Vitamin D deficiency and hepatitis viruses-associated liver diseases: A literature review

Table 1 Representative studies on vitamin D deficiency in chronic hepatitis B virus patients

Study populationDiagnosisSample size (n)	Study design	Length of follow-up	Vitamin D cutoff (ng/mL)	(%)	Main results	Ref.
China CHB (n = 560)	Multicenter, randomized, controlled	104 wk from initiation of antiviral treatment	< 20: deficiency < 30: insufficiency ≥ 30: sufficiency	21 55 24	Vitamin 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-sectional	NA	< 14: severe deficiency ≥ 14: deficiency < 30 sufficiency	27 66 7	Vitamin D deficiency significantly associated with HBV genotype B	Zhu et al[93], 2016
Vietnam CHB (n = 165) LC (n = 127) HCC (n = 108)	Cross-sectional	NA	< 10: severe deficiency < 20: deficiency < 30: insufficiency ≥ 30: sufficiency	10.4 41.5 32.4 15.7	Vitamin 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 correlated	Hoan et al[4], 2016
China CHB (n = 115) LC ( = 115) HC ( = 115)	Cross-sectional	NA	< 10: deficiency < 20: insufficiency ≥ 20: sufficiency	83 17 0	Vitamin 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-sectional	NA	< 10: deficiency < 20: insufficiency ≥ 20: sufficiency	34.8 45.4 19.8	Vitamin D deficiency independently associated with advanced liver fibrosis	Ko et al[154], 2016
Iran CHB (n = 84)	Cross-sectional	NA	< 10: deficiency < 20: insufficiency ≥ 20: sufficiency	17.9 34.5 47.6	No significant association of vitamin D levels in treated and treatment-naïve patients	Sali et al[155], 2016
Multicenter in Europe, Asia and North America CHB (n = 737)	Randomized, open-label, active-controlled clinical trial	48 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: sufficiency	58 35 7	Reduced 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 outcomes	Chan et al[19], 2015
China CHB (n = 426)	Cross-sectional	NA	< 32 insufficiency ≥ 32 sufficiency	82 18	Vitamin D deficiency common among patients with CHB and associated with adverse clinical outcomes	Wong et al[78], 2015
China CHB (n = 242)	Cross-sectional	NA	< 20: deficiency < 30: insufficiency ≥ 30: sufficiency	8.7 31.4 60	Higher 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 patients	Yu et al[23], 2015
China CHB (n = 133)	Cross-sectional	NA	< 14: deficiency < 30: insufficiency ≥ 30: sufficiency	27 66.2 6.8	Higher prevalence of vitamin D insufficiency in HBV genotype B patients than in genotype C patients Vitamin D levels not associated with other clinical parameters	Zhu et al[93], 2016
Germany CHB (n = 203)	Cross-sectional	NA	< 10: deficiency < 20: insufficiency ≥ 20: sufficiency	34 47 19	HBV DNA viral loads as strong predictor of low vitamin D levels in CHB patients	Farnik et al[12], 2013
Egypt OBI (n = 16) CHB (n = 52)	Cross-sectional	NA	< 10: deficiency < 30: insufficiency ≥ 30: sufficiency	OBI: 12.5 CHB: 40.4 OBI: 62.5 CHB: 59.6 OBI: 25 CHB: 0	Vitamin D levels significantly higher in OBI than in CHB patients Serum level of vitamin D inversely correlated with HBV DNA loads	Mashaly et al[156], 2016
China CHB (n = 128)	Cross-sectional	NA	< 10: deficiency < 20: insufficiency ≥ 20: sufficiency	13.3 61.7 25	Vitamin D levels negatively correlated with HBV DNA loads Effective antiviral therapy might increase the level of vitamin D in CHB patients	Chen et al[11], 2015
Iran CHB (n = 173)	Cross-sectional	NA	< 10: deficiency < 20: insufficiency ≥ 20: sufficiency	58 39 3	Vitamin D levels inversely correlated with HBV DNA levels	Mohamadkhani et al[89], 2015

CHB: Chronic hepatitis B; LC: Liver cirrhosis; HCC: Hepatocellular carcinoma; CLD: Chronic liver disease; OBI: Occult hepatitis B infection; NA: Not applicable.

Table 2 Representative studies regarding vitamin D status in chronic hepatitis C virus patients

Study populationDiagnosisSample size (n)Study objective	Study design	Length of follow-up	Vitamin D cutoff (ng/mL)	(%)	Main results	Ref.
Italy CHC (n = 197) HCV genotype 1 controls (n = 49)	Cross-sectional	NA	< 30: deficiency ≥ 30: sufficiency	73 27	Low vitamin D linked to severe fibrosis and low SVR in IFN-based treatment	Petta et al[6], 2010
United States CHC (n = 218) LC (n = 123) Non-LC (n = 95)	Prospective	12 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: sufficiency	43 33 24	Vitamin D deficiency associated with HCV–related LC and with hepatic function No significant association between SVR12 and serum vitamin D levels at baseline	Backstedt et al[18], 2017
Switzerland CHC (n = 269) HCV genotypes 1-4	Case-control	NA	< 30: deficiency ≥ 30: sufficiency	74 26	No significant association between SVR and serum vitamin D levels irrespective of genotypes	Lange et al[20], 2012
Spain CHC genotypes 1-4 (n = 182)	Cross-sectional	NA	< 20: deficiency < 30: insufficiency ≥ 30: sufficiency	36 41 23	Vitamin D deficiency not related to biochemical and virological variables or to the stage of fibrosis stage	Ladero et al[157], 2013
Northern Italy CHC ( = 211) HCV genotypes 1-5	Prospective	24 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: sufficiency	46.4 53.6	SVR24 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, respectively	Bitetto et al[25], 2011
Multicenter study, United States Cases (histological progression or clinical decompensation; ( = 129), controls (n = 129)	Nested case-control study	Over 4 yr	At baseline: cases: 44.8 controls, 44.0	Not stated	No difference in vitamin D levels in patients with and without progression of HCV-associated liver disease	Corey et al[158], 2012
Multicenter study, Japan CHC (n = 247) HCV genotype 1b	Case-control	NA	< 20: deficiency < 30: insufficiency ≥ 30: sufficiency At baseline: 22(6–64)	Not stated	NS5A Y93H and L31M resistance-associated variants associated with vitamin D deficiency	Okubo et al[159], 2016
Multicenter study, France HCV-HIV coinfection (n = 189)	Cross-sectional	NA	< 30: deficiency ≥ 30: sufficiency	85 15	Low 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 levels	Terrier et al[7], 2011
Japan CHC (n = 619)	Cross-sectional	NA	< 20: deficiency < 30: insufficiency ≥ 30: sufficiency	47 36.7 16.3	Vitamin D levels influenced by gender, age, hemoglobin level, albumin and seasonality	Atsukawa et al[160], 2015
Egypt CHC (n = 70) controls (n = 50)	Cross-sectional	NA	At baseline Cases: 18.6 Control: 56	NA	Vitamin D decreased in HCV patients	Reda et al.[161], 2015
Australia CHC (n = 274) HCV genotype 1	Case-control	NA	< 20: deficiency < 30: insufficiency ≥ 30: sufficiency	16 48 36	Baseline vitamin D levels not associated with SVR or fibrosis stage in HCV genotype 1 but deficiency associated with high activity	Kitson et al[16], 2013
Japan CHC (n = 177)	Prospective	24 wk after cessation of antiviral therapy	Not stated	NA	SVR24 rates: 65% in patients with vitamin D levels > 18 ng/mL vs 38.5% in patients with vitamin D levels of < 18 ng/mL	Atsukawa et al[162], 2014
Egypt CHC (n = 101) HCV genotype 4 Vitamin D supplementation group (n = 50), controls (n = 51)	Randomized prospective	Until 72 wk from start of antiviral therapy SVR was assessed at week 72 from initiation of antiviral treatment	< 20: deficiency ≥ 20: insufficiency ≥ 30: sufficiency	95 5 0	No impact of vitamin D supplementation on SVR in HCV genotype 4 patients No correlation between vitamin D levels and stage of liver fibrosis	Esmat et al[15], 2015
Israel CHC (n = 72) HCV genotype 1 Vitamin D supplementation group (n = 36), controls (n = 36)	Randomized prospective	24 wk after cessation of antiviral treatment	< 10: severe deficiency < 20: insufficiency ≥ 20: sufficiency	21 59 20	Addition 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 prospective	24 wk after cessation of antiviral treatment	< 12: deficiency < 32: insufficiency ≥ 32: sufficiency	26 54 20	Addition 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 1	Randomized controlled	Until 72 wk from initiation of antiviral therapy	Not stated	Not stated	No impact of vitamin D levels on efficacy of antiviral therapy in naïve genotype 1 HCV patients	Belle et al[24], 2017
Egypt CHC (n = 66) Vitamin D group (n = 20) controls (n = 30)	Randomized prospective	24 wk after cessation of antiviral treatment	< 12: deficiency < 32: insufficiency ≥ 32: sufficiency	33.3 43.3 23.4	Addition of vitamin D to conventional Peg-IFNα/RBV therapy improved SVR24	Eltayeb et al[26], 2015
Germany CHC (n = 468) HCV genotypes 1-3	Retrospective	24 wk after cessation of antiviral treatment	< 30: deficiency ≥ 30: sufficiency	66 34	Vitamin 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 1-2	Retrospective	SVR was assessed at week 48 (HCV genotype 1) and at week 24 (HCV genotype 2) from initiation of antiviral treatment	Not stated	Not stated	Vitamin D can suppress HCV replication in hepatic cell lines Vitamin D serum levels associated with both SRV and RVR to Peg-IFNα based therapy	Jee-Fu et al[13], 2017
Germany CHC (n = 398) HCV genotype 1	Retrospective	SVR was assessed at week 24 from initiation of antiviral treatment	At baseline 18.7 (3-84.3)	Not stated	Addition of vitamin D to Peg-IFNα/RBV therapy for treatment-naïve patients with chronic HCV genotype 1: no significant association with SVR	Grammatikos et al[94], 2014
Austria HCV-HIV coinfection (n = 65)	Retrospective	24 wk after cessation of antiviral treatment	< 10: deficiency < 30: insufficiency ≥ 30: sufficiency	57 23 20	Low vitamin D levels may impair virological response to Peg-IFNα/RBV therapy, especially in difficult-to-treat patients	Mandorfer et al[163], 2013
Italy CHC (n = 42) Vitamin D supplementation group (n = 15) controls (n = 27)	Retrospective	SVR was assessed at week 48 from initiation of antiviral treatment	< 10: severe deficiency < 20: insufficiency ≥ 20: sufficiency	Not stated	Vitamin 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 1	Retrospective	24 wk after cessation of antiviral treatment	< 12: severe deficiency < 20: insufficiency ≥ 20: sufficiency	19 48 33	Higher vitamin D levels not associated with SVR in Peg-IFNα/RBV therapy	Loftfield 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-analysis	NA	< 10: severe deficiency < 20: deficiency < 30: insufficiency ≥ 30: sufficiency	Not stated	Low 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 SVR	Garcia-Alvarez et al[86], 2014
Meta-analysis To clarify any association between baseline vitamin D levels and SVR (n = 2605) (11 studies)	Meta-analysis	NA	Not stated	NA	Baseline vitamin D levels not associated with SVR in Peg-IFNα/RBV therapy, regardless of genotype Effect of vitamin D supplementation on SVR to be determined	Kitson 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-analysis	NA	Not stated	NA	Lower 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-analysis	NA	At baseline 17-43 ng/mL	NA	High 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 genotype	Villar 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-analysis	NA	NA	NA	Vitamin D supplementation significantly increased SVR rates to Peg-IFNα/RBV at 24 wk	Kim et al[96], 2017

CHC: Chronic hepatitis C; LC: Liver cirrhosis; ALF: Acute liver fairlure; IFNα: Interferon alpha; RBV: Ribavirin; Peg-IFN: Pegylated interferon; SVR: Sustained virolagical response; RVR: Rapid virological response; NA: Not applicable.