype 1 but deficiency associated with high activityKitson et al[16], 2013
Japan CHC (n = 177)Prospective24 wk after cessation of antiviral therapyNot statedNASVR24 rates: 65% in patients with vitamin D levels > 18 ng/mL vs 38.5% in patients with vitamin D levels of < 18 ng/mLAtsukawa et al[162], 2014
Egypt CHC (n = 101) HCV genotype 4 Vitamin D supplementation group (n = 50), controls (n = 51)Randomized prospectiveUntil 72 wk from start of antiviral therapy SVR was assessed at week 72 from initiation of antiviral treatment< 20: deficiency ≥ 20: insufficiency ≥ 30: sufficiency95 5 0No impact of vitamin D supplementation on SVR in HCV genotype 4 patients No correlation between vitamin D levels and stage of liver fibrosisEsmat et al[15], 2015
Israel CHC (n = 72) HCV genotype 1 Vitamin D supplementation group (n = 36), controls (n = 36)Randomized prospective24 wk after cessation of antiviral treatment< 10: severe deficiency < 20: insufficiency ≥ 20: sufficiency21 59 20Addition of vitamin D to Peg-IFNα/RBV therapy improves SVR24 (86% vs 42%)Abu-Mouch et al[17], 2011
Israel CHC ( = 50) HCV genotype 2 and 3 Vitamin D supplementation group (n = 20), controls (n = 30)Randomized prospective24 wk after cessation of antiviral treatment< 12: deficiency < 32: insufficiency ≥ 32: sufficiency26 54 20Addition of vitamin D to IFNα/RBV therapy improves SVR24 (95% in treated group vs 77% in controls)Nimer et al[21], 2012
France CHC (n = 516) HCV genotype 1Randomized controlledUntil 72 wk from initiation of antiviral therapyNot statedNot statedNo impact of vitamin D levels on efficacy of antiviral therapy in naïve genotype 1 HCV patientsBelle et al[24], 2017
Egypt CHC (n = 66) Vitamin D group (n = 20) controls (n = 30)Randomized prospective24 wk after cessation of antiviral treatment< 12: deficiency < 32: insufficiency ≥ 32: sufficiency33.3 43.3 23.4Addition of vitamin D to conventional Peg-IFNα/RBV therapy improved SVR24Eltayeb et al[26], 2015
Germany CHC (n = 468) HCV genotypes 1-3Retrospective24 wk after cessation of antiviral treatment< 30: deficiency ≥ 30: sufficiency66 34Vitamin D deficiency correlated with SVR in HCV genotype 2 and 3 patients (50% vs 81%: SVR24 for patients with and without severe vitamin D deficiency)Lange et al[80], 2011
Taiwan CHC (n = 132) HCV genotype 1-2RetrospectiveSVR was assessed at week 48 (HCV genotype 1) and at week 24 (HCV genotype 2) from initiation of antiviral treatmentNot statedNot statedVitamin D can suppress HCV replication in hepatic cell lines Vitamin D serum levels associated with both SRV and RVR to Peg-IFNα based therapyJee-Fu et al[13], 2017
Germany CHC (n = 398) HCV genotype 1RetrospectiveSVR was assessed at week 24 from initiation of antiviral treatmentAt baseline 18.7 (3-84.3)Not statedAddition of vitamin D to Peg-IFNα/RBV therapy for treatment-naïve patients with chronic HCV genotype 1: no significant association with SVRGrammatikos et al[94], 2014
Austria HCV-HIV coinfection (n = 65)Retrospective24 wk after cessation of antiviral treatment< 10: deficiency < 30: insufficiency ≥ 30: sufficiency57 23 20Low vitamin D levels may impair virological response to Peg-IFNα/RBV therapy, especially in difficult-to-treat patientsMandorfer et al[163], 2013
Italy CHC (n = 42) Vitamin D supplementation group (n = 15) controls (n = 27)RetrospectiveSVR was assessed at week 48 from initiation of antiviral treatment< 10: severe deficiency < 20: insufficiency ≥ 20: sufficiencyNot statedVitamin D supplementation improves SVR rate following Peg-IFNα/RBV therapy (54% in vitamin D group vs 18.5% in control group)Bitetto et al[98], 2011a
Multicenter study, United States CHC (n = 1292) HCV genotype 1Retrospective24 wk after cessation of antiviral treatment< 12: severe deficiency < 20: insufficiency ≥ 20: sufficiency19 48 33Higher vitamin D levels not associated with SVR in Peg-IFNα/RBV therapyLoftfield et al[27], 2016
Meta-analysis To assess vitamin D levels related to ALF and/or SVR (n = 3755) (11 studies for SVR, 7 studies for ALF)Meta-analysisNA< 10: severe deficiency < 20: deficiency < 30: insufficiency ≥ 30: sufficiencyNot statedLow vitamin D levels related to ALF Low vitamin D levels at baseline in CHC patients were associated with a higher likelihood of having ALF and lower odds of achieving SVRGarcia-Alvarez et al[86], 2014
Meta-analysis To clarify any association between baseline vitamin D levels and SVR (n = 2605) (11 studies)Meta-analysisNANot statedNABaseline vitamin D levels not associated with SVR in Peg-IFNα/RBV therapy, regardless of genotype Effect of vitamin D supplementation on SVR to be determinedKitson et al[95], 2014
Meta-analysis To assess the association of vitamin D levels with the severity of liver fibrosis in CHC (n = 8321) (6 studies)Meta-analysisNANot statedNALower serum vitamin D is a risk factor for severity of liver fibrosis in chronic HCV patients.Luo et al[97], 2014
Meta-analysis To evaluate the association between vitamin D levels and SVR in CHC (n = 1575) (8 observational and 3 interventional studies)Meta-analysisNAAt baseline 17-43 ng/mLNAHigh SVR rates observed in patients with vitamin D levels > 30 ng/mL High SVR rates observed in CHC patients supplemented with vitamin D, regardless of genotypeVillar et al[28], 2013
Meta-analysis To access the association between vitamin D supplementation and SVR rate to PEG-IFN/RBV in CHC (n = 548) (7 studies)Meta-analysisNANANAVitamin D supplementation significantly increased SVR rates to Peg-IFNα/RBV at 24 wkKim et al[96], 2017
Vitamin D deficiency and chronic hepatitis B

So far, most studies on associations of HBV-related liver diseases with vitamin D deficiency were cross-sectional studies (Table 1). In such study designs, any fluctuation of vitamin D levels over the course of HBV infection cannot be assessed and a causative association of vitamin D levels with HBV-related liver diseases cannot reliably be established.

Vitamin D is significantly associated with virus replication in chronic HBV infection. Recently, several studies have shown that insufficient vitamin D levels most likely fail to suppress HBV replication and contribute to poor clinical courses[4,11,12,89]. Vitamin D levels are positively correlated with albumin levels and platelet counts and, inversely, with ALT levels during the active phase of hepatitis B[19,39,78]. Serum levels of < 10 ng/mL can be predictive for low serum albumin levels and the severity of chronic liver disease[22,75]. However, other studies have reported that vitamin D insufficiency was not correlated with liver function parameters, possibly due to the fact that vitamin D levels depend also on the composition of study cohorts and the study designs[4,11]. Liver disease progression in patients with chronic hepatitis B appears also to be influenced crucially by distinct viral factors, in particular by the infecting HBV genotypes. Genotypes C and B are the major causes of chronic hepatitis B and subsequent LC and HCC in East Asia[90-92]. Recent studies indicate that patients infected with genotype B had a higher prevalence of vitamin D insufficiency than those infected by the C genotype[23,93].

To the best of our knowledge, there are only two studies which have investigated the association of baseline vitamin D levels with sustained virological response (SVR) to nucleoside/nucleotide analogues (NUC) or IFNα in addition to treatment with NUC in chronic hepatitis B. It was shown that the baseline levels (cutoff value: 30 ng/mL) can predict the virological response at week 104 (67% in the insufficiency group vs 82% in the sufficient group, P < 0.001) in patients with chronic hepatitis B treated with NUC[29]. Chan et al[19], however, concluded, inconsistent with the findings given in Ref. 29, that baseline vitamin D levels are not associated with more favorable treatment outcomes in patients treated with either tenofovir disoproxil fumarate (TDF) plus Peg-IFNα or TDF or Peg-IFNα monotherapy[19]. Further prospective studies assessing associations of baseline vitamin D levels and treatment outcomes in chronic hepatitis B, particularly in the IFNα-based therapy, are worth to be conducted.

Association of vitamin D deficiency with SVR to antiviral therapy in chronic hepatitis C patients

In several studies the role of the vitamin D status as well as the effects of vitamin D supplementation on the efficacy of IFNα plus RBV in the treatment of chronic hepatitis C have been investigated (Table 2). Most studies showed high prevalences of vitamin D deficiency and significant associations of low baseline levels of 25(OH)D at the time of antiviral therapy initiation and lower odds of achieving SVR, which is defined as undetectable serum HCV RNA level at 24 wk after cessation of treatment. However, other studies reported rather inconsistent and partly contradicting results[7,16,20,94], possibly due to heterogeneity in patient inclusion criteria (HCV infection or HIV/HCV coinfection, ethnicity) and characteristics of vitamin D assessment (seasonality, cutoff values, laboratory methods)[86].

To date, five meta-analyses have described an association of baseline vitamin D levels with SVR[28,86,95-97] (Table 2). One study showed a significant association of SVR with vitamin D deficiency. Low odds of achieving SVR rates were found in patients with vitamin D levels of < 20 ng/mL compared to patients with levels of ≥ 20 ng/mL (OR = 0.5, 95%CI: 0.3-0.9)[86]. A similar result was found in another study, which reported high rates of SVR in HCV patients with vitamin D levels of ≥ 30 ng/mL (OR = 1.6; 95%CI: 1.1-2.2) and in patients supplemented with vitamin D (OR = 4.6; 95%CI: 1.7-12.6), regardless of viral genotypes[28]. In contrast, Kitson et al[95] reported that baseline 25(OH)D levels were not associated with SVR in Peg-IFN/RBV treatment, also regardless of the viral genotype involved[95]. The main differences in these meta-analyses are the study designs and patient selection strategies, as, for instance, studies involving patients with HCV/HIV coinfections were excluded in the third meta-analysis, but included in the other meta-analyses.

When looking at the effect of vitamin D supplementation as an adjuvant to IFNα/RBV therapy for treatment of chronic HCV infections, some evidence indicates that vitamin D supplementation improves the SVR (Table 2). SVR rates in patients supplemented with vitamin D depend on the infecting HCV genotypes, and range from 54%-86% for HCV genotype 1 (18.5% and 42% in the non-supplemented control groups)[17,98] up to 95% for HCV genotype 2 and 3 infections (77% in the non-supplemented control group)[21]. A meta-analysis including eleven studies reported high odds of SVR (OR = 4.6, 95%CI: 1.7-12.6) in vitamin D supplemented groups compared to non-supplemented patient groups, regardless of genotypes[28]. A retrospective study in Italy has assessed the effect of supportive vitamin D treatment in combination with antiviral therapy (IFNα plus RBV) in recurrent HCV infections of patients who had undergone liver transplantation. Vitamin D supplementation could increase SVR rates significantly[98]. In contrast, other studies showed inconsistent results for the HCV genotypes 4 and 1[15]. Randomized prospective studies with small sample sizes and lacking a placebo-controlled arm challenge the application of vitamin D as an adjuvant substance in order to enhance SVR[15,17,21,26]. Although vitamin D may be relevant in the treatment of chronic hepatitis C, further randomized, placebo-armed studies are required in order to confirm whether vitamin D supplementation in fact improves the SVR in combination with IFN in HCV infections.


In an assessment of liver cirrhosis (LC) mortality in 187 countries during the period from 1980 to 2010, global fatalities increased from approximately 676000 in 1980 to more than 1 million in 2010, accounting for approximately 2% of all causes of death[99]. There is growing evidence that vitamin D deficiency is associated with progression of LC caused by various etiologies, mainly by HBV and HCV infection, but also by alcoholic and NAFLD[4,10,39,75,100-104]. Vitamin D deficiency reflects also hepatic dysfunction and is associated with mortality in patients with LC, regardless of underlying causes[102,104].

The association of vitamin D with LC has been more intensively discussed in chronic hepatitis C and in NAFLD patients, rather than in chronic hepatitis B. A recent meta-analysis included seven studies in order to assess vitamin D serum levels and advanced liver fibrosis in patients with chronic hepatitis C. Low vitamin D levels were related to advanced fibrosis, with two cutoff values set of either 10 ng/mL (OR = 2.5, 95%CI: 1.2-4.7) or 30 ng/mL (OR = 2.2, 95%CI: 1.2-4.0)[86]. With regard to chronic hepatitis B, two studies have recently reported a strong and inverse correlation of serum vitamin D levels with progression of LC[45]. Abnormal vitamin D metabolism in LC was described almost four decades ago[105,106]. It was mainly attributed to impaired hydroxylation resulting from impaired liver function[100]. In LC patients, vitamin D deficiency is also caused by dietary lacks, malabsorption and decreased hepatic production of vitamin D binding protein[75,107,108].

Vitamin D is involved in inhibition of inflammation and liver fibrosis, substantiated by the observation that VDR knockout mice spontaneously develop hepatic fibrosis[77,109]. The function of vitamin D in mesenchymal multipotent cells is to decrease expression of collagen and profibrotic factors [transforming growth factor beta 1 (TGFβ1) and serpin family E member 1 (SERPINE1)][110], suggesting vitamin D supplementation as preventive and supportive treatment in LC[110]. Furthermore, vitamin D directly inhibits the proliferation and profibrotic phenotype of hepatic stellate cells and reduces thioacetamide-induced liver fibrosis in an animal model[109]. There are several lines of evidence to support an inverse association of vitamin D levels with liver fibrosis induced by chronic viral hepatitis[4,100,111,112]. More specifically, a high expression of hepatic Toll-like receptors (TLR2 and TLR4) can result in the production of tumor necrosis factor alpha (TNFα) in chronic hepatitis C[113]. This cytokine is shown to modulate fibrosis[114,115]. In this context, vitamin D might elicit an anti-inflammatory mechanism by downregulating the expression of TLR2 and TLR4 molecules. Recent in-vivo studies have documented on the reduced production of TNFα by monocytes, macrophages and myeloid dendritic cells treated with vitamin D[116,117]. Corroborating the findings, a yet another study show that circulating vitamin D levels inversely correlate with TLR2 and TLR4 expression[118].

Fibrotic conditions appear to be reversible and even curable[119,120] when interventions are initiated at early stages[121]. Several observations have underlined the importance of vitamin D supplementation in the treatment of chronic liver diseases. However, so far there have been no randomized prospective trials to assess the role of vitamin D supplementation in the treatment of LC.


Both incidences and mortality rates of certain cancers are higher in northern latitudes, where sunlight exposure is rather scarce[122,123]. Sound epidemiologic studies have shown that vitamin D deficiency is associated with an increased risk of colon, breast, prostrate, and ovarian cancers[124-130]. Not much information is, however, available on an association of serum vitamin D levels with either the risk or the incidence and mortality rates of HCC caused by chronic viral hepatitis.

In a recent cross-sectional study from Vietnam a high prevalence of vitamin D deficiency was observed in HBV-related HCC patients compared to healthy individuals, and vitamin D deficiency was associated with unfavorable courses of the disease[4]. In chronic hepatitis C, distinct single nucleotide polymorphisms in genes related to the vitamin D signaling pathway, including cytochrome P450 family 2 subfamily R member 1 [CYP2R1, encoding the liver 25-hydroxylase (rs1993116, rs10741657)], 7-dehydrocholesterol reductase [DHCR7, encoding the 7-dehydrocholesterol reductase (rs7944926, rs12785878)] were investigated and an association between the human genotypes and reduced 25(OH)D3 serum levels in the development of HCV-related HCC was observed[131]. Another study indicated that vitamin D might be a potential biomarker for the development of HCC in patients with chronic hepatitis C[132]. In addition, a large prospective cohort study examined the association between serum vitamin D levels and the incidence of liver cancer among 520000 participants in ten European countries[76]. During more than 10 years of follow-up, a total of 204 HCC cases, mostly due to HBV and HCV infection, were identified. Serum levels of 25(OH)D were inversely associated with the risk of HCC. This finding was in agreement with another prospective study showing that lower serum 25(OH)D3 concentrations in 200 HCC patients, also caused largely by HBV and HCV infection, were associated with poor outcomes and end stages of HCC, classified according to the BCLC (Barcelona Clinic Liver Cancer) staging system and the Cancer of the Liver Italian Program (CLIP) score[133]. Overall survival rates of HCC patients with serum 25(OH)D3 levels of ≤ 10 ng/mL were significantly lower than those of patients with serum levels > 10 ng/mL. In addition, the levels were independently associated with the overall survival in a multivariate analysis[133]. Apparently, vitamin D deficiency is associated with tumor progression and a poor prognosis in HCC patients. Although the results suggest this role of vitamin D in HCC, it remains to be determined further whether the association holds and is causal.


Vitamin D has numerous additional functions in the prevention of cancer due to its antiproliferative, proapoptotic, differentiating, antiangiogenic and antiinvasive properties[134-136]. Several in vitro and in vivo studies have suggested that vitamin D inhibits growth of HCC cell lines and effectively suppresses DNA damage[137-139]. Data from several preclinical studies have assigned an important role of vitamin D in prevention and treatment of certain malignancies[135,140,141]. Furthermore, in a randomized clinical trial (; identifier NCT00352170) vitamin D and calcium supplementation have substantially reduced the risk of cancer[142]. These observations have raised increasing awareness of ensuring adequate vitamin D levels in order to reduce the risk of neoplasms.

The vitamin D analogues paricalcitol, doxercalciferol and tacalcitol have meanwhile been approved for application in patients with osteoporosis and psoriasis[143] and analogues of vitamin D receptor activators such as maxacalcitol (OCT), 16-ene analogs, 19-nor analogs, LG190119 have been tested in preclinical studies on diabetes, several cancers (e.g., leukemia, colon, breast, prostate, pancreatic cancer)[144-146]. With regard to HCC, the vitamin D analogue seocalcitol, which has proven effects in animal models of cancer[147-149] has been investigated in patients with inoperable HCC in a phase II clinical trial (; identifier NCT00051532)[150]. Seocalcitol may be effective in the treatment of HCC, especially in early stages when prolonged treatment can be instituted. In addition, seocalcitol is 50-200 times more effective in inhibiting proliferation and differentiation of human cancer cell lines than natural vitamin D3[151].

In a phase 1 clinical trial the safety of high doses of vitamin D administered in lipiodol and directly injected into the hepatic artery of 8 patients with refractory HCC was evaluated[152]. Lipiodol is an oily substance consisting of polyunsaturated esters enriched in iodine used as a vector for chemoembolization or internal radiotherapy in unresectable HCCs[153]. Although this study was not specifically designed as a pilot study of vitamin D efficacy in HCC, the results showed a certain stabilization of tumor marker levels, suggesting some efficacy of vitamin D[152]. Another clinical trial (; identifier NCT01575717) is currently performed to assess the effect of two different doses of vitamin D3 (2000 IU vs 4000 IU) on serum 25OHD levels in HCC patients on liver transplant lists. Nevertheless, so far, there are no approved vitamin D analogues available for supportive HCC treatment.


Vitamin D deficiency is very common and frequently observed in HBV- and HCV-associated chronic liver diseases. It negatively affects the clinical courses and promotes progression of liver diseases, but causal relations are still not fully understood. Several lines support that sufficient vitamin D levels play an important role during antiviral treatment of HBV and HCV infections. However, the effect of vitamin D supplementation in combination with IFN-RBV based therapy on virological responses is still unclear. Various non-skeletal effects of vitamin D, including antiinflammatory, antifibrotic and antitumor properties have emphasized an association of vitamin D deficiency with unfavorable liver disease outcomes, in particular, liver cirrhosis. There is currently no approved recommendation for vitamin D supplementation and vitamin D analogues as supportive adjuvant treatment regimes in viral hepatitis and related chronic disorders. Further randomized, placebo-armed studies need to be performed in order to confirm whether supplementation of vitamin D or vitamin D analogues improve SVRs in combination with specific antiviral treatment strategies in HBV or HCV infections.


Hoang Van Tong gratefully acknowledges financial support from Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 108.02-2017.15. Thirumalaisamy P Velavan acknowledges the support from Federal Ministry of Education and Research, Germany (BMBF01DP17047).


Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Germany

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P- Reviewer: Abenavoli L, Gonzalez-Reimers E, Lai GY, Morini S S- Editor: Gong ZM L- Editor:A E- Editor: Ma YJ

1.  Holick MFVitamin D deficiency. N Engl J Med. 2007;357:266-281.  [PubMed]  [DOI]
2.  Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2:76-89.  [PubMed]  [DOI]
3.  Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87:1080S-1086S.  [PubMed]  [DOI]
4.  Hoan NX, Khuyen N, Binh MT, Giang DP, Van Tong H, Hoan PQ, Trung NT, Anh DT, Toan NL, Meyer CG. Association of vitamin D deficiency with hepatitis B virus - related liver diseases. BMC Infect Dis. 2016;16:507.  [PubMed]  [DOI]
5.  Zhao XY, Li J, Wang JH, Habib S, Wei W, Sun SJ, Strobel HW, Jia JD. Vitamin D serum level is associated with Child-Pugh score and metabolic enzyme imbalances, but not viral load in chronic hepatitis B patients. Medicine (Baltimore). 2016;95:e3926.  [PubMed]  [DOI]
6.  Petta S, Cammà C, Scazzone C, Tripodo C, Di Marco V, Bono A, Cabibi D, Licata G, Porcasi R, Marchesini G. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51:1158-1167.  [PubMed]  [DOI]
7.  Terrier B, Carrat F, Geri G, Pol S, Piroth L, Halfon P, Poynard T, Souberbielle JC, Cacoub P. Low 25-OH vitamin D serum levels correlate with severe fibrosis in HIV-HCV co-infected patients with chronic hepatitis. J Hepatol. 2011;55:756-761.  [PubMed]  [DOI]
8.  Iruzubieta P, Terán Á, Crespo J, Fábrega EVitamin D deficiency in chronic liver disease. World J Hepatol. 2014;6:901-915.  [PubMed]  [DOI]
9.  Stokes CS, Volmer DA, Grünhage F, Lammert F. Vitamin D in chronic liver disease. Liver Int. 2013;33:338-352.  [PubMed]  [DOI]
10.  Barchetta I, Cimini FA, Cavallo MG. Vitamin D Supplementation and Non-Alcoholic Fatty Liver Disease: Present and Future. Nutrients. 2017;9:10-15.  [PubMed]  [DOI]
11.  Chen EQ, Bai L, Zhou TY, Fe M, Zhang DM, Tang H. Sustained suppression of viral replication in improving vitamin D serum concentrations in patients with chronic hepatitis B. Sci Rep. 2015;5:15441.  [PubMed]  [DOI]
12.  Farnik H, Bojunga J, Berger A, Allwinn R, Waidmann O, Kronenberger B, Keppler OT, Zeuzem S, Sarrazin C, Lange CM. Low vitamin D serum concentration is associated with high levels of hepatitis B virus replication in chronically infected patients. Hepatology. 2013;58:1270-1276.  [PubMed]  [DOI]
13.  Huang JF, Ko YM, Huang CF, Yeh ML, Dai CY, Hsieh MH, Huang CI, Yang HL, Wang SC, Lin ZY. 25-Hydroxy vitamin D suppresses hepatitis C virus replication and contributes to rapid virological response of treatment efficacy. Hepatol Res. 2017;47:1383-1389.  [PubMed]  [DOI]
14.  Gutierrez JA, Jones KA, Flores R, Singhania A, Woelk CH, Schooley RT, Wyles DL. Vitamin D Metabolites Inhibit Hepatitis C Virus and Modulate Cellular Gene Expression. J Virol Antivir Res. 2014;3.  [PubMed]  [DOI]
15.  Esmat G, El Raziky M, Elsharkawy A, Sabry D, Hassany M, Ahmed A, Assem N, El Kassas M, Doss W. Impact of vitamin D supplementation on sustained virological response in chronic hepatitis C genotype 4 patients treated by pegylated interferon/ribavirin. J Interferon Cytokine Res. 2015;35:49-54.  [PubMed]  [DOI]
16.  Kitson MT, Dore GJ, George J, Button P, McCaughan GW, Crawford DH, Sievert W, Weltman MD, Cheng WS, Roberts SK. Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection. J Hepatol. 2013;58:467-472.  [PubMed]  [DOI]
17.  Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol. 2011;17:5184-5190.  [PubMed]  [DOI]
18.  Backstedt D, Pedersen M, Choi M, Seetharam A. 25-Vitamin D levels in chronic hepatitis C infection: association with cirrhosis and sustained virologic response. Ann Gastroenterol. 2017;30:344-348.  [PubMed]  [DOI]
19.  Chan HL, Elkhashab M, Trinh H, Tak WY, Ma X, Chuang WL, Kim YJ, Martins EB, Lin L, Dinh P. Association of baseline vitamin D levels with clinical parameters and treatment outcomes in chronic hepatitis B. J Hepatol. 2015;63:1086-1092.  [PubMed]  [DOI]
20.  Lange CM, Bibert S, Kutalik Z, Burgisser P, Cerny A, Dufour JF, Geier A, Gerlach TJ, Heim MH, Malinverni R. A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C. PLoS One. 2012;7:e40159.  [PubMed]  [DOI]
21.  Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients. World J Gastroenterol. 2012;18:800-805.  [PubMed]  [DOI]
22.  Rode A, Fourlanos S, Nicoll A. Oral vitamin D replacement is effective in chronic liver disease. Gastroenterol Clin Biol. 2010;34:618-620.  [PubMed]  [DOI]
23.  Yu R, Sun J, Zheng Z, Chen J, Fan R, Liang X, Zhu Y, Liu Y, Shen S, Hou J. Association between vitamin D level and viral load or fibrosis stage in chronic hepatitis B patients from Southern China. J Gastroenterol Hepatol. 2015;30:566-574.  [PubMed]  [DOI]
24.  Belle A, Gizard E, Conroy G, Lopez A, Bouvier-Alias M, Rouanet S, Peyrin-Biroulet L, Pawlotsky JM, Bronowicki JP. 25-OH vitamin D level has no impact on the efficacy of antiviral therapy in naïve genotype 1 HCV-infected patients. United European Gastroenterol J. 2017;5:69-75.  [PubMed]  [DOI]
25.  Bitetto D, Fattovich G, Fabris C, Ceriani E, Falleti E, Fornasiere E, Pasino M, Ieluzzi D, Cussigh A, Cmet S. Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C. Hepatology. 2011;53:1118-1126.  [PubMed]  [DOI]
26.  Eltayeb AA, Abdou MA, Abdel-aal AM, Othman MH. Vitamin D status and viral response to therapy in hepatitis C infected children. World J Gastroenterol. 2015;21:1284-1291.  [PubMed]  [DOI]
27.  Loftfield E, O’Brien TR, Pfeiffer RM, Howell CD, Horst R, Prokunina-Olsson L, Weinstein SJ, Albanes D, Morgan TR, Freedman ND. Vitamin D Status and Virologic Response to HCV Therapy in the HALT-C and VIRAHEP-C Trials. PLoS One. 2016;11:e0166036.  [PubMed]  [DOI]
28.  Villar LM, Del Campo JA, Ranchal I, Lampe E, Romero-Gomez M. Association between vitamin D and hepatitis C virus infection: a meta-analysis. World J Gastroenterol. 2013;19:5917-5924.  [PubMed]  [DOI]
29.  Yu R, Tan D, Ning Q, Niu J, Bai X, Chen S, Cheng J, Yu Y, Wang H, Xu M. Association of baseline vitamin D level with genetic determinants and virologic response in patients with chronic hepatitis B. Hepatol Res. 2017; Epub ahead of print.  [PubMed]  [DOI]
30.  Wintermeyer E, Ihle C, Ehnert S, Stöckle U, Ochs G, de Zwart P, Flesch I, Bahrs C, Nussler AK. Crucial Role of Vitamin D in the Musculoskeletal System. Nutrients. 2016;8:(6). E319.  [PubMed]  [DOI]
31.  DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689S-1696S.  [PubMed]  [DOI]
32.  Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. 2008;88:491S-499S.  [PubMed]  [DOI]
33.  Aranow CVitamin D and the immune system. J Investig Med. 2011;59:881-886.  [PubMed]  [DOI]
34.  Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010;10:482-496.  [PubMed]  [DOI]
35.  Yang L, Ma J, Zhang X, Fan Y, Wang L. Protective role of the vitamin D receptor. Cell Immunol. 2012;279:160-166.  [PubMed]  [DOI]
36.  Bikle DNonclassic actions of vitamin D. J Clin Endocrinol Metab. 2009;94:26-34.  [PubMed]  [DOI]
37.  Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, Margolis KL, Ockene JK, Phillips L, Pottern L. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354:684-696.  [PubMed]  [DOI]
38.  Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010;9:941-955.  [PubMed]  [DOI]
39.  Targher G, Bertolini L, Scala L, Cigolini M, Zenari L, Falezza G, Arcaro G. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2007;17:517-524.  [PubMed]  [DOI]
40.  Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab. 2011;96:E447-E452.  [PubMed]  [DOI]
41.  Bikle DDVitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;21:319-329.  [PubMed]  [DOI]
42.  Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D, Nickelsen T. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab. 2001;86:1212-1221.  [PubMed]  [DOI]
43.  Wacker M, Holick MF. Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinol. 2013;5:51-108.  [PubMed]  [DOI]
44.  Kimlin MG, Olds WJ, Moore MR. Location and vitamin D synthesis: is the hypothesis validated by geophysical data? J Photochem Photobiol B. 2007;86:234-239.  [PubMed]  [DOI]
45.  Holick MFSunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2008;624:1-15.  [PubMed]  [DOI]
46.  Cheng TC, Lu Z, Holick MH. Photobiology of vitamin D. Holick MF, editor Vitamin D: Molecular Biology, Physiology, and Clinical Applications. New Jork: Humana Press 1999; 17-37.  [PubMed]  [DOI]
47.  Sarkar S, Hewison M, Studzinski GP, Li YC, Kalia V. Role of vitamin D in cytotoxic T lymphocyte immunity to pathogens and cancer. Crit Rev Clin Lab Sci. 2016;53:132-145.  [PubMed]  [DOI]
48.  Stanbury SW, Torkington P, Lumb GA, Adams PH, de Silva P, Taylor CM. Asian rickets and osteomalacia: patterns of parathyroid response in vitamin D deficiency. Proc Nutr Soc. 1975;34:111-117.  [PubMed]  [DOI]
49.  Holick MF, Siris ES, Binkley N, Beard MK, Khan A, Katzer JT, Petruschke RA, Chen E, de Papp AE. Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab. 2005;90:3215-3224.  [PubMed]  [DOI]
50.  Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-783.  [PubMed]  [DOI]
51.  Rosen CJClinical practice. Vitamin D insufficiency. N Engl J Med. 2011;364:248-254.  [PubMed]  [DOI]
52.  van den Berg KS, Marijnissen RM, van den Brink RH, Naarding P, Comijs HC, Oude Voshaar RC. Vitamin D deficiency, depression course and mortality: Longitudinal results from the Netherlands Study on Depression in Older persons (NESDO). J Psychosom Res. 2016;83:50-56.  [PubMed]  [DOI]
53.  Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med. 2002;112:659-662.  [PubMed]  [DOI]
54.  Chailurkit LO, Aekplakorn W, Ongphiphadhanakul B. Regional variation and determinants of vitamin D status in sunshine-abundant Thailand. BMC Public Health. 2011;11:853.  [PubMed]  [DOI]
55.  Choi HS, Oh HJ, Choi H, Choi WH, Kim JG, Kim KM, Kim KJ, Rhee Y, Lim SK. Vitamin D insufficiency in Korea--a greater threat to younger generation: the Korea National Health and Nutrition Examination Survey (KNHANES) 2008. J Clin Endocrinol Metab. 2011;96:643-651.  [PubMed]  [DOI]
56.  Lu L, Yu Z, Pan A, Hu FB, Franco OH, Li H, Li X, Yang X, Chen Y, Lin X. Plasma 25-hydroxyvitamin D concentration and metabolic syndrome among middle-aged and elderly Chinese individuals. Diabetes Care. 2009;32:1278-1283.  [PubMed]  [DOI]
57.  Fraser DRVitamin D-deficiency in Asia. J Steroid Biochem Mol Biol. 2004;89-90:491-495.  [PubMed]  [DOI]
58.  Nimitphong H, Holick MF. Vitamin D status and sun exposure in southeast Asia. Dermatoendocrinol. 2013;5:34-37.  [PubMed]  [DOI]
59.  Nguyen HT, von Schoultz B, Nguyen TV, Dzung DN, Duc PT, Thuy VT, Hirschberg AL. Vitamin D deficiency in northern Vietnam: prevalence, risk factors and associations with bone mineral density. Bone. 2012;51:1029-1034.  [PubMed]  [DOI]
60.  Brock K, Cant R, Clemson L, Mason RS, Fraser DR. Effects of diet and exercise on plasma vitamin D (25(OH)D) levels in Vietnamese immigrant elderly in Sydney, Australia. J Steroid Biochem Mol Biol. 2007;103:786-792.  [PubMed]  [DOI]
61.  Gibney KB, MacGregor L, Leder K, Torresi J, Marshall C, Ebeling PR, Biggs BA. Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa. Clin Infect Dis. 2008;46:443-446.  [PubMed]  [DOI]
62.  Prentice A, Schoenmakers I, Jones KS, Jarjou LM, Goldberg GR. Vitamin D Deficiency and Its Health Consequences in Africa. Clin Rev Bone Miner Metab. 2009;7:94-106.  [PubMed]  [DOI]
63.  Cusick SE, Opoka RO, Lund TC, John CC, Polgreen LE. Vitamin D insufficiency is common in Ugandan children and is associated with severe malaria. PLoS One. 2014;9:e113185.  [PubMed]  [DOI]
64.  Kibirige D, Mutebi E, Ssekitoleko R, Worodria W, Mayanja-Kizza H. Vitamin D deficiency among adult patients with tuberculosis: a cross sectional study from a national referral hospital in Uganda. BMC Res Notes. 2013;6:293.  [PubMed]  [DOI]
65.  Mehta S, Giovannucci E, Mugusi FM, Spiegelman D, Aboud S, Hertzmark E, Msamanga GI, Hunter D, Fawzi WW. Vitamin D status of HIV-infected women and its association with HIV disease progression, anemia, and mortality. PLoS One. 2010;5:e8770.  [PubMed]  [DOI]
66.  Gutiérrez OM, Farwell WR, Kermah D, Taylor EN. Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and Nutrition Examination Survey. Osteoporos Int. 2011;22:1745-1753.  [PubMed]  [DOI]
67.  Emilion E, Emilion R. Estimation of the 25(OH) vitamin D threshold below which secondary hyperparathyroidism may occur among African migrant women in Paris. Int J Vitam Nutr Res. 2011;81:218-224.  [PubMed]  [DOI]
68.  Kruger MC, Kruger IM, Wentzel-Viljoen E, Kruger A. Urbanization of black South African women may increase risk of low bone mass due to low vitamin D status, low calcium intake, and high bone turnover. Nutr Res. 2011;31:748-758.  [PubMed]  [DOI]
69.  Chocano-Bedoya P, Ronnenberg AG. Vitamin D and tuberculosis. Nutr Rev. 2009;67:289-293.  [PubMed]  [DOI]
70.  Daley P, Jagannathan V, John KR, Sarojini J, Latha A, Vieth R, Suzana S, Jeyaseelan L, Christopher DJ, Smieja M. Adjunctive vitamin D for treatment of active tuberculosis in India: a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2015;15:528-534.  [PubMed]  [DOI]
71.  Talat N, Perry S, Parsonnet J, Dawood G, Hussain R. Vitamin d deficiency and tuberculosis progression. Emerg Infect Dis. 2010;16:853-855.  [PubMed]  [DOI]
72.  Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134:1129-1140.  [PubMed]  [DOI]
73.  Fleming DM, Elliot AJ. Epidemic influenza and vitamin D. Epidemiol Infect. 2007;135:1091-1092; author reply 1092-1095.  [PubMed]  [DOI]
74.  Schwalfenberg G. Vitamin D for influenza. Can Fam Physician. 2015;61:507.  [PubMed]  [DOI]
75.  Fisher L, Fisher A. Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease. Clin Gastroenterol Hepatol. 2007;5:513-520.  [PubMed]  [DOI]
76.  Fedirko V, Duarte-Salles T, Bamia C, Trichopoulou A, Aleksandrova K, Trichopoulos D, Trepo E, Tjønneland A, Olsen A, Overvad K. Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study. Hepatology. 2014;60:1222-1230.  [PubMed]  [DOI]
77.  Ding N, Yu RT, Subramaniam N, Sherman MH, Wilson C, Rao R, Leblanc M, Coulter S, He M, Scott C. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell. 2013;153:601-613.  [PubMed]  [DOI]
78.  Wong GL, Chan HL, Chan HY, Tse CH, Chim AM, Lo AO, Wong VW. Adverse effects of vitamin D deficiency on outcomes of patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2015;13:783-790.e1.  [PubMed]  [DOI]
79.  Trépo E, Ouziel R, Pradat P, Momozawa Y, Quertinmont E, Gervy C, Gustot T, Degré D, Vercruysse V, Deltenre P. Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease. J Hepatol. 2013;59:344-350.  [PubMed]  [DOI]
80.  Lange CM, Bojunga J, Ramos-Lopez E, von Wagner M, Hassler A, Vermehren J, Herrmann E, Badenhoop K, Zeuzem S, Sarrazin C. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol. 2011;54:887-893.  [PubMed]  [DOI]
81.  Eliades M, Spyrou E. Vitamin D: a new player in non-alcoholic fatty liver disease? World J Gastroenterol. 2015;21:1718-1727.  [PubMed]  [DOI]
82.  Kwok RM, Torres DM, Harrison SA. Vitamin D and nonalcoholic fatty liver disease (NAFLD): is it more than just an association? Hepatology. 2013;58:1166-1174.  [PubMed]  [DOI]
83.  Ha Y, Hwang SG, Rim KS. The Association between Vitamin D Insufficiency and Nonalcoholic Fatty Liver Disease: A Population-Based Study. Nutrients. 2017;9:pii: E806.  [PubMed]  [DOI]
84.  Barchetta I, Del Ben M, Angelico F, Di Martino M, Fraioli A, La Torre G, Saulle R, Perri L, Morini S, Tiberti C. No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. BMC Med. 2016;14:92.  [PubMed]  [DOI]
85.  Sharifi N, Amani R, Hajiani E, Cheraghian B. Does vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trial. Endocrine. 2014;47:70-80.  [PubMed]  [DOI]
86.  García-Álvarez M, Pineda-Tenor D, Jiménez-Sousa MA, Fernández-Rodríguez A, Guzmán-Fulgencio M, Resino S. Relationship of vitamin D status with advanced liver fibrosis and response to hepatitis C virus therapy: a meta-analysis. Hepatology. 2014;60:1541-1550.  [PubMed]  [DOI]
87.  Colvin HM, Mitchell AE.  Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Washington (DC): National Academies Press (US): Macmillan 2010; .  [PubMed]  [DOI]
88.  WHO. Global hepatitis report, 2017.  Available from:  [PubMed]  [DOI]
89.  Mohamadkhani A, Bastani F, Khorrami S, Ghanbari R, Eghtesad S, Sharafkhah M, Montazeri G, Poustchi H. Negative Association of Plasma Levels of Vitamin D and miR-378 With Viral Load in Patients With Chronic Hepatitis B Infection. Hepat Mon. 2015;15:e28315.  [PubMed]  [DOI]
90.  Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology. 2000;118:554-559.  [PubMed]  [DOI]
91.  Tong S, Revill P. Overview of hepatitis B viral replication and genetic variability. J Hepatol. 2016;64:S4-S16.  [PubMed]  [DOI]
92.  Zhang ZH, Wu CC, Chen XW, Li X, Li J, Lu MJ. Genetic variation of hepatitis B virus and its significance for pathogenesis. World J Gastroenterol. 2016;22:126-144.  [PubMed]  [DOI]
93.  Zhu H, Liu X, Ding Y, Zhou H, Wang Y, Zhou Z, Li X, Zhang Z, Dong C. Relationships between low serum vitamin D levels and HBV “a” determinant mutations in chronic hepatitis B patients. J Infect Dev Ctries. 2016;10:1025-1030.  [PubMed]  [DOI]
94.  Grammatikos G, Lange C, Susser S, Schwendy S, Dikopoulos N, Buggisch P, Encke J, Teuber G, Goeser T, Thimme R. Vitamin D levels vary during antiviral treatment but are unable to predict treatment outcome in HCV genotype 1 infected patients. PLoS One. 2014;9:e87974.  [PubMed]  [DOI]
95.  Kitson MT, Sarrazin C, Toniutto P, Eslick GD, Roberts SK. Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis. J Hepatol. 2014;61:1247-1252.  [PubMed]  [DOI]
96.  Kim HB, Myung SK, Lee YJ, Park BJ. Efficacy of vitamin D supplementation in combination with conventional antiviral therapy in patients with chronic hepatitis C infection: a meta-analysis of randomised controlled trials. J Hum Nutr Diet. 2017; Epub ahead of print.  [PubMed]  [DOI]
97.  Luo YQ, Wu XX, Ling ZX, Cheng YW, Yuan L, Xiang C. Association between serum vitamin D and severity of liver fibrosis in chronic hepatitis C patients: a systematic meta-analysis. J Zhejiang Univ Sci B. 2014;15:900-906.  [PubMed]  [DOI]
98.  Bitetto D, Fabris C, Fornasiere E, Pipan C, Fumolo E, Cussigh A, Bignulin S, Cmet S, Fontanini E, Falleti E. Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transpl Int. 2011;24:43-50.  [PubMed]  [DOI]
99.  Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J, Murray CJ, Naghavi M. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med. 2014;12:145.  [PubMed]  [DOI]
100.  Konstantakis C, Tselekouni P, Kalafateli M, Triantos C. Vitamin D deficiency in patients with liver cirrhosis. Ann Gastroenterol. 2016;29:297-306.  [PubMed]  [DOI]
101.  El-Maouche D, Mehta SH, Sutcliffe CG, Higgins Y, Torbenson MS, Moore RD, Thomas DL, Sulkowski MS, Brown TT. Vitamin D deficiency and its relation to bone mineral density and liver fibrosis in HIV-HCV coinfection. Antivir Ther. 2013;18:237-242.  [PubMed]  [DOI]
102.  Stokes CS, Krawczyk M, Reichel C, Lammert F, Grünhage F. Vitamin D deficiency is associated with mortality in patients with advanced liver cirrhosis. Eur J Clin Invest. 2014;44:176-183.  [PubMed]  [DOI]
103.  Lim LY, Chalasani N. Vitamin d deficiency in patients with chronic liver disease and cirrhosis. Curr Gastroenterol Rep. 2012;14:67-73.  [PubMed]  [DOI]
104.  Paternostro R, Wagner D, Reiberger T, Mandorfer M, Schwarzer R, Ferlitsch M, Trauner M, Peck-Radosavljevic M, Ferlitsch A. Low 25-OH-vitamin D levels reflect hepatic dysfunction and are associated with mortality in patients with liver cirrhosis. Wien Klin Wochenschr. 2017;129:8-15.  [PubMed]  [DOI]
105.  Jung RT, Davie M, Hunter JO, Chalmers TM, Lawson DE. Abnormal vitamin D metabolism in cirrhosis. Gut. 1978;19:290-293.  [PubMed]  [DOI]
106.  Long RG, Skinner RK, Wills MR, Sherlock S. Serum-25-hydroxy-vitamin-D in untreated parenchymal and cholestatic liver disease. Lancet. 1976;2:650-652.  [PubMed]  [DOI]
107.  Pappa HM, Bern E, Kamin D, Grand RJ. Vitamin D status in gastrointestinal and liver disease. Curr Opin Gastroenterol. 2008;24:176-183.  [PubMed]  [DOI]
108.  Malham M, Jørgensen SP, Ott P, Agnholt J, Vilstrup H, Borre M, Dahlerup JF. Vitamin D deficiency in cirrhosis relates to liver dysfunction rather than aetiology. World J Gastroenterol. 2011;17:922-925.  [PubMed]  [DOI]
109.  Abramovitch S, Dahan-Bachar L, Sharvit E, Weisman Y, Ben Tov A, Brazowski E, Reif S. Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats. Gut. 2011;60:1728-1737.  [PubMed]  [DOI]
110.  Artaza JN, Norris KC. Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells. J Endocrinol. 2009;200:207-221.  [PubMed]  [DOI]
111.  Gutierrez JA, Parikh N, Branch AD. Classical and emerging roles of vitamin D in hepatitis C virus infection. Semin Liver Dis. 2011;31:387-398.  [PubMed]  [DOI]
112.  Cholongitas E, Theocharidou E, Goulis J, Tsochatzis E, Akriviadis E, Burroughs K. Review article: the extra-skeletal effects of vitamin D in chronic hepatitis C infection. Aliment Pharmacol Ther. 2012;35:634-646.  [PubMed]  [DOI]
113.  Berzsenyi MD, Roberts SK, Preiss S, Woollard DJ, Beard MR, Skinner NA, Bowden DS, Visvanathan K. Hepatic TLR2 &amp; TLR4 expression correlates with hepatic inflammation and TNF-α in HCV &amp; HCV/HIV infection. J Viral Hepat. 2011;18:852-860.  [PubMed]  [DOI]
114.  Goral V, Atayan Y, Kaplan A. The relation between pathogenesis of liver cirrhosis, hepatic encephalopathy and serum cytokine levels: what is the role of tumor necrosis factor α? Hepatogastroenterology. 2011;58:943-948.  [PubMed]  [DOI]
115.  Wang X, Chen YX, Xu CF, Zhao GN, Huang YX, Wang QL. Relationship between tumor necrosis factor-alphaand liver fibrosis. World J Gastroenterol. 1998;4:18.  [PubMed]  [DOI]
116.  Kuo YT, Kuo CH, Lam KP, Chu YT, Wang WL, Huang CH, Hung CH. Effects of vitamin D3 on expression of tumor necrosis factor-alpha and chemokines by monocytes. J Food Sci. 2010;75:H200-H204.  [PubMed]  [DOI]
117.  Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, Zügel U, Steinmeyer A, Pollak A, Roth E. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. 2006;36:361-370.  [PubMed]  [DOI]
118.  Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet’s disease. Rheumatology (Oxford). 2008;47:840-848.  [PubMed]  [DOI]
119.  Fallowfield JA, Kendall TJ, Iredale JP. Reversal of fibrosis: no longer a pipe dream? Clin Liver Dis. 2006;10:481-497, viii.  [PubMed]  [DOI]
120.  Iredale JPModels of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest. 2007;117:539-548.  [PubMed]  [DOI]
121.  Kisseleva T, Brenner DA. Hepatic stellate cells and the reversal of fibrosis. J Gastroenterol Hepatol. 2006;21 Suppl 3:S84-S87.  [PubMed]  [DOI]
122.  Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF. The role of vitamin D in cancer prevention. Am J Public Health. 2006;96:252-261.  [PubMed]  [DOI]
123.  Bertino JRLandmark Study: The Relation of Solar Radiation to Cancer Mortality in North America. Cancer Res. 2016;76:185.  [PubMed]  [DOI]
124.  Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980;9:227-231.  [PubMed]  [DOI]
125.  Davis CD, Milner JA. Vitamin D and colon cancer. Expert Rev Gastroenterol Hepatol. 2011;5:67-81.  [PubMed]  [DOI]
126.  Lefkowitz ES, Garland CF. Sunlight, vitamin D, and ovarian cancer mortality rates in US women. Int J Epidemiol. 1994;23:1133-1136.  [PubMed]  [DOI]
127.  Moan J, Dahlback A, Lagunova Z, Cicarma E, Porojnicu AC. Solar radiation, vitamin D and cancer incidence and mortality in Norway. Anticancer Res. 2009;29:3501-3509.  [PubMed]  [DOI]
128.  Schwartz GGVitamin D and the epidemiology of prostate cancer. Semin Dial. 2005;18:276-289.  [PubMed]  [DOI]
129.  Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis). Anticancer Res. 1990;10:1307-1311.  [PubMed]  [DOI]
130.  Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet. 1989;2:1176-1178.  [PubMed]  [DOI]
131.  Lange CM, Miki D, Ochi H, Nischalke HD, Bojunga J, Bibert S, Morikawa K, Gouttenoire J, Cerny A, Dufour JF. Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development. PLoS One. 2013;8:e64053.  [PubMed]  [DOI]
132.  Hammad LN, Abdelraouf SM, Hassanein FS, Mohamed WA, Schaalan MF. Circulating IL-6, IL-17 and vitamin D in hepatocellular carcinoma: potential biomarkers for a more favorable prognosis? J Immunotoxicol. 2013;10:380-386.  [PubMed]  [DOI]
133.  Finkelmeier F, Kronenberger B, Köberle V, Bojunga J, Zeuzem S, Trojan J, Piiper A, Waidmann O. Severe 25-hydroxyvitamin D deficiency identifies a poor prognosis in patients with hepatocellular carcinoma - a prospective cohort study. Aliment Pharmacol Ther. 2014;39:1204-1212.  [PubMed]  [DOI]
134.  Vanoirbeek E, Krishnan A, Eelen G, Verlinden L, Bouillon R, Feldman D, Verstuyf A. The anti-cancer and anti-inflammatory actions of 1,25(OH)₂D₃. Best Pract Res Clin Endocrinol Metab. 2011;25:593-604.  [PubMed]  [DOI]
135.  Deeb KK, Trump DL, Johnson CS. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer. 2007;7:684-700.  [PubMed]  [DOI]
136.  Vuolo L, Di Somma C, Faggiano A, Colao A. Vitamin D and cancer. Front Endocrinol (Lausanne). 2012;3:58.  [PubMed]  [DOI]
137.  Pourgholami MH, Akhter J, Lu Y, Morris DL. In vitro and in vivo inhibition of liver cancer cells by 1,25-dihydroxyvitamin D3. Cancer Lett. 2000;151:97-102.  [PubMed]  [DOI]
138.  Caputo A, Pourgholami MH, Akhter J, Morris DL. 1,25-Dihydroxyvitamin D(3) induced cell cycle arrest in the human primary liver cancer cell line HepG2. Hepatol Res. 2003;26:34-39.  [PubMed]  [DOI]
139.  Ghous Z, Akhter J, Pourgholami MH, Morris DL. Inhibition of hepatocellular cancer by EB1089: in vitro and in vive study. Anticancer Res. 2008;28:3757-3761.  [PubMed]  [DOI]
140.  Krishnan AV, Trump DL, Johnson CS, Feldman D. The role of vitamin D in cancer prevention and treatment. Endocrinol Metab Clin North Am. 2010;39:401-418, table of contents.  [PubMed]  [DOI]
141.  Trump DL, Deeb KK, Johnson CS. Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy. Cancer J. 2010;16:1-9.  [PubMed]  [DOI]
142.  Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586-1591.  [PubMed]  [DOI]
143.  Leyssens C, Verlinden L, Verstuyf A. The future of vitamin D analogs. Front Physiol. 2014;5:122.  [PubMed]  [DOI]
144.  Brown AJ, Slatopolsky E. Vitamin D analogs: therapeutic applications and mechanisms for selectivity. Mol Aspects Med. 2008;29:433-452.  [PubMed]  [DOI]
145.  Fujii H, Nakai K, Yonekura Y, Kono K, Goto S, Hirata M, Shinohara M, Nishi S, Fukagawa M. The Vitamin D Receptor Activator Maxacalcitol Provides Cardioprotective Effects in Diabetes Mellitus. Cardiovasc Drugs Ther. 2015;29:499-507.  [PubMed]  [DOI]
146.  Chiang KC, Yeh CN, Hsu JT, Yeh TS, Jan YY, Wu CT, Chen HY, Jwo SC, Takano M, Kittaka A. Evaluation of the potential therapeutic role of a new generation of vitamin D analog, MART-10, in human pancreatic cancer cells in vitro and in vivo. Cell Cycle. 2013;12:1316-1325.  [PubMed]  [DOI]
147.  Akhter J, Chen X, Bowrey P, Bolton EJ, Morris DL. Vitamin D3 analog, EB1089, inhibits growth of subcutaneous xenografts of the human colon cancer cell line, LoVo, in a nude mouse model. Dis Colon Rectum. 1997;40:317-321.  [PubMed]  [DOI]
148.  Lokeshwar BL, Schwartz GG, Selzer MG, Burnstein KL, Zhuang SH, Block NL, Binderup L. Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23-dihydroxyvitamin D (calcitriol) and EB1089. Cancer Epidemiol Biomarkers Prev. 1999;8:241-248.  [PubMed]  [DOI]
149.  Colston KW, James SY, Ofori-Kuragu EA, Binderup L, Grant AG. Vitamin D receptors and anti-proliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro. Br J Cancer. 1997;76:1017-1020.  [PubMed]  [DOI]
150.  Dalhoff K, Dancey J, Astrup L, Skovsgaard T, Hamberg KJ, Lofts FJ, Rosmorduc O, Erlinger S, Bach Hansen J, Steward WP. A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma. Br J Cancer. 2003;89:252-257.  [PubMed]  [DOI]
151.  Hansen CM, Mäenpää PH. EB 1089, a novel vitamin D analog with strong antiproliferative and differentiation-inducing effects on target cells. Biochem Pharmacol. 1997;54:1173-1179.  [PubMed]  [DOI]
152.  Morris DL, Jourdan JL, Finlay I, Gruenberger T, The MP, Pourgholami MH. Hepatic intra-arterial injection of 1,25-dihydroxyvitamin D3 in lipiodol: Pilot study in patients with hepatocellular carcinoma. Int J Oncol. 2002;21:901-906.  [PubMed]  [DOI]
153.  Huang D, Chen Y, Chen S, Zeng Q, Zhao J, Wu R, Li Y. TACE plus percutaneous chemotherapy-lipiodol treatment of unresectable pedunculated hepatocellular carcinoma. Medicine (Baltimore). 2017;96:e7650.  [PubMed]  [DOI]
154.  Ko BJ, Kim YS, Kim SG, Park JH, Lee SH, Jeong SW, Jang JY, Kim HS, Kim BS, Kim SM. Relationship between 25-Hydroxyvitamin D Levels and Liver Fibrosis as Assessed by Transient Elastography in Patients with Chronic Liver Disease. Gut Liver. 2016;10:818-825.  [PubMed]  [DOI]
155.  Sali S, Tavakolpour S, Farkhondemehr B. Comparison of Vitamin D Levels in Naive, Treated, and Inactive Carriers with Chronic Hepatitis B Virus. J Clin Transl Hepatol. 2016;4:306-309.  [PubMed]  [DOI]
156.  Mashaly M, Sayed EE, Shaker GA, Anwar R, Abbas NF, Zakaria S, Barakat EA. Occult and Chronic Hepatitis B Infection: Relation of Viral Load to Serum Level of 25 Hydroxy Vitamin D. Int J Curr Microbiol App Sci. 2016;5:660-669.  [PubMed]  [DOI]
157.  Ladero JM, Torrejón MJ, Sánchez-Pobre P, Suárez A, Cuenca F, de la Orden V, Devesa MJ, Rodrigo M, Estrada V, López-Alonso G. Vitamin D deficiency and vitamin D therapy in chronic hepatitis C. Ann Hepatol. 2013;12:199-204.  [PubMed]  [DOI]
158.  Corey KE, Zheng H, Mendez-Navarro J, Delgado-Borrego A, Dienstag JL, Chung RT; HALT-C Trial GroupSerum vitamin D levels are not predictive of the progression of chronic liver disease in hepatitis C patients with advanced fibrosis. PLoS One. 2012;7:e27144.  [PubMed]  [DOI]
159.  Okubo T, Atsukawa M, Tsubota A, Shimada N, Abe H, Yoshizawa K, Arai T, Nakagawa A, Itokawa N, Kondo C. Association between vitamin D deficiency and pre-existing resistance-associated hepatitis C virus NS5A variants. Hepatol Res. 2017;47:641-649.  [PubMed]  [DOI]
160.  Atsukawa M, Tsubota A, Shimada N, Yoshizawa K, Abe H, Asano T, Ohkubo Y, Araki M, Ikegami T, Kondo C. Influencing factors on serum 25-hydroxyvitamin D3 levels in Japanese chronic hepatitis C patients. BMC Infect Dis. 2015;15:344.  [PubMed]  [DOI]
161.  Reda R, Abbas AA, Mohammed M, El Fedawy SF, Ghareeb H, El Kabarity RH, Abo-Shady RA, Zakaria D. The Interplay between Zinc, Vitamin D and, IL-17 in Patients with Chronic Hepatitis C Liver Disease. J Immunol Res. 2015;2015:846348.  [PubMed]  [DOI]
162.  Atsukawa M, Tsubota A, Shimada N, Abe H, Kondo C, Itokawa N, Nakagawa A, Iwakiri K, Kawamoto C, Aizawa Y. Serum 25(OH)D3 levels affect treatment outcomes for telaprevir/peg-interferon/ribavirin combination therapy in genotype 1b chronic hepatitis C. Dig Liver Dis. 2014;46:738-743.  [PubMed]  [DOI]
163.  Mandorfer M, Reiberger T, Payer BA, Ferlitsch A, Breitenecker F, Aichelburg MC, Obermayer-Pietsch B, Rieger A, Trauner M, Peck-Radosavljevic M; Vienna &amp; & Liver Study GroupLow vitamin D levels are associated with impaired virologic response to PEGIFN + RBV therapy in HIV-hepatitis C virus coinfected patients. AIDS. 2013;27:227-232.  [PubMed]  [DOI]