Review article: the extra-skeletal effects of vitamin D in chronic hepatitis C infection

Authors

  • E. Cholongitas,

    1. 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
    Search for more papers by this author
  • E. Theocharidou,

    1. The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital, London, UK
    Search for more papers by this author
  • J. Goulis,

    1. 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
    Search for more papers by this author
  • E. Tsochatzis,

    1. The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital, London, UK
    Search for more papers by this author
  • E. Akriviadis,

    1. 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
    Search for more papers by this author
  • A. K. Burroughs

    Corresponding author
    1. The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital, London, UK
    • 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
    Search for more papers by this author

  • This uncommissioned review article was subject to full peer-review.

Correspondence to:

Prof. A. K. Burroughs, Liver Transplantation and Hepatobililary Medicine, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK.

E-mail: andrew.burroughs@nhs.net

Summary

Background

Recent interest has focused on the extra-skeletal effects of vitamin D, in particular, in patients with chronic hepatitis C.

Aims

To review data in the literature regarding the extra-skeletal effects of vitamin D in patients with chronic hepatitis C, with and without liver transplantation.

Methods

A Medline search was performed for relevant studies up to August 2011 using the terms ‘vitamin D’ ‘chronic liver disease’ and ‘hepatitis C’.

Results

Vitamin D deficiency is very frequent before liver transplantation ranging between 51% and 92%, whereas, in the liver transplantation setting, the prevalence of vitamin D deficiency is also high. Severe liver disease may increase the risk of vitamin D deficiency and vice versa, as there may be a relationship between vitamin D deficiency and fibrosis. In patients with chronic hepatitis C and those with recurrent of hepatitis C after liver transplantation, recent clinical data shows that a higher serum vitamin D level is an independent predictor of sustained virological response (SVR) following anti-viral therapy, and that a higher SVR is achieved with vitamin D supplementation.

Conclusions

Larger randomised clinical studies with adequate statistical power are needed to confirm these potentially very important nonskeletal effects of vitamin D in patients with chronic hepatitis C.

Introduction

Vitamin D is a term used to describe several related compounds.[1] The metabolism of vitamin D includes the conversion of 7-dehydrocholesterol to previtamin D in the skin after exposure to solar ultraviolet B radiation, which is then isomerised to vitamin D. Vitamin D is also ingested with food as ergocalciferol (vitamin D2) from plants and cholecalciferol (vitamin D3) from animals. Both forms containing a single hydroxyl group at the 3rd carbon, are then released and circulated in serum, and bound to the vitamin D-binding protein. Vitamin D is transported to the liver where it becomes biologically active as 25-hydroxy vitamin D (25-OH vitamin D) via hydroxylation of the 25th position, which is the form of vitamin D storage in the body.[2] The second hydroxylation takes place in the renal proximal tubule, with the production of 1,25-dihydroxyvitamin D [1,25(OH)2 vitamin D], via mitochondrial 1a-hydroxylase enzyme, which is the biologically active form of vitamin D. Vitamin D acts via its receptor (vitamin D receptor, VDR) on responsive genes, affecting their transcription,[3] such as those coding for regulation of calcium homeostasis and turnover of bone metabolism.[4]

The importance of vitamin D is related mainly to calcium-related effects on the skeleton. The classic physiological roles of vitamin D are to increase intestinal calcium absorption in the small intestine and to stimulate calcium transport from bone and kidney to the blood. Thus, vitamin D deficiency affects bone development leading to rickets in children (or osteomalacia in adults) and increased risk of osteoporosis.[5]

Recent interest has focused on the nonskeletal effects of vitamin D in several systems. Low 25-OH vitamin D concentrations may be related to increased prevalence of various cancers (e.g. colon, prostate, breast) and autoimmune diseases, as well as cardiovascular events, possible due to the higher frequency of insulin resistance, diabetes mellitus type II and metabolic syndrome.[6] These extra-skeletal actions of vitamin D are related to the presence of VDR in several cells, such as macrophages, natural killer cells, T and B cells, such that vitamin D is also a key regulator of innate immunity in humans. Indeed, vitamin D regulates more than 200 genes, associated with immune response, cellular proliferation and differentiation, apoptosis and angiogenesis.[7] Finally, a recent in vitro study suggested an interaction between vitamin D and CYP24A1 gene expression in hepatocellular carcinoma, which affected the response and resistance of tumour cells in relation to the anticancer activity of vitamin D.[8] Recent studies have also shown that vitamin D is implicated in the severity of liver dysfunction and rejection rates[9] in liver transplant recipients.

This review focuses on patients with chronic hepatitis C (CHC), in whom vitamin D has been associated with the severity of fibrosis, and more recently, the response to anti-viral therapy in patients with CHC and in those after liver transplantation.

Search Strategy

Medline/PubMed was searched up to October 2011 using the terms ‘vitamin D’ and ‘hepatitis C’ or ‘osteoporosis’. Two authors (EC, ETh) identified articles independently, which could be potentially included after having screened titles and abstracts. In addition, a manual search of all references of relevant review articles and of the retrieved original studies, as well as of abstracts from the major Hepatology and Liver Transplant congresses during the last 2 years was performed.

Study selection

Randomised trials or observational cohort studies with adult CHC patients were included if they fulfilled one of the following criteria: (i) had data on the incidence of vitamin D deficiency; (ii) had data of the association of vitamin D with severity of liver function or severity of liver fibrosis; and (iii) evaluation of the impact of vitamin D on the response to anti-viral therapy, including studies with HIV/HCV co-infection patients. Each study in the list of the preselected papers was evaluated by two independent reviewers (EC, AKB) to determine whether it fulfilled the inclusion criteria.

EC and ETh performed data extraction, and any conflicts were arbitrated by AKB. In total, 141 articles were initially identified from the literature search, but only 30[9-38] articles fulfilled the inclusion criteria (Figure 1). For studies that evaluated the impact of vitamin D on the response to anti-viral therapy, we considered randomised, controlled trials as high-quality evidence, prospective cohort studies as intermediate-quality evidence and retrospective cohort studies as low quality evidence. Thus, there was only one randomised, controlled trial;[21] five studies were prospective cohort studies[11, 20, 23, 36, 37] and six were retrospective cohort studies.[16, 18, 22, 24, 35, 38]

Figure 1.

Study flow diagram.

Vitamin D in Chronic Hepatitis C Infection

Prevalence of vitamin D deficiency

In five studies[10, 12, 13, 25, 26] evaluating chronic hepatitis C, the proportion of patients with vitamin D deficiency ranged between 51% and 92%. However, different cut-offs for the lower limit of the normal range were used (ranging between 20 and 32 ng/mL)[10, 12, 13, 25, 26]; in one large study of 100 patients (51 with cirrhosis), vitamin D deficiency was rare, found in only 3%.[14] However, in the latter study,[14] the normal range was not given. In another seven studies,[19, 27-32] the mean or median values of vitamin D were below or at the lower limit of the normal ranges in all studies (14.1–30.2 ng/mL), but the proportion of HCV patients with vitamin D deficiency was not stated. Finally, in one study,[11] both the proportion of patients with vitamin D deficiency (73% of 149 CHC patients had <30 ng/mL) and mean vitamin D levels (25.1 ng/mL) were given (Table 1).

Table 1. Studies on the prevalence of vitamin D in patients with chronic hepatitis C liver disease before liver transplantation
Author (Ref) (Country)Patients, nAetiologyPatients with cirrhosis, n (%)Control groupPatients with inadequate vitamin D, n (%)Serum levels of vitamin DComments
  1. NA, not available.

  2. a

    Unknown definition of vitamin D deficiency.

Solis-Herruzo et al.[27] (Spain)32Chronic hepatitis CNANoNAMean: 30.2 ng/mL
Duarte et al.[14] (Brazil)100Chronic hepatitis C51 (51)No3 (3)a Vitamin D was lower in men compared with women
Carey et al.[28] (US)68Chronic hepatitis C60 (88)NoNAMean: 15.4 ± 9.3 ng/mLHCV patients had lower bone density, but fewer fracture than alcoholic patients
Schiefke et al.[29] (Germany)30Chronic hepatitis CNANoNAMedian: 28.05 ng/mL
Yenice et al.[30] (Turkey)30Chronic hepatitis CNAYesNAMean vitamin D: 14.16 ng/mLPremenopausal women: 17.01 vs. post-menopausal women: 11.32 ng/mL (< 0.05)
Fisher et al.[10] (Australia)10038 (38%) with HCV51 (51) (10 patients with HCV cirrhosis)No91 (91) had <20 ng/mL Vitamin D <50 nmol/L in 68 patients; 50–80 nmol/L in 23 patients.
Hofmann et al.[31] (Germany)30Chronic hepatitis C6 (20)NoNAMean: 30.1 ± 19.2 ng/mLAnti-viral therapy led to an on-treatment increase of bone density
Nanda et al.[32] (Ireland)20Chronic hepatitis C (postmeno-pausal women)2 (10)YesNAMedian: 23 ng/mLHigher levels of vitamin D in controls (69.3 ng/mL)
George et al.[25] (India)7210 (14%) had HCV100%72 (100)90% had <20 ng/mLNAVitamin D was not different between patients with low or normal bone mineral density
Petta et al.[11] (Italy)197Chronic hepatitis C18 (9)Yes144 (73) had <30 ng/mLMean: 25.1 ± 9.9 ng/mLFemale gender was an independent factor of vitamin D deficiency
Arteh et al.[12] (US)118100 (85%) with HCV61 (52) (43 patients with HCV cirrhosis)no109 (92.4) had <32 ng/mL [92 (92%) of 100 with HCV had <32 ng/mL]NAFemale gender, African American race and cirrhosis were independent predictors of severe vitamin D deficiency
Miroliaee et al.[13] (Iran)9028 (31%) with HCV51 (57) (16 patients with HCV cirrhosis)YesVitamin D deficiency (<20 ng/mL) was found in 46 (51.1) patients Lower serum level of vitamin D was associated with hyperbilirubinemia, hypoalbuminemia and thrombocytopenia
Choudhary et al.[19] (India)19Chronic hepatitis C19 (100)yesNA18.89 ± 15.40 ng/mLAlcoholic and viral groups had similar baseline vitamin D levels
Nusbaum J et al.[26] (US)160 (all cirrhosis139 (87%) with CHC160 (100)No149 (92) had vitamin D <32 ng/mLNA

The pathogenic factors implicated in deranged vitamin D metabolism in patients with chronic liver diseases have not been elucidated. Although in cholestatic chronic liver disease, deficiency of vitamin D has been attributed to malabsorption of lipid soluble vitamins (A, D, E, K), in patients with chronic liver disease, in general, liver dysfunction may interfere with vitamin D synthesis. Thus, although separate data for CHC patients were not available,[9, 10, 13, 15, 26, 33] the results were consistent: worse liver function was associated with lower vitamin D levels (Table 2). Thus, vitamin D levels were higher in patients with Child-Pugh A (range: 18.39–95.7 ng/mL) compared with those with Child-Pugh B (range: 13.1–60.3 ng/mL) or Child-Pugh C (range: 9.11–46 ng/mL).[10, 15, 33] These findings have been confirmed by two studies[9, 26] using the Model for End Stage Liver Disease (MELD) score for evaluation of liver dysfunction (Table 2).

Table 2. Literature data on the vitamin D deficiency and severity of liver disease in studies with cohorts of CHC patients
Author (Ref)CountryPatients, nAetiologySerum levels of vitamin D (based on severity of liver disease)Comments
  1. NA, not available; pts, patients.

Gallego-Rojo et al.[33]Spain32Viral hepatitis (24 with HCV)

Child-Pugh class

A: 48.3, B:26, C: 12 ng/mL (< 0.05)

Gonzalez-Calvin[15]Spain40Viral hepatitis

Child-Pugh class

A: 95.7, B: 60.3, C: 46 ng/mL (< 0.05)

Fisher et al.[10]Australia10038 (38%) with HCV

Child-Pugh class

A: 18.39, B: 13.1, C: 9.11 ng/mL (< 0.001)

Serum vitamin D independently correlated with INR (= 0.018) and serum albumin (= 0.007)
Miroliaee et al.[13]Iran9028 (31%) with HCVNoncirrhotics: 32.6 ± 12.2 vs. Cirrhotics: 16.35 ± 9 ng/mL (< 0.001)The prevalence of vitamin D deficiency was significantly higher in cirrhotic vs. noncirrhotic patients (76.5% vs. 17.9%; < 0.001),
Bitetto et al.[9]Italy13376 (57%) with viral hepatitisOnly 11 (23.4%) of 47 patients with MELD score >15 had vitamin D >12.5 ng/mLMELD score was the only independent predictor of a low basal vitamin D value
Nusbaum J et al.[26]US160 (all cirrhosis)139 (87%) with CHCPatients with vitamin D >20 ng/mL had significantly lower MELD score compared to those with vitamin D 7–19 ng/mL or <7 ng/mL (11.9 vs. 13 vs. 17.2, < 0.0001)MELD score was significantly associated with Vitamin D level (= 0.0007).

However, impaired hepatic synthesis of vitamin D cannot be considered as the only mechanism of deficiency, as some studies report an adequate production of 25-OH vitamin D even in advanced stages of liver disease.[14, 39] Other contributing co-factors could be the lower exposure to sunlight, malnutrition and a potential direct effect of HCV on vitamin D metabolism or an indirect effect via induction of cytokines or oxidative stress.[16] In fact, Lange et al.[16] found that even in HCV patients with no fibrosis or minor fibrosis, there was a higher incidence of vitamin D deficiency compared with healthy controls.[16] In the same study,[16] vitamin D concentrations were determined before and after anti-viral therapy – there was a trend towards a lower incidence of severe vitamin D deficiency after HCV eradication (33% vs. 26%, = 0.092).

Vitamin D and severity of liver fibrosis

Severe liver disease does increase the risk of vitamin D deficiency. There is also evidence that low vitamin D serum levels can lead to worse fibrosis, increase the rate of development to cirrhosis and also increase fibrosis in other body systems. In the respiratory system, the administration of 1,25 (OH)2 vitamin D induces down regulation of pro-fibrogenic transforming growth factor (TGF)-1 and other mesenchymal and epithelial cell markers. Thus, vitamin D may be a biologically relevant inhibitor of the pro-fibrotic phenotype of lung fibroblasts and epithelial cells.[40]

Pathogenic factors for vitamin D deficiency in severe liver fibrosis

Vitamin D is a potent regulator of proliferation, differentiation and migration of fibroblasts and vascular smooth muscle cells affecting the composition of extra-cellular matrix.[41] Thus, low vitamin D could be a signal for fibrogenesis via the secretion of TGF-1 or may affect the equilibrium between certain matrix metalloproteinases (MMPs) (such as MMP-2 and -9) and their inhibitors, leading to increased collagen production. MMP-2 and MMP-9 are of particular interest in liver, because they are critically involved in the degradation of collagen IV and fibronectin in the space of Disse.[42] In mice models, vitamin D increases the antifibrotic action of natural killer cells.[43] In addition, as T cells are activated via a vitamin D pathway, it could be that low serum vitamin D concentrations inhibit T cell function, thus reducing their capacity to inactivate hepatitis C virus. The resulting increased necroinflammation would aggravate fibrosis in patients with CHC.[44] Vitamin D has been implicated in the control of programmed cell death (i.e. apoptosis). In the liver, it acts as an antiapoptotic factor on hepatocytes.[45] Apoptosis of hepatocytes has been recognised as a significant trigger factor for accumulation of extra-cellular matrix, fibrogenesis and finally cirrhosis.

All of the above factors could explain not only the high prevalence of vitamin D deficiency in CHC patients but also the association between the severity of vitamin D deficiency and the severity of liver fibrosis. This has been shown in several recent studies[11, 16, 22, 23] (Table 3). However, Kastens et al.[17] found no association between the severity of liver fibrosis and levels of vitamin D in 157 patients with CHC of various genotypes (no further data were available), and Stauber et al.[18] found no significant difference in vitamin D levels in 179 genotype 1/4 CHC patients with fibrosis stage F0–2 compared with F3–4 (23.0 ± 13.7 ng/mL vs. 20.2 ± 10.8 ng/mL, > 0.05).

Table 3. Studies on the prevalence of vitamin D deficiency and severity of liver fibrosis in patients with chronic hepatitis C infection
Author (Ref)CountryPatients, nLevels of vitamin D (vs. control)Levels of vitamin D (based on severity of fibrosis)Comments
  1. NA, not applicable.

Petta et al.[11]Italy19725.07 ± 9.92 ng/mL vs. 43.06 ± 10.19 ng/mL (< 0.001)Scheuer score 1–2: 21.9 ± 8.8 vs. Scheuer score ≥3: 26.3 ± 10.0 ng/mL (= 0.005)Low serum vitamin D independently associated with severe fibrosis
Lange et al.[16]Germany46866% of patients had vitamin D <20 ng/mL (vs. 41% of the control group) (< 0.00001)63% of METAVIR F0–F1 had vitamin D <20 ng/mL (vs. 73% of METAVIR F2–F4), (= 0.003)Significant correlation of the CYP27B1-1260 promoter polymorphism rs10877012 with 1,25-hydroxyvitamin D serum levels
Kastens et al.[17]Germany157NAno association between severity of liver fibrosis and levels of vitamin DLower serum zinc levels were significantly associated with advanced fibrosis
Stauber et al.[18]Austria179NAMETAVIR F0–2: 23.0 ± 13.7 ng/mL (vs. METAVIR F3–4: 20.2 ± 10.8 ng/mL) (> 0.05)
Bitetto et al.[22]Italy211Median: 20.7 ng/mL (range: 2.1–59.6)Among the patients with vitamin D ≤10 ng/mL, 76.2% had fibrosis stage >2 (Ishal score) and 23.8% had fibrosis stage ≤2 (< 0.05)In multivariate analysis, the histology grade (OR 3.42) and drawing the blood sample in the winter or spring months (OR 2.79) were the only independent predictors of low vitamin D serum levels
Terrier et al.[23]France189 (HIV-HCV co-infected)Mean: 18.5 ± 9.8 ng/mLMETAVIR F3/F4 vs. F1/F2: 16.2 ± 10.0 vs. 19.2 ± 9.3 ng/mL, (= 0.06)In multivariate analysis, low serum vitamin D was independently associated with severe liver fibrosis (= 0.04) after adjustment for age, steatosis, male and trimester

Thus, low serum vitamin D status may represent a pro-fibrogenic entity, and may contribute in part to the progression of histological lesions in CHC. Therefore, correction of vitamin D insufficiency may have important therapeutic implications as a ‘general’ antifibrotic agent in CHC by preventing hepatic apoptosis and thus fibrogenesis.[46]

Vitamin D and Response to Anti-Viral Therapy

Vitamin D in nontransplant HCV patients

Most of the clinical data supports a beneficial effect of vitamin D on virological response in HCV patients[11, 16, 18, 20-24, 34-38] (Table 4). Two studies[11, 20] including 177 CHC genotype 1-naïve patients who received PEG-interferon with ribavirin for 48 weeks showed that in the logistic regression analysis, vitamin D levels were independent factors associated with sustained virological response (SVR). For example, in the study by Petta et al.[11] low cholesterol (OR, 1.009; 95% CI, 1.000–1.018; P < 0.04), low 25-OH vitamin D levels (OR, 1.039; 95% CI, 1.002–1.077; P < 0.03) and greater steatosis (OR, 0.971; 95% CI, 0.944–0.999; P < 0.04) were the only independent negative predictors of SVR. However, a recent abstract[18] showed no association between vitamin D and SVR in 179 treatment-naïve patients with genotype 1/4 CHC who received PEG-interferon and ribavirin for 48 weeks (vitamin levels in SVR patients 22.0 ± 12.1 ng/mL vs. 22.7 ± 14.4 ng/mL in non-SVR patients, > 0.05). In addition, Lange et al.[16] found that only in CHC genotype 2/3 patients (treated with PEG-interferon and ribavirin for 24 weeks), but not in the group of CHC genotype 1 patients, was vitamin D deficiency associated with lower SVR rates compared with those with higher vitamin D levels (50% vs. 81%, respectively, < 0.0001). Notably, in a vitro study, [47] physiological doses of vitamin D neither affected HCV-RNA replication nor the production of infectious particles .

Table 4. Studies evaluating the impact of vitamin D replacement on response to anti-viral therapy in patients with chronic hepatitis C
Author (Ref) (Country)Patients, nGenotypeAnti-viral therapyDose/duration of vitamin DCut-off for vitamin D deficiencySustained viral response (SVR), n (%)Comments
  1. BMI, body mass index; PEG, pegylated, SVR, sustained virological response.

  2. a

    The same study group found that vitamin D was also associated with the achievement of rapid and early virological response in 155 patients with genotype 1 CHC.[34]

  3. b

    Vitamin D deficiency (25-OH vitamin D <10 ng/mL) was not associated with SVR in HCV genotype 1 patients.

Petta et al.[11]a (Italy)197Genotype 1PEG-interferon plus ribavirin for 48 weeks30 ng/mL70 (35.5)Low 25-OH vitamin D levels was an independent factor of SVR (OR: 1.039; P < 0.03)
Mouch et al.[21] (Israel)40Genotype 2/3PEG-interferon plus ribavirin (800–1200 mg/day for 24 weeks1000–4000 IU/day for 24 weeks32 ng/mLAdministration of vitamin D was associated with higher SVR rates [95% (19/20) vs. 85% (17/20), < 0.01)].Vitamin D levels (OR 3.9, < 0.01) and BMI (OR 2.6, < 0.001) were independent predictors of SVR
Nseir et al.[20] (Israel)80Genotype 1PEG-interferon plus ribavirin for 48 weeks20 ng/mL34 (40)Responders had higher vitamin D levels than nonresponders (42.1 ± 6.0 vs. 27.3 ± 5.2 ng/mL, < 0.001)
Lange J et al.[16]b (Germany)468Genotype 1/2/3Interferon (or PEG-interferon) plus ribavirin (±amantadine) for 24 or 48 weeks10 ng/mLThe overall SVR: 60% (genotype 1, 2, 3: 52%, 85%, and 72%, respectively)In genotype 2/3 patients, vitamin D serum concentrations were an independent predictors of SVR (= 0.009)
Stauber et al.[18] (Austria)179Genotype 1/4PEG-interferon plus ribavirin for 24–72 weeks30 ng/mL104 (58)Vitamin D levels were not different in patients with SVR (22.0 ± 12.1 ng/mL) vs. no SVR (22.7 ± 14.4 ng/mL)
Bitetto et al.[22] (Italy)21195 (45.0%) patients with genotype 1PEG-interferon plus ribavirin for 24–48 weeks20 ng/mL134 (63.5)Vitamin D may be complementary to that of the IL-28B polymorphism to predict SVR achievement.
Jazwinski A et al.[35] (1041) (US)82 African AmericanGenotype 1PEG-interferon plus ribavirin-20 ng/mL8 (9.8)There was no difference between median vitamin D levels in patients with SVR
Almerighi C et al.[36] (1049) Italy42 (non-responders)Genotype 1PEG-interferon plus ribavirin for 24 or 48 weeks5000 IU/day induction therapy for 1 monthNA4%High dose of vitamin D is safe, but did not improve the SVR
Bitetto et al.[24] (Italy)42 (with recurrent HCV after LT)32 (76%) patients with genotype 1Interferon (or PEG-interferon) plus ribavirin for 48 weeks800 IU/day started at median time 425 days before anti-viral therapy20 ng/mL13 (31)Administration of vitamin D was associated with higher SVR rates (8/15 vs. 5/27, respectively, < 0.02)
Terrier et al.[23] (France)189 (HIV-HCV co-infected)115 (61%) genotype 1/4Interferon (or PEG-interferon) plus ribavirin for 48 weeks10 ng/mL61 (33)No correlation between vitamin D and SVR
Soumekh A et al.[37] (USA, Australia)88 (HIV-HCV co-infected)88% genotype 1/4PEG-interferon plus ribavirin30 ng/mL13 (15)Higher baseline and on-treatment levels of vitamin D show positive associations with treatment outcomes.
Reiberger T et al.[38] Austria84 (HIV-HCV co-infected)47 (56%) genotype 1PEG-interferon plus ribavirin-30 ng/mL43 (52)SVR rates were significantly higher in HCV-HIV coinfected patients with normal vitamin D levels

It is known that vitamin D deficiency is more prevalent among blacks compared with nonblacks, and this finding together with the decreased prevalence among blacks of an interleukin (IL)-28B C/C allele, could explain the lower SVR in this patient group with HCV infection.[48] However, Jazwinski et al.[35] found no association between vitamin D levels and SVR in 82 African American genotype 1 CHC-naïve patients, who had been treated with PEG-IFN and RBV: eight patients (9.8%) who achieved SVR compared with 74 patients without SVR (90.2%), had similar baseline median vitamin D levels (23.3 ng/mL vs. 19.3 ng/mL, = 0.82). In nonblack CHC patients, Bitetto et al.[22] suggested that evaluating vitamin D concentrations may be complementary to evaluating IL-28B polymorphism, to predict the likelihood of SVR. The authors evaluated 211 consecutive CHC-naïve patients who received PEG-interferon and ribavirin: IL-28B rs12979860 C/C allele and high vitamin D serum levels, were independently associated with SVR, whereas the non-C/C genotype and vitamin D levels <20 ng/mL were associated with the lowest SVR rate [SVR in 9 (22.5%) of 40 HCV patients].

Two studies documented the impact of vitamin D administration in CHC patients during anti-viral therapy. Almerighi et al.[36] were the first to evaluate 22 nonresponders CHC genotype 1 patients with advanced fibrosis or cirrhosis and with normal baseline vitamin D values (mean 64 ± 36 ng/mL). The patients received induction therapy with high doses of vitamin D (cholecalciferol 5000 IU/day) for 1 month, followed by PEG-IFN and RBV (1000–1400 mg/day) and vitamin D (1500 IU/day). Twelve (54%) patients achieved early virological response, and only one (4%) had SVR. The authors concluded that vitamin D therapy had no impact on SVR in this group of difficult to treat patients. Mouch et al.[21] evaluated 40 patients with genotype 2/3 hepatitis C infection with contrasting results: patients who received PEG-interferon with ribavirin (800–1200 mg/day) together with oral vitamin D (1000–4000 IU/day) for 24 weeks, (compared with those who received the same standard of care without vitamin D), had a significantly higher SVR rate [95% (19/20) vs. 85% (17/20), < 0.01) despite a higher body mass index (BMI) (29 vs. 26, < 0.001) and higher baseline viral load (>600 000 IU/mL) (45% vs. 40%, < 0.01).

In HIV–HCV co-infection, one fully published study[23] and two recent abstracts[37, 38] evaluated the impact of vitamin D on SVR. In two studies[37, 38], 172 patients were treated with PEG-interferon and ribavirin for at least 24 weeks. Soumekh A[37] found that low serum vitamin D levels (less than 18 ng/mL) was the only independent factor significantly associated with not achieving SVR, whereas, in the study by Reiberger et al.[38], HCV-RNA reduction at week 4 was significantly less frequently in patients with vitamin D insufficiency compared with those with normal vitamin D levels (log drop in HCV-RNA (−3.65 vs. −4.01 IU/mL, = 0.046). In contrast to the two previous studies,[37, 38] Terrier et al.[23] evaluated 189 HIV–HCV co-infected patients who received interferon with ribavirin therapy: low serum vitamin D was inversely correlated with the histological Metavir fibrosis score (r = −0.16; = 0.027), with liver fibrosis as assessed using the FibroTest (r = −0.22; = 0.008) and serum a2-macroglobulin levels (r = −0.23; = 0.006). However, low serum vitamin D was not associated with HCV-RNA response to anti-viral therapy or the markers of HIV-related immunodeficiency, such as CD4 T cell count and HIV viral load.

Vitamin D in transplanted HCV patients

Although vitamin D status after renal transplantation has been extensively evaluated, there is scanty data for liver transplantation (LT). Only one study from Israel evaluated vitamin D deficiency after long-term follow-up: serum 25-OH vitamin D values were below the normal range in 13 (68%) of 19 patients, with seven patients having vitamin D deficiency (serum level below 10 μg/L) and 10 being vitamin D insufficient (serum level between 10 and 15 μg/L), 2–12 years after LT.[49]

Regardless of the true prevalence of vitamin D deficiency after LT, recent studies have evaluated the effect of vitamin D on virological response after anti-viral therapy in patients with recurrence of HCV infection after LT. Bitetto et al.[24] found that patients with severe vitamin D deficiency (= 10, vitamin D <10 ng/mL) almost never achieved SVR [1/10 (10%)], in contrast to those with near normal 25-OH vitamin D levels (= 12, >20 ng/mL) [SVR: 6/12 (50%)]. In addition, patients who were supplemented with vitamin D (cholecalciferol 800 IU/day) during anti-viral therapy achieved a SVR more frequently than patients who were not supplemented [8/15 (53%) vs. 5/27 (18.5%), respectively, < 0.02].

In the same study,[24] a potential synergistic effect between baseline 25-OH vitamin D levels and cholecalciferol supplementation was evaluated. Patients were divided into three groups: group 1 – (= 22) comprising patients with basal serum 25-OH vitamin D <20 ng/mL, not supplemented with cholecalciferol; group 2 – (= 13) patients with basal serum 25-OH vitamin D >20 ng/mL not supplemented with cholecalciferol (= 5) or patients with basal serum 25-OH vitamin D <20 ng/mL and cholecalciferol supplementation (= 8); and group 3 – (= 7) patients with serum 25-OH vitamin D >20 ng/mL and cholecalciferol supplementation. A significant linear trend was observed, from group 1 to group 3, in the rate of SVR [4/22 (18%) vs. 4/13 (31%) vs. 5/7 (71%), respectively, < 0.02]. This finding was independent of HCV genotypes. In their Cox proportional hazard model analysis, cholecalciferol supplementation (in the presence of a normal or near normal baseline serum vitamin D concentration), and non-1 genotypes were the only variables independently associated with SVR.

Pitfalls in vitamin D measurement

It is important to realise that no study considered the fact that circulating serum vitamin D is bound to vitamin D-binding protein and albumin, which may lead to an artificially high prevalence of vitamin D deficiency in patients with advanced liver disease and hypoalbuminemia.[50] In addition, another important issue is the season, in which the blood sample for vitamin D measurement is drawn; autumn and winter months were independently associated with low vitamin D serum levels,[23, 51] and may account for some of the variability in the results. Another important issue is that different laboratory assays for vitamin D have been used, either automated (e.g. chromatography) or not (e.g. radioimmunoassay). Although there is good agreement between these assays, variations in measurement have been attributed to differences in assay calibration.[52]

Conclusions

The biological activities of vitamin D are considered particularly complex,[53] partly because its receptor is expressed in several types of cells. Several recent studies suggest that vitamin D has important extra-skeletal actions in CHC in both pre- and post-LT settings. The prevalence of vitamin D deficiency is high among patients with CHC (Table 1). We found that although in one study,[14] only 3% had vitamin D deficiency (no definition of deficiency was provided), all the other studies[10-13, 19, 25-32] suggested that a significant proportion of patients had inadequate levels of vitamin D, which ranged between 51% and 92%, or the mean/median values of vitamin D were below the upper limit of the normal range (<30 ng/mL), used in the studies.

In addition, vitamin D deficiency is associated with the severity of liver dysfunction assessed using Child-Pugh or MELD scores (Table 2). The association of vitamin D and severity of histological lesions are conflicting, as three studies[11, 16, 22] found lower levels of vitamin D in CHC patients with greater fibrosis, but another two studies[17, 18] found no clear association, whereas in one study[23] with HCV/HIV co-infection patients, the association was marginally significant (Table 3). Nevertheless, it seems reasonable that in patients with CHC and low serum levels of vitamin D, a higher sun light exposure could be recommended as a minimum therapeutic intervention. Alternatively, vitamin D as cholecalciferol 800–1000 IU/day could be prescribed, with follow-up to avoid hypervitaminosis. However, well-designed studies showing slower progression of fibrosis under vitamin D supplementation are needed for final recommendations. Although HCV infection has a more aggressive course after LT, no study has evaluated the impact of serum vitamin D on fibrosis progression after LT. In addition, the exact interaction between hepatitis C virus and vitamin D has not been elucidated.

Recent studies have shown the association of serum levels of vitamin D with attainment of SVR in patients with CHC (Table 4). Vitamin D can be used as a complementary variable to IL-28B polymorphism to predict attainment of SVR.[22] On the basis of the available data, we suggest evaluation of vitamin D levels before starting anti-viral therapy in naïve CHC patients, and in the presence of vitamin D deficiency, it might be preferable to correct the deficiency, first by giving cholecalciferol 800–1000 IU/day, which is the currently recommended dose for vitamin D supplementation. However, it should be noted that different cut-off values for definition of vitamin D deficiency have been used, ranging from <10 to <32 ng/mL (Table 4). Vitamin D levels lower than 20–30 ng/mL are reasonable to use as a cut-off for vitamin D supplementation, as most studies have considered either of these cut-offs to define vitamin D deficiency (Table 4). Alternatively, vitamin D supplementation could be started at the same time as with anti-viral therapy, but this was only assessed in one study in nontransplanted treatment-naïve CHC patients[21] (using a relatively high dosage of vitamin D, i.e. 1000–4000 IU/day), and in only one study[24] in the post-LT setting (using a standard dose of 800 IU/day). Based on the available data,[36] vitamin D administration seems to have no impact on SVR in nonresponders CHC genotype 1 patients. However, most data have been derived from Caucasian populations, whereas only one study evaluated the impact of vitamin D in ethnic black CHC patients. Further well-designed clinical studies are needed to confirm the beneficial effect of vitamin D on SVR rates after anti-viral therapy for HCV and the threshold for replacement of vitamin D before or after LT. The impact of vitamin D supplementation on SVR in CHC patients treated with the new direct acting anti-viral agents (i.e. boceprevir and telaprevir) will also need evaluation.

Acknowledgements

Declaration of personal and funding interests: None.

Ancillary