Systematic Reviews
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 18, 2017; 9(5): 278-287
Published online Feb 18, 2017. doi: 10.4254/wjh.v9.i5.278
Influence of vitamin D on liver fibrosis in chronic hepatitis C: A systematic review and meta-analysis of the pooled clinical trials data
Alia S Dadabhai, Behnam Saberi, Katie Lobner, Russell T Shinohara, Gerard E Mullin
Alia S Dadabhai, Behnam Saberi, Katie Lobner, Gerard E Mullin, Division of Gastroenterology and Hepatology, the Johns Hopkins University School of Medicine, Baltimore, MD 21224, United States
Russell T Shinohara, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
Author contributions: Dadabhai AS, Saberi B and Mullin GE contributed equally to the data evaluation, manuscript preparation, editing, figures, and final submission; Shinohara RT provided biostatistics methodology oversight, data extractions and meta-analysis with pooled data figure preparation and manuscript preparation and editing; Lobner K provided informatics methodology support, conducted the literature search, and reviewed and edited the manuscript.
Conflict-of-interest statement: All the authors declare that they have no competing interests.
Data sharing statement: Technical appendix, statistical code, and dataset are available from the corresponding author at adadabh1@jhmi.edu.
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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Alia S Dadabhai, MD, Assistant Professor, Division of Gastroenterology and Hepatology, the Johns Hopkins University School of Medicine, 4940 Eastern Ave A504, Baltimore, MD 21224, United States. adadabh1@jhmi.edu
Telephone: +1-410-5507857 Fax: +1-410-5507861
Received: November 16, 2016
Peer-review started: November 21, 2016
First decision: December 1, 2016
Revised: December 14, 2016
Accepted: January 2, 2017
Article in press: January 3, 2017
Published online: February 18, 2017

Abstract
AIM

To investigate the relationship between vitamin D and liver fibrosis in hepatitis C-monoinfected or hepatitis C virus (HCV)-human immunodeficiency virus (HIV) co-infected patients.

METHODS

Pertinent studies were located by a library literature search in PubMed/Embase/Cochrane/Scopus/LILACS by two individual reviewers. Inclusion criteria: (1) studies with patients with HCV or co-infected HCV/HIV; (2) studies with patients ≥ 18 years old; (3) studies that evaluated liver fibrosis stage, only based on liver biopsy; and (4) studies that reported serum or plasma 25(OH)D levels. Studies that included pediatric patients, other etiologies of liver disease, or did not use liver biopsy for fibrosis evaluation, or studies with inadequate data were excluded. Estimated measures of association reported in the literature, as well as corresponding measures of uncertainty, were recorded and corresponding odds ratios with 95%CI were included in a meta-analysis.

RESULTS

The pooled data of this systematic review showed that 9 of the 12 studies correlated advanced liver disease defined as a Metavir value of F3/4 with 25(OH) D level insufficiency. The meta-analysis indicated a significant association across studies.

CONCLUSION

Low vitamin D status is common in chronic Hepatitis C patients and is associated with advanced liver fibrosis.

Key Words: Vitamin D, Liver fibrosis, Hepatitis C virus, Chronic hepatitis C

Core tip: Vitamin D levels are associated with more advanced fibrosis in chronic hepatitis C.



INTRODUCTION

Hepatitis C virus (HCV) infection remains one of the most common etiologies of liver disease worldwide. A number of epidemiological papers have addressed the global prevalence of Hepatitis C. Lanini et al[1] reported that 100 million people globally have serological evidence of current or past HCV infection causing 700000 deaths annually while others suggest that the actual occurrence is double[2]. HCV remains the most common indication for liver transplantation in the United States[3]. Chronic infection with HCV can lead to liver inflammation, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver fibrosis is a result of excessive accumulation of extracellular matrix proteins, as part of the wound healing response to chronic injury and chronic inflammation[4]. Various factors have been associated with progression of fibrosis including duration of infection, age, male sex, diabetes, alcohol consumption and human immunodeficiency virus (HIV) co-infection[5].

Vitamin D is a hormone that has numerous biological properties that influence host physiology by regulating epigenetic regulation of more than 2000 genes throughout the body. Vitamin D is best known for its role in maintaining bone mineralization but has diverse and profound influences which can determine disease development and outcome. Although referred to as a vitamin, this steroid hormone is synthesized in the body by a series of hydroxylation reactions that occur in skin (7-hydroxylation), the liver (25-hydroxylation) and the kidney (1-hydroxylation)[6] (Figure 1). Reduction of the enzymatic conversion of 7-dehydrocholesterol to 1.25 hydroxy vitamin D at any of the three conversion steps can result in suboptimal vitamin D status[7]. Vitamin D has a number of influences on innate and adaptive immunity which are pertinent to study in conditions that are driven by chronic inflammation and maladaptive tissue injury[8,9]. Given the ubiquitous distribution of vitamin D receptors in virtually every cell in the body-suboptimal vitamin D status has been studied for its relationship to numerous diseases[10]. For example, there is substantial evidence that vitamin D benefits rheumatoid arthritis, due to its immunomodulatory effect[11]. The role of vitamin D in various cancers has been established linked to its antiproliferative action mediated through vitamin D nuclear receptor[12]. There have been numerous reports on lower serum vitamin D levels in patients with chronic liver disease from various etiologies[13]. In chronic HCV, Low vitamin D levels have been reported in 46% to 92% of patients[10] raising suspicion of its potential contribution to disease pathogenesis. There is growing evidence from various groups, that vitamin D levels are inversely correlated with liver inflammation and stage of liver fibrosis in patients with HCV; however, the studies are heterogeneous with occasionally the results are conflicting. Additionally, the methods of reporting liver fibrosis were variable.

Figure 1
Figure 1 Vitamin D metabolism. Vitamin D has diverse influences throughout the body as vitamin D receptors present on virtually every cell. The actions of vitamin D can be subdivided into two larger categories: Calcemic and non-calcemic actions. The non-calcemic actions of vitamin D are legion and have been reviewed elsewhere[6,54-58]. Reproduced with permission[6].

The aim of this study was to evaluate the relationship between vitamin D status and hepatic fibrosis based on histopathological staging in patients with chronic HCV mono-infection or co-infected HIV-HCV infection, by performing a systematic review of the scientific literature followed by a meta-analysis.

MATERIALS AND METHODS
Search method

Applicable studies were identified by a library literature search in Pubmed/Embase/Cochrane/Scopus/LILACS utilizing the PRISMA checklist[14] “Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated” and the Cochrane review reporting guidelines (6.6.2.2)[15]. The search terms were as follows: [“Liver cirrhosis” or “liver” and (“cirrhosis” or “fibrosis”)] and [“vitamin D” or “Ergocalciferols” or “25 hydroxyvitamin D” or “25 hydroxy vitamin D” or “25 hydroxy D” or “25(OH)D”]. Also, the studies cited by the selected articles were searched for further pertinent studies. The search was performed before July 6, 2016.

Selection criteria

The title and abstract of the studies were carefully reviewed by two individual reviewers, based on the inclusion and exclusion criteria. If there was an agreement between two reviewers, then the study was selected for further analysis. When there was a disagreement, a third reviewer determined if the study qualified for inclusion. Once the articles met the criteria, then the text was reviewed, and data extraction was completed.

Inclusion criteria: (1) studies with patients with HCV or co-infected HCV/HIV; (2) studies with patients ≥ 18 years old; (3) studies that evaluated liver fibrosis stage, only based on liver biopsy; and (4) studies that reported serum or plasma 25(OH)D levels. Exclusion criteria: (1) liver diseases other than hepatitis C; (2) studies with inadequate data; (3) studies that used non-invasive methods in evaluating liver fibrosis; and (4) age < 18 years.

Data extraction

A total of 12 studies were included for extraction which was performed by two independent reviewers based on data quality, sufficiency, and relevance. Disagreements were resolved by a third reviewer to reach a consensus. The following data were extracted: Last name of the first author, demographic information of patients, publication year, sample size, HCV genotype, presence or absence of HIV co-infection, pathological fibrosis stage using Metavir score, vitamin D levels, and association of serum vitamin D level and fibrosis stage (Figure 2). The quality of evidence was ascertained by two independent reviewers using The Grading of Recommendations Assessment, Development and Evaluation (GRADE) analysis whereby very low = 1, low = 2, moderate = 3, high = 4[16]. The strength of recommendations were 1 (strong) or 2 (weak)[17]. When there was a disagreement, a third reviewer determined GRADE assessment and strength of recommendations.

Figure 2
Figure 2 Flowchart of study selection process. Eighteen hundred and twelve articles were identified using PubMed (n = 468)/EMBASE (n = 1269)/Cochrane (n = 23)/Scopus (n = 42)/LILACS (n = 10) search engines. Detailed evaluation of the articles by at least two independent reviewers (total of three) narrowed the studies to twelve (n = 2521) based upon inclusion and exclusion criteria as listed in Table 1.
Statistical analysis
Table 1 Pooled data of vitamin D levels and liver fibrosis from the 12 included studies.
YearAuthorCountryDesignnHCV GTHIVDefinition of vitamin D insufficiency (I)/deficiency (D)Outcome (serum vitamin D and liver fibrosis)P value/OR 95%CIGRADE quality of evidence very low = 1, low = 2, moderate = 3, high = 4 and strength of recommendation: 2 = strong 1 = weak
2010PettaItalyProspective1971No< 30 ng/mL for low vitamin D levelLow 25(OH)D associated with severe fibrosis (F3/F4)0.942 [0.893, 0.994] P = 0.009GRADE 3
Strong
2011TerrierFranceProspective1891,-4 otherYes< 10 ng/mL D, 10-30 ng/mL (I)Low 25(OH)D correlate with severe fibrosis (F3/F4)P = 0.04GRADE 3
Strong
2012LangeSwedenRetrospective4961, 4No< 10 ng/mL D, < 20 ng/mL (I)Advanced fibrosis stage F2-F4 vs F0-F1 associated with low 25(OH)D0.31 [0.12, 0.82] P = 0.018GRADE 2
Weak
2012WeintraubUnited StatesCross-sectional1711No< 20 ng/mL or < 30 ng/mL (I)Higher 25(OH)D predictive of milder fibrosis (F0-F2) in white patients but not in African AmericansP = 0.007GRADE 2
Weak
2012BaurSwitzerlandCohort2511, 3No< 20 ng/mL (I)(1) 25(OH)D lower in more advanced fibrosis (F2 vs F0-1); (2) low 25-OH vitamin D associated with rapid fibrosis progression rate.P = 0.005,GRADE 3
P = 0.013
Strong
2013El-MaoucheUnited StatesProspective116-Yes< 15 ng/mL (D)(1) The prevalence of significant fibrosis (F2 ≥ 2) was similar among those with and without lowP = 0.43GRADE 3
Vitamin D; (2) low 25(OH)D not associated with significant fibrosis after adjusting for other confounders1.37 [0.77, 2.44]
2013MandorferAustriaProspective651, 4Yes< 10 ng/mL D, 10-30 ng/mL (I)Patients withP = 0.009Strong
D-DEF displayed a higher prevalence of advanced liverGRADE 3
2013KitsonAustralia and New ZealandProspective2741No< 50 nmol/L D < 75 nmol/L (I)Fibrosis than patients with D-NORM Baseline 25(OH)D level did not vary with fibrosis stage (F3/4 vs F0-2)P = 0.18Strong
GRADE 3
2013AmanzadaGermanyProspective1911Yes< 30 ng/mL (I)Low 25(OH)D associated with advance fibrosis (F0-2 vs F3/4)P = 0.02Strong
GRADE 3
2014GerovaBulgariaRetrospective2961, 4No< 25 nmol/L (D), 25-50 nmol/L for profound (I), 50 –80 nmol/L for mild (I)Lower 25OHD levels were registered in cases with advanced fibrosis compared to those with mild or absent fibrosisP >0.05Strong
GRADE 2
2014Guzman-FulgencioSpainRetrospective1741, 4Yes< 10 ng/mL (D), 10-30 ng/mL (I)Low 25(OH)D deficiency associated with advanced fibrosis (F3/4 vs F0-2)P = 0.005Weak
GRADE 2
2015EsmatEgyptProspective1014No< 20 ng/mL (D), 20-30 (I)No correlation found between vitamin D levels and stage of liver fibrosisP = 0.26Weak
GRADE 3

All statistical computations were conducted in R (Version 3.3.1, R Foundation for Statistical Computing, Vienna, Austria, 2016)[18]. Estimated odds ratios (OR) reported in the literature, as well as 95%CI, were inverted when necessary and included in a meta-analysis. In several studies, the odds ratio for severe fibrosis corresponding to vitamin D deficiency was not reported, but the distribution (mean and standard deviation or inter-quartile range) of vitamin D levels were reported for subjects with and without severe fibrosis separately. To estimate the odds ratio from these studies, a Monte Carlo simulation approach was adopted: For each such study, 1000 simulated studies were created assuming that vitamin D levels were normally distributed with the reported parameters and the observed number of subjects in each group. The odds ratio for severe fibrosis comparing vitamin D levels with a cutoff of 15 ng/mL was estimated for each simulated dataset. A sensitivity analysis was also conducted by using thresholds of 20 ng/mL and 30 ng/mL. The average odds ratio across simulated datasets were then estimated, and quantile-based confidence intervals were also recorded and included into the meta-analysis. A random-effects meta-analysis fit using restricted maximum likelihood was then fit using the Metafor package in R[19]. P < 0.05 was considered statistically significant.

RESULTS

The initial protocol established a series of mesh terms used to identify articles that would evaluate the severity of liver fibrosis in chronic hepatitis C patients with vitamin D levels. Eighteen hundred and twelve articles were found using PubMed (n = 468)/EMBASE (n = 1269)/Cochrane (n = 23)/Scopus (n = 42)/LILACS (n = 10) search engines. Mesh terms used were liver fibrosis/vitamin d/cirrhosis/Ergocalciferols/25 hydroxyvitamin/25 hydroxy d/25(OH) D. Detailed evaluation of the articles by at least two independent reviewers (total of three) assessed the sufficiency of data, method of fibrosis qualification, relevance to the topic to narrow the studies to twelve. The data extraction algorithm is summarized in Figure 3. Table 1 reflects the characteristics of the studies relating fibrosis to chronic hepatitis C and vitamin D level. When patients were stratified according to vitamin D status, we found substantial differences between the levels of severity of liver fibrosis. The sensitivity analysis with different cutoffs for the Monte Carlo simulations showed robustness of the result to the choice of cutoff, with significant effects for all thresholds employed.

Figure 3
Figure 3 Meta-analysis of the pooled data from the 12 included studies. The odds ratio for severe fibrosis comparing low vitamin D levels was estimated by meta-analyzing studies including a total of 2521 patients. Details concerning the analytic strategy are provided in the Materials and Methods section.
Definition of vitamin D levels

Vitamin D insufficiency was defined in most studies as below < 30 ng/mL, and deficiency ranged from < 20 ng/mL to 10 ng/mL. While there was some variability in these definitions, there was consistency in the lower limit of normal being < 30 ng/mL. Two of the studies used nmol/L to express 25(OH)D, but were consistent with vitamin D insufficiency below the lower limit of normal < 80 nmol/L.

Association between vitamin D deficiency and severity of liver disease

Among the articles used for data extraction, there were seven prospective studies, three retrospective studies, one cross-sectional analysis, and one cohort study (Table 1). In a review of the results, nine studies demonstrated a significant association between plasma levels of vitamin D and degree of HCV-related hepatic fibrosis. Three studies showed no correlation was found between vitamin D levels and stage of liver fibrosis. Patient characteristics between these studies were all similar and could not account for the variability of the findings between the three negative studies and the nine positive studies. Only one of the three negative studies was conducted in the northern hemisphere. Overall, hepatitis C genotypes were not different among the negative studies, although El-Maouche et al[20] did not identify which genotype(s) were included. The forest plot of the data used in this systematic review showed that advanced liver disease defined as a Metavir value of F3/4 was associated with severe 25(OH)D insufficiency as follows; OR (95%CI): 1.88 (1.27, 2.77), and I2 (total heterogeneity/total variability): 66.94% indicated substatial heterogeneity between studies.

Plasma vitamin D levels and seasonal variation

Notably there were several latitudes identified in the studies which can affect Vitamin D levels, however, the scope of this difference in this analysis’s outcome was not assessed. In the article by Guzmán-Fulgencio et al[21] significant seasonal variation of plasma 25(OH)D levels was observed with the subjects in the first semester (winter/spring) having lower plasma 25(OH)D levels than patients evaluated in the second semester (summer/autumn) (P < 0.001). A higher percentage of patients with vitamin D deficiency (25(OH)D < 25 nmol/L) was found in the first semester (winter/spring) (P < 0.001). Since not all the studies identified the time frame of vitamin D levels and biopsy procurement, we were unable to qualify the significance of this on the study results.

DISCUSSION

The results of our systematic analysis of the literature demonstrated an association between advanced liver fibrosis (defined as Metavir F3/F4) in chronic hepatitis C (CHC) with vitamin D status as reflected by 25-hydroxyvitamin D [25(OH)D] serum levels. In nine[21-29] of twelve studies (75%) that qualified for data extraction (Tables 1 and 2) the final analysis demonstrated an overall association between low vitamin D status as defined as serum 25(OH)D < 15 ng/mL with advanced liver fibrosis (F3/F4 stage disease) in CHC as proven by biopsy analysis for fibrosis stage. These data are highly consistent with prior reports, and the expected pathophysiological interference of 25-hydroxylation of vitamin D as liver fibrosis increases and functional hepatic capacity decreases over the course of hepatitis C disease progression[6].

Table 2 Selection criteria for inclusion and exclusion.
Inclusion criteria
Age ≥ 18 yr
Studies including mono-infected HCV or co-infected HCV/HIV
Studies that evaluated liver fibrosis stage, only based on liver histology
Studies that reported serum or plasma 25(OH)D levels
Exclusion criteria
Age < 18 yr
Other etiologies of liver disease, other than hepatitis C
Studies that used non-invasive methods in evaluating liver fibrosis
Inadequate data

A recent systematic review of the literature by Abbasi et al[30] studied the relationship between low vitamin D status [< 20 ng/mL 25 OH(D)] and the severity of the CLD. A comparatively abridged search strategy yielded 641 articles for consideration and ultimately 19 articles and 4895 study patients with CLD for data extraction showing that almost 80% of patients with chronic liver disease had severe vitamin D deficiency. García-Álvarez et al[31] conducted a systematic review evaluating the relationship of vitamin D status to advanced liver fibrosis in CHC-naïve patients and sustained virological response (SVR) to therapy using pegylated interferon/ribavirin (Peg-IFN/RBV). Seven of fourteen papers utilized for their extraction evaluated advanced liver fibrosis (1083 patients) and eleven for SVR (2672 patients). Approximately 70% of CHC patients had low 25(OH)D whereby the definition of insufficiency varied (20 or 30 ng/mL), and 50% of the HCV-infected patients had 25(OH)D levels < 10 or 20 ng/mL. Overall, low vitamin D status was related to a diagnosis of advanced stage of liver disease. Luo et al utilized a search methodology restricted to PubMed and Embase databases before October 2013 included studies that analyzed the association between serum vitamin D status and the severity of liver fibrosis in 8231 CHC patients without other restrictions yielding six global studies for data extraction[13]. One study recruited 6567 participants as part of the Swiss Hepatitis C Cohort Study[23] raising concerns for skewing of the extracted data. The mean data from extracted studies suggested that lower serum vitamin D is a risk factor for progressive liver fibrosis in CHC patients. However, there was a high heterogeneity and inconsistencies depending upon data set utilized (OR data studies vs mean data extracted). Our search methodology instead included 2521 patients which incorporated the 2012 study by Lange et al[32] which evaluated 468 HCV patients treated with alpha interferon-based regimens for vitamin D status and advanced disease demonstrating that fibrosis stages F2-F4 vs F0-F1 associated with low 25(OH)D.

The nine studies showing a positive association between low vitamin D with an advanced stage of fibrosis had variations in their definition of vitamin D status which challenged our ability to Meta-analyze the data. Low vitamin D was stratified according to by either insufficient (I) or deficient (D) (Table 1) in eight[21-27,29] of the nine studies. Gerova et al[28] used three categories; mild insufficiency, profound insufficiency, and deficiency. Overall, of the twelve papers in our final analysis, two[28,33] utilized nmol/L to measure serum 25(OH) vitamin D status. Insufficiency was defined as < 30 ng/mL in seven with another two using equivalent levels in nmol/L[28,34], < 20 ng/mL in two[23,25] while El-Maouche studied only deficient patients (< 15 ng/mL)[20]. The definition of “deficiency” was utilized by all but two[20,34] of the studies as < 10 ng/mL 25(OH) vitamin D. The prevalence of vitamin D deficiency in a population depends on upon the definition used [< 20 or < 30 ng/mL (50 or 75 nmol/L)]. In the National Health and Nutrition Examination Survey (NHANES), 41.6 percent of United States adults had (25[OH]D) levels < 20 ng/mL (50 nmol/L)[35]. The Institute of Medicine recommends the attainment of the serum 25(OH)D levels of > 20 < 40 ng/mL (50 to 100 nmol/L), however, many define sufficient vitamin D status as 25(OH)D > 30 and < 50 ng/mL (75 to 125 nmol/L)[36,37].

Hepatitis C genotype (1-6) did not change the outcome of analyses between advanced fibrosis in CHC with vitamin D status[20,33,34]. The geographical latitudes of study site and variable seasonal fluctuations have provided challenges to vitamin D status, but did not appear to influence the outcome of the negative outcome studies[20,33,34] Esmat et al[34] conducted a open-labelled RCT of 101 HVC4 Egyptian patients undergoing standard of care (SOC) Peg-IFN/RBV plus/minus 15000 IU vitamin D3 (cholecalciferol). The fibrosis stage (F1-F3) at baseline was not different according to 25(OH) vitamin D levels. El-Maouche et al[20] evaluated HIV-HCV co-infected patients for histological fibrosis using the Metavir system [0 (no fibrosis) to 4 (cirrhosis)] and used banked serum as a source for vitamin D determination. Similar to Esmat et al[34], the prevalence of significant fibrosis (F2 ≥ 2) was similar among those with and without low vitamin D while low 25(OH)D status was not associated with significant fibrosis after adjusting for other confounders. Finally, Kitson et al[38] from Australia evaluated pre-treatment 25-hydroxyvitamin D [25(OH)D] level in a cohort of 274 treatment-naive patients with HCV-1 to evaluate the association between vitamin D status, virological response, and liver histology after 48 wk of pegylated interferon alfa-2a plus ribavirin therapy. Baseline 25(OH)D level did not vary with fibrosis stage (F3/4 vs F0-2).

The manner by which vitamin D may influence the course of CHC may be due to effects on viral clearance, immune modulation, cell differentiation and proliferation and inflammation regulation. Vitamin D is not only involved in calcium homeostasis but has also has been associated with the mechanism of cellular proliferation, and immunomodulation[39]. Several studies have shown that vitamin D levels are inversely correlated with stage of liver fibrosis in patients with CHC. Nine[21-29] of the twelve studies that we included for data extraction reported the inverse correlation of vitamin D levels with the stage of liver fibrosis in patients with CHC. Vitamin D has anti-inflammatory, anti-proliferative and anti-fibrotic effects that dampen inflammatory cell recruitment to the liver and mitigate hepatic fibrosis progression[40]. HCV may also have its own direct actions that impair vitamin D activity and status. It has been hypothesized that HCV affects 25-hydroxylation of vitamin D through cytokine induction or oxidative stress or through disruption in lipid metabolism where HCV suppress 25(OH)D levels due to a decrease in the production of vitamin D precursor, 7-dehydrocholesterol[10].

The profound relationship of vitamin D to immunity and inflammation, and our findings raise questions about how vitamin D status may impact the outcome of the many non-HCV chronic liver diseases. Individuals with chronic liver disease have significant global prevalence, morbidity, poor quality of life and mortality. Prior works have demonstrated adverse survival outcomes in patients with lowered vitamin D status[41,42]. In our analyses, we excluded papers reporting the analysis of vitamin D in chronic liver diseases other than HCV including chronic hepatitis B (CHB) which has a higher global prevalence of approximately 300 million infected individuals. Yu et al[43] evaluated the potential association between serum vitamin D level and liver histology or virological parameters in treatment-naïve patients with chronic hepatitis B infection in Southern China. They reported that patients infected with genotype B had a higher prevalence of vitamin D insufficiency than individuals with CHC. Furthermore, in chronic hepatitis B patients, serum 25(OH) D was not correlated with viral load or fibrosis. Mi et al[44] reported that vitamin D status was not different among Asians with non-cirrhotic CHB and CHC.

Low vitamin D status is associated with the risk of progression and the severity of hepatic inflammation in patients with non-alcoholic fatty liver disease[45,46]. Primary biliary cirrhosis has been extensively analyzed for correlations of vitamin D status predicting the outcome to ursodeoxycholic acid (UCDA) therapy and the influence of vitamin D supplementation to UCDA intervention[47-49]. Autoimmune hepatitis (AIH) has also been studied for the potential influence of vitamin D given the epidemiological association of this hormone with a number of diseases with autoimmunity[50,51]. However, there are not sufficient studies to draw meaningful conclusions of serum 25(OH)D and AIH at this time.

Altered vitamin D physiology via resistance from genetic polymorphisms of the vitamin D receptor (VDR) could also influence the outcome of CHC. Baur et al[25] demonstrated that low 25(OH)D plasma levels and VDR bAt[CCA]haplotype were associated with rapid fibrosis progression in CHC, separately and synergistic when co-present. Petta et al[52] reported that low hepatic VDR expression was inversely related to the severity of advanced liver fibrosis in patients with genotype 1 cCHC patients. Grunhage reported that a single nucleotide polymorphism (SNP) linked to the DHCR7 gene coding vitamin D precursor dehydrocholesterol was related to altered serum 25(OH)D in chronic liver disease patients with no or mild fibrosis[53].

CHC with severely low vitamin D status is accompanied by advanced liver fibrosis. Interventional trials aimed to normalize vitamin D status in early stages of CHC may shed light on whether correction of vitamin D status in this patient population should become the standard of care.

COMMENTS
Background

Hepatitis C remains a global health burden affecting over 100 million people worldwide. There is growing evidence that vitamin D is inversely associated with liver inflammation and fibrosis in patients with chronic hepatitis C.

Research frontiers

Currently hepatitis C is being dramatically eradicated with DAA therapy. Possible augmentation of DAA therapy by vitamin D in those patients who already have fibrosis may decrease long term damage in the liver parenchyma.

Innovations and breakthroughs

The pooled data of this systematic review showed that 9 of the 12 studies correlated advanced liver disease defined as a Metavir value of F3/4 with 25(OH) D level insufficiency. The meta-analysis indicated a significant association across studies. Low vitamin D status is common in chronic Hepatitis C patients and is associated with advanced liver fibrosis.

Applications

Augmentation of standard hepatitis C therapy of direct acting antiviral meds with vitamin D may assist with long term decrease in liver fibrosis.

Peer-review

This is a very interesting and informative paper, and it deserves publication.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: United States

Peer-review report classification

Grade A (Excellent): A

Grade B (Very good): B, B, B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: El-Bendary MM, Ferraioli G, Ramsay MA, Wong GLH S- Editor: Qi Y L- Editor: A E- Editor: Li D

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