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Vitamin D supplementation and immune-related markers: an update from nutrigenetic and nutrigenomic studies. Br J Nutr 2022; 128. [PMCID: PMC9557210 DOI: 10.1017/s0007114522002392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Vitamin D is both a nutrient and a neurologic hormone that plays a critical role in modulating immune responses. While low levels of vitamin D are associated with increased susceptibility to infections and immune-related disorders, vitamin D supplementation has demonstrated immunomodulatory effects that can be protective against various diseases and infections. Vitamin D receptor is expressed in immune cells that have the ability to synthesise the active vitamin D metabolite. Thus, vitamin D acts in an autocrine manner in a local immunologic milieu in fighting against infections. Nutrigenetics and nutrigenomics are the new disciplines of nutritional science that explore the interaction between nutrients and genes using distinct approaches to decipher the mechanisms by which nutrients can influence disease development. Though molecular and observational studies have proved the immunomodulatory effects of vitamin D, only very few studies have documented the molecular insights of vitamin D supplementation. Until recently, researchers have investigated only a few selected genes involved in the vitamin D metabolic pathway that may influence the response to vitamin D supplementation and possibly disease risk. This review summarises the impact of vitamin D supplementation on immune markers from nutrigenetics and nutrigenomics perspective based on evidence collected through a structured search using PubMed, EMBASE, Science Direct and Web of Science. The research gaps and shortcomings from the existing data and future research direction of vitamin D supplementation on various immune-related disorders are discussed.
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Aggeletopoulou I, Thomopoulos K, Mouzaki A, Triantos C. Vitamin D-VDR Novel Anti-Inflammatory Molecules-New Insights into Their Effects on Liver Diseases. Int J Mol Sci 2022; 23:8465. [PMID: 35955597 PMCID: PMC9369388 DOI: 10.3390/ijms23158465] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/26/2022] [Accepted: 07/28/2022] [Indexed: 02/05/2023] Open
Abstract
There is consistent evidence that vitamin D deficiency is strongly associated with liver dysfunction, disease severity, and poor prognosis in patients with liver disease. Vitamin D and its receptor (VDR) contribute to the regulation of innate and adaptive immune responses. The presence of genetic variants of vitamin D- and VDR-associated genes has been associated with liver disease progression. In our recent work, we summarized the progress in understanding the molecular mechanisms involved in vitamin D-VDR signaling and discussed the functional significance of VDR signaling in specific cell populations in liver disease. The current review focuses on the complex interaction between immune and liver cells in the maintenance of liver homeostasis and the development of liver injury, the interplay of vitamin D and VDR in the development and outcome of liver disease, the role of vitamin D- and VDR-associated genetic variants in modulating the occurrence and severity of liver disease, and the therapeutic value of vitamin D supplementation in various liver diseases. The association of the vitamin D-VDR complex with liver dysfunction shows great potential for clinical application and supports its use as a prognostic index and diagnostic tool.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, GR-26504 Patras, Greece;
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, GR-26504 Patras, Greece;
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
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Bjelakovic M, Nikolova D, Bjelakovic G, Gluud C. Vitamin D supplementation for chronic liver diseases in adults. Cochrane Database Syst Rev 2021; 8:CD011564. [PMID: 34431511 PMCID: PMC8407054 DOI: 10.1002/14651858.cd011564.pub3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Vitamin D deficiency is often reported in people with chronic liver diseases. Improving vitamin D status could therefore be beneficial for people with chronic liver diseases. OBJECTIVES To assess the beneficial and harmful effects of vitamin D supplementation in adults with chronic liver diseases. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and enquired experts and pharmaceutical companies as to additional trials. All searches were up to November 2020. SELECTION CRITERIA Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of evidence. MAIN RESULTS We included 27 randomised clinical trials with 1979 adult participants. This review update added 12 trials with 945 participants. We assessed all trials as at high risk of bias. All trials had a parallel-group design. Eleven trials were conducted in high-income countries and 16 trials in middle-income countries. Ten trials included participants with chronic hepatitis C, five trials participants with liver cirrhosis, 11 trials participants with non-alcoholic fatty liver disease, and one trial liver transplant recipients. All of the included trials reported the baseline vitamin D status of participants. Participants in nine trials had baseline serum 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), whilst participants in the remaining 18 trials were vitamin D insufficient (less than 20 ng/mL). Twenty-four trials administered vitamin D orally, two trials intramuscularly, and one trial intramuscularly and orally. In all 27 trials, the mean duration of vitamin D supplementation was 6 months, and the mean follow-up of participants from randomisation was 7 months. Twenty trials (1592 participants; 44% women; mean age 48 years) tested vitamin D3 (cholecalciferol); three trials (156 participants; 28% women; mean age 54 years) tested vitamin D2; four trials (291 participants; 60% women; mean age 52 years) tested 1,25-dihydroxyvitamin D; and one trial (18 participants; 0% women; mean age 52 years) tested 25-hydroxyvitamin D. One trial did not report the form of vitamin D. Twelve trials used a placebo, whilst the other 15 trials used no intervention in the control group. Fourteen trials appeared to be free of vested interest. Eleven trials did not provide any information on clinical trial support or sponsorship. Two trials were funded by industry. We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on all-cause mortality (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.51 to 1.45; 27 trials; 1979 participants). The mean follow-up was 7 months (range 1 to 18 months). We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) (follow-up: 12 months); serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants); myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants); thyroiditis (RR 0.33, 95% CI 0.01 to 7.91; 1 trial; 68 participants); circular haemorrhoidal prolapse (RR 3.00, 95% CI 0.14 to 65.9; 1 trial; 20 participants); bronchopneumonia (RR 0.33, 95% CI 0.02 to 7.32; 1 trial 20 participants); and non-serious adverse events. The certainty of evidence for all outcomes is very low. We found no data on liver-related morbidity such as gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, ascites, or liver cancer. There were also no data on health-related quality of life. The evidence is also very uncertain regarding the effect of vitamin D versus placebo or no intervention on rapid, early, and sustained virological response in people with chronic hepatitis C. AUTHORS' CONCLUSIONS Given the high risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, vitamin D supplementation versus placebo or no intervention may increase or reduce all-cause mortality, liver-related mortality, serious adverse events, or non-serious adverse events in adults with chronic liver diseases. There is a lack of data on liver-related morbidity and health-related quality of life. Further evidence on clinically important outcomes analysed in this review is needed.
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Affiliation(s)
- Milica Bjelakovic
- Clinic of Gastroenterology and Hepatology, Clinical Centre Nis, Nis, Serbia
| | - Dimitrinka Nikolova
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Goran Bjelakovic
- Clinic of Gastroenterology and Hepatology, Clinical Centre Nis, Nis, Serbia
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
| | - Christian Gluud
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Abstract
Until the development of direct-acting antivirals (DAAs), interferon (IFN)-based therapy had been the primary treatment strategy for patients with chronic hepatitis C, even though this therapy has a therapeutic limitations and considerable side effects. Therefore, many efforts have been made to improve the efficacy of treatment. Several clinical studies have clearly shown that supplementation with vitamin D of IFN-based therapy improves treatment efficacy. To clarify the molecular mechanisms of the effect of vitamin D on IFN-based therapy, several researchers have performed basic research with cell culture models of hepatitis C virus (HCV). Consequently, two vitamin D3 metabolites, 25-hydroxyvitamin D3 (25-(OH)D3) and 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3), have been suggested to have anti-HCV effects. 25-(OH)D3 inhibits HCV production by suppressing infectious virus assembly through reducing apolipoprotein expression, while 1α,25-(OH)2D3 inhibits HCV production by modulating IFN signaling and/or inducing various host factors associated with the inhibition of viral genome replication. In addition, an antimicrobial peptide, LL-37, which is known to be partly regulated by vitamin D, was also reported to exhibit an anti-HCV effect by disrupting infectious viral particles directly. In conclusion, vitamin D3 supplementation improves the response rate of IFN-based therapy via the direct and/or indirect anti-HCV effects of vitamin D3 metabolites.
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Affiliation(s)
- Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
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Chen HW, Chiu YL, Hsieh TY, Chen PJ, Huang TY, Lin HH, Shih YL, Lin JC. Relationships Between Vitamin D Status and Cytokine: Results from Interferon-Based Therapy in Non-Cirrhotic, Treatment-Naïve Patients with Chronic Hepatitis C Infection. J Inflamm Res 2021; 13:1207-1218. [PMID: 33402842 PMCID: PMC7778440 DOI: 10.2147/jir.s283768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/11/2020] [Indexed: 12/13/2022] Open
Abstract
Background Vitamin D contributes to bone health and extra-skeletal effects. The mechanisms underlying vitamin D metabolism have not been extensively evaluated. The relationships between vitamin D and inflammatory cytokines are debated. Our objective was to investigate whether supplemental interferons are associated with longitudinal change of vitamin D status in humans. Methods A total of 48 patients with 24 or 48 weeks of pegylated interferon-α plus ribavirin therapy were examined for serum 25-hydroxyvitamin D (25[OH]D) level before treatment, at the end of treatment, and 24 weeks after treatment. In addition, we analyzed publicly available RNA sequencing data from accession GSE42697 and GSE7123 in the Gene Expression Omnibus. Findings The overall sustained virologic response (SVR) rate was 62.5%. There was no statistically significant association between baseline 25(OH)D concentrations and liver fibrosis. In patients with SVR, serum 25(OH)D increased markedly at end-of-treatment and decreased markedly by the end of the 24-week follow-up period. In the non-SVR group, this treatment-dependent change was lost. In gene expression analysis, the vitamin D biosynthesis process was activated in subjects with SVR, but not in patients without SVR. Furthermore, vitamin D receptor (VDR) signaling in peripheral blood mononuclear cells (PBMCs) was triggered in marked responders but not in poor responders. Conclusion In the aggregate, these data suggest that interferons have a regulatory influence on vitamin D status that can contribute to VDR signaling in PBMCs.
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Affiliation(s)
- Hsuan-Wei Chen
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Lin Chiu
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Tsai-Yuan Hsieh
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Peng-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tien-Yu Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hsuan-Hwai Lin
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Lueng Shih
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jung-Chun Lin
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Kondo Y, Kogure T, Ninomiya M, Fukuda R, Monma N, Ikeo K, Tanaka Y. The reduction of miR146b-5p in monocytes and T cells could contribute to the immunopathogenesis of hepatitis C virus infection. Sci Rep 2019; 9:13393. [PMID: 31527804 PMCID: PMC6746729 DOI: 10.1038/s41598-019-49706-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 08/30/2019] [Indexed: 02/06/2023] Open
Abstract
It has been reported that various kinds of miRNAs could affect the pathogenesis of hepatitis C virus infection. Recently, our group reported that deep-sequencing analysis was useful to detect disease-specific miRNAs. The aim of this study is to identify the HCV-specific miRNAs that could contribute to the immunopathogenesis of HCV by using clinical samples and in vitro analysis. Five miRNAs (hsa-miR181a-2-3p, hsa-miR-374a-3p, hsa-miR374a-5p, hsa-miR-204-5p and hsa-miR146b-5p) were shown to be significantly downregulated in CH-C by deep sequence analysis. The average ratio (PBMCs miRNAs/serum miRNAs) of hsa-miR146b-5p was highest among all the miRNAs. Moreover, serum hsa-miR146b-5p was significantly down-regulated in CH-C patients in comparison to CH-B patients and healthy subjects. The expression of hsa-miR146b-5p in CD3+ T cells and CD14+ monocytes of CH-C patients was significantly lower than that of the other groups. The hsa-miR146b-5p expression in CD14+ monocytes of SVR patients treated with Peg-IFN/RBV was significantly higher than in those of non-SVR patients treated with Peg IFN/RBV. However, the hsa-miR146b-5p expression in CD14+ monocytes of SVR patients treated with DCV and ASV was comparable to that in monocytes of non-SVR patients treated with DCV and ASV. Moreover, the expression levels of hsa-miR146b-5p in CD14+ monocytes were significantly increased after achieving SVR and 1(OH)Vitamin D3 treatment. Further, the expression of HCV-Core could suppress miR146b-5p expression in immune cells and affect the expression of various kinds of cytokines by affecting the NF-κB signaling. In conclusion, the reduction of miR146b-5p in monocytes and T cells could contribute to the immunopathogenesis of hepatitis C virus infection.
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Affiliation(s)
- Yasuteru Kondo
- Department of Hepatology, Sendai Kousei Hospital, 4-15 Hirose, Aoba, Sendai City, Miyagi, Japan.
- Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, 467-8601, Japan.
| | - Takayuki Kogure
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo, Aoba, Sendai City, Miyagi, Japan
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo, Aoba, Sendai City, Miyagi, Japan
| | - Ryo Fukuda
- Department of Hepatology, Sendai Kousei Hospital, 4-15 Hirose, Aoba, Sendai City, Miyagi, Japan
| | - Norikazu Monma
- Center for information Biology, National Institute of Genetics, Mishima, Japan
| | - Kazuho Ikeo
- Center for information Biology, National Institute of Genetics, Mishima, Japan
| | - Yasuhito Tanaka
- Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, 467-8601, Japan
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Murayama A, Saitoh H, Takeuchi A, Yamada N, Matsumura T, Shiina M, Muramatsu M, Wakita T, Imawari M, Kato T. Vitamin D derivatives inhibit hepatitis C virus production through the suppression of apolipoprotein. Antiviral Res 2018; 160:55-63. [PMID: 30339849 DOI: 10.1016/j.antiviral.2018.10.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 09/21/2018] [Accepted: 10/14/2018] [Indexed: 01/28/2023]
Abstract
Supplementation with vitamin D (VD) has been reported to improve the efficacy of interferon-based therapy for chronic hepatitis C. We found that 25-hydroxyvitamin D3 (25-(OH)D3), one of the metabolites of VD, has antiviral effects by inhibiting the infectious virus production of the hepatitis C virus (HCV). In this study, to clarify the underlying mechanisms of the anti-HCV effects, we searched VD derivatives that have anti-HCV effects and identified the common target molecule in the HCV life cycle by using an HCV cell culture system. After infection of Huh-7.5.1 cells with cell culture-generated HCV, VD derivatives were added to culture media, and the propagation of HCV was assessed by measuring the HCV core antigen levels in culture media and cell lysates. To determine the step in the HCV life cycle affected by these compounds, the single-cycle virus production assay was used with a CD81-negative cell line. Of the 14 structural derivatives of VD, an anti-HCV effect was detected in 9 compounds. Cell viability was not affected by these effective compounds. The 2 representative VD derivatives inhibited the infectious virus production in the single-cycle virus production assay. Treatment with these compounds and 25-(OH)D3 suppressed the expression of apolipoprotein A1 and C3, which are known to be involved in infectious virus production of HCV, and the knockdown of these apolipoproteins reduced infectious virus production. In conclusion, we identified several compounds with anti-HCV activity by screening VD derivatives. These compounds reduce the infectious virus production of HCV by suppressing the expression of apolipoproteins in host cells.
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Affiliation(s)
- Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroshi Saitoh
- Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Tokyo, Japan
| | - Akiko Takeuchi
- Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Tokyo, Japan
| | - Norie Yamada
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takuya Matsumura
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Masaaki Shiina
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan; Department of Gastroenterology and Hepatology, Shin-Yurigaoka General Hospital, Kawasaki, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Michio Imawari
- Research Institute for Gastrointestinal and Liver Diseases, Shin-Yurigaoka General Hospital, Kawasaki, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
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8
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Abstract
In the past few years, a growing body of clinical evidence has highlighted the risk of vitamin D deficiency in patients with chronic hepatitis C and that vitamin D levels are associated with the course of hepatitis C virus (HCV) infection, adverse effects, and treatment response to peginterferon/ribavirin. Recently, studies have found that vitamin D status is related to drug resistance and increased risk of infection in patients with liver cirrhosis. Vitamin D-related gene polymorphisms have been found to explain the interactions between vitamin D deficiency and HCV infection, offering a new perspective toward understanding the current problems such as the development of insulin resistance and racial differences in sustained virological response. Studies have been conducted to determine whether vitamin D supplementation as an adjuvant yields a better result compared with traditional HCV treatment. Here, we provide a brief review of the past and present knowledge of vitamin D in HCV infection.
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9
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Bjelakovic G, Nikolova D, Bjelakovic M, Gluud C, Cochrane Hepato‐Biliary Group. Vitamin D supplementation for chronic liver diseases in adults. Cochrane Database Syst Rev 2017; 11:CD011564. [PMID: 29099543 PMCID: PMC6485973 DOI: 10.1002/14651858.cd011564.pub2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Vitamin D deficiency is often reported in people with chronic liver diseases. Therefore, improving vitamin D status could have a beneficial effect on people with chronic liver diseases. OBJECTIVES To assess the beneficial and harmful effects of vitamin D supplementation in people with chronic liver diseases. SEARCH METHODS We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science. We also searched databases of ongoing trials and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. All searches were up to January 2017. SELECTION CRITERIA Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by The Cochrane Collaboration. We contacted authors of the trials to ask for missing information. We conducted random-effects and fixed-effect meta-analyses. For dichotomous outcomes, we calculated risk ratios (RRs), and for continuous outcomes, we calculated mean differences (MD), both with 95% confidence intervals (CI) and Trial Sequential Analyses-adjusted CIs. We calculated Peto odds ratio (OR) for rare events. We considered risk of bias in domains to assess the risk of systematic errors. We conducted Trial Sequential Analyses to control the risk of random errors. We assessed the quality of the evidence with GRADE. MAIN RESULTS We included 15 randomised clinical trials with 1034 participants randomised. All trials had a parallel group design. Nine trials were conducted in high-income countries and six trials in middle-income countries. All trials were at high risk of bias. Six trials included participants with chronic hepatitis C, four trials included participants with liver cirrhosis, four trials included participants with non-alcoholic fatty liver disease, and one trial included liver transplant recipients. All included trials reported the baseline vitamin D status of participants. Participants in six trials had baseline 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), while participants in the remaining nine trials were vitamin D insufficient (less than 20 ng/mL). All trials administered vitamin D orally. Mean duration of vitamin D supplementation was 0.5 years and follow-up was 0.6 years. Eleven trials (831 participants; 40% women; mean age 52 years) tested vitamin D3, one trial (18 men; mean age 61 years) with three intervention groups tested vitamin D2 and 25-dihydroxyvitamin D in separate groups, and three trials (185 participants; 55% women; mean age 55 years) tested 1,25-dihydroxyvitamin D. Seven trials used placebo, and eight trials used no intervention in the control group.The effect of vitamin D on all-cause mortality at the end of follow-up is uncertain because the results were imprecise (Peto OR 0.70, 95% CI 0.09 to 5.38; I2 = 32%; 15 trials; 1034 participants; very low quality evidence). Trial Sequential Analysis on all-cause mortality was performed based on a mortality rate in the control group of 10%, a relative risk reduction of 28% in the experimental intervention group, a type I error of 2.5%, and type II error of 10% (90% power). There was no diversity. The required information size was 6396 participants. The cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit or harm after the 15th trial, and the Trial Sequential Analyses-adjusted CI was 0.00 to 2534.The effect of vitamin D on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) and on serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants), myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants), and thyroiditis (RR 0.33 95% CI 0.01 to 7.91; 1 trial; 68 participants) is uncertain because the results were imprecise. The evidence on all these outcomes is of very low quality. The effect of vitamin D3 on non-serious adverse events such as glossitis (RR 3.70, 95% CI 0.16 to 87.6; 1 trial; 65 participants; very low quality of evidence) is uncertain because the result was imprecise.Due to few data, we did not conduct Trial Sequential Analysis on liver-related mortality, and serious and non-serious adverse events.We found no data on liver-related morbidity and health-related quality of life in the randomised trials included in this review. AUTHORS' CONCLUSIONS We are uncertain as to whether vitamin D supplements in the form of vitamin D3, vitamin D2, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D have important effect on all-cause mortality, liver-related mortality, or on serious or non-serious adverse events because the results were imprecise. There is no evidence on the effect of vitamin D supplementation on liver-related morbidity and health-related quality of life. Our conclusions are based on few trials with an insufficient number of participants and on lack of data on clinically important outcomes. In addition, the analysed trials are at high risk of bias with significant intertrial heterogeneity. The overall quality of evidence is very low.
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Affiliation(s)
- Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
- Clinical Centre NisClinic of Gastroenterology and HepatologyBoulevard Dr Zorana Djindjica 48NisSerbia18000
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Marko Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Komolmit P, Charoensuk K, Thanapirom K, Suksawatamnuay S, Thaimai P, Chirathaworn C, Poovorawan Y. Correction of vitamin D deficiency facilitated suppression of IP-10 and DPP IV levels in patients with chronic hepatitis C: A randomised double-blinded, placebo-control trial. PLoS One 2017; 12:e0174608. [PMID: 28376103 PMCID: PMC5380326 DOI: 10.1371/journal.pone.0174608] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 03/12/2017] [Indexed: 12/31/2022] Open
Abstract
UNLABELLED Vitamin D deficiency was common among patients with chronic hepatitis C (CHC) and had negative influence on treatment outcome. Correction of vitamin D deficiency improved treatment response. Interferon gamma-induced protein 10 (IP-10) and enzyme dipeptidyl peptidase-4 (DPP IV) involved in inflammatory responses in CHC. Their higher levels at pretreatment of CHC could predict poorer responses. Vitamin D suppressed expression of IP-10 from monocytes in vitro. In CHC patients, DPP IV involved in IP-10 regulation. We hypothesized that correction of vitamin D insufficiency or deficiency in CHC patients might restore immune dysregulation through a pathway linked to the TH1/Th2 cytokines, IP-10 or DPP IV. We conducted a double-blind, placebo-controlled trial. 80 CHC patients with vitamin D levels less than 30 ng/mL were assigned to receive vitamin D (40) or placebo (40) supplements for 6 weeks. The levels of 25-hydroxyvitamin D [25(OH)D], Th1/Th2 cytokines, IP-10 and DPP IV were measured at baseline and at the 6th week. At the end of study, the mean 25(OH)D level in vitamin D group was significantly increased and normalised. There were no changes in the level of Th1/Th2 cytokines. Our important finding revealed that upon correction of vitamin D insufficiency or deficiency, the serum IP-10 and DPP IV levels were decreased significantly as compare to the placebo group (delta changes; 83.27 vs -133.80; 95% CI [-326.910, -40.758], p = 0.0125, and 271.04 vs -518.69; 95% CI [-1179,15, -59.781], p = 0.0305, respectively. As previous evidences suggested that each factor individually influenced and predicted outcome of CHC treatment. Our results offer a new insight and help to piece the puzzle of vitamin D deficiency, IP-10 and DPP IV together in CHC. TRIAL REGISTRATION Thai Clinical Trials Registry TCTR20160429001.
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Affiliation(s)
- Piyawat Komolmit
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Kriangsak Charoensuk
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Division of Gastroenterology, Department of Internal medicine, Buddhachinaraj Hospital School of Medicine, Phitsanulok, Thailand
| | - Kessarin Thanapirom
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Sirinporn Suksawatamnuay
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Panarat Thaimai
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Chintana Chirathaworn
- Division of Immunology, Department of Microbiology, Chulalongkorn university, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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11
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Kondo Y. Hepatitis C infected patients need vitamin D3 supplementation in the era of direct acting antivirals treatment. World J Gastroenterol 2017; 23:1325-1327. [PMID: 28293078 PMCID: PMC5330816 DOI: 10.3748/wjg.v23.i8.1325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 12/05/2016] [Accepted: 12/21/2016] [Indexed: 02/06/2023] Open
Abstract
It has been reported that the serum level of vitamin D3 (VitD3) could affect the natural course of chronic hepatitis C (CH-C) and the response to treatment with pegylated interferon (Peg-IFN) and ribavirin. Although several mechanisms for the favorable effects of VitD3 supplementation were reported, the total effect of VitD3 supplementation remains unclear. Previously, we reported that supplementation with 1(OH)VitD3 could enhance the Th1 response inducing not only a favorable immune response for viral eradication but also HCC control. Recently, the main treatment of CH-C should be direct acting antivirals (DAAs) without Peg-IFN. Peg-IFN is a strong immune-modulator. Therefore, an immunological analysis should be carried out to understand the effect of VitD3 after treatment of DAAs without Peg-IFN. The induction of a favorable immune response by adding VitD3 might be able to suppress the hepatocarcinogenesis after achieving SVR, especially in children and elderly patients with severe fibrosis lacking sufficient amounts of VitD3.
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12
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Matsumura T, Sugiyama N, Murayama A, Yamada N, Shiina M, Asabe S, Wakita T, Imawari M, Kato T. Antimicrobial peptide LL-37 attenuates infection of hepatitis C virus. Hepatol Res 2016; 46:924-32. [PMID: 26606891 DOI: 10.1111/hepr.12627] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 11/09/2015] [Accepted: 11/18/2015] [Indexed: 12/20/2022]
Abstract
AIM Although recent studies indicate that supplementation with vitamin D (VD) potentiates a sustained viral response by interferon-based therapy to chronic hepatitis C, detailed mechanisms are not fully defined. The production of cathelicidin, an antimicrobial peptide, has been demonstrated to be part of the VD-dependent antimicrobial pathway in innate immunity. Cathelicidin is known to directly kill or inhibit the growth of microbial pathogens including mycobacteria and viruses. METHODS We used a hepatitis C virus (HCV) cell culture system to clarify the anti-HCV effects of the human cathelicidin, LL-37. HuH-7 cells were administrated with LL-37 and infected with cell culture-generated HCV (HCVcc). HCV propagation was estimated by measuring the level of HCV core antigen (Ag). RESULTS Treatment with LL-37 resulted in decreased intra- and extracellular levels of HCV core Ag, suggesting inhibition of HCV propagation. To assess the effects of LL-37 on HCV replication, JFH-1 subgenomic replicon RNA-transfected cells were treated with LL-37. However, inhibition of HCV replication was not detected by this assay. To clarify the effects on HCV infection, we treated HCVcc with LL-37 and removed the antimicrobial peptide prior to use of the virus in infection. This exposure of HCVcc to LL-37 diminished the infectivity titers in a dose-dependent fashion. Iodixanol density gradient analysis revealed that the peak fraction of infectivity titer was eliminated by LL-37 treatment. CONCLUSION The VD-associated antimicrobial peptide LL-37 attenuated the infectivity of HCV. This anti-HCV effect of LL-37 may explain the contribution of VD to the improved efficacy of interferon-based therapy.
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Affiliation(s)
- Takuya Matsumura
- Department of Virology II, National Institute of Infectious Diseases, Tokyo.,Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo
| | - Nao Sugiyama
- Department of Virology II, National Institute of Infectious Diseases, Tokyo
| | - Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, Tokyo
| | - Norie Yamada
- Department of Virology II, National Institute of Infectious Diseases, Tokyo
| | - Masaaki Shiina
- Department of Gastroenterology and Hepatology, Shin-Yurigaoka General Hospital, Kawasaki
| | - Shinichi Asabe
- Division of Gastroenterology, Saitama Medical Center, Jichi Medical University, Saitama
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo
| | - Michio Imawari
- Research Institute for Gastrointestinal and Liver Diseases, Shin-Yurigaoka General Hospital, Kawasaki, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Tokyo
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13
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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 2016; 5:69-75. [PMID: 28405324 DOI: 10.1177/2050640616640157] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 02/24/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND AIM The impact of 25-OH vitamin D on sustained viral response (SVR) to antiviral therapy and on fibrosis progression in hepatitis C is debated. We assessed the impact of 25-OH vitamin D concentration on the efficacy of antiviral therapy in naïve genotype 1 hepatitis C virus (HCV)-infected patients. METHODS The study population consisted of treatment-naïve genotype 1 patients enrolled in a randomised controlled trial. A total of 516 patients received peginterferon α-2a 180 µg/week plus ribavirin 800 mg/day for 24 weeks. There were 349 patients with undetectable HCV RNA (<50 IU/ml) at week 24 (W24) who were randomised to continue dual therapy (n = 173) or to continue peginterferon alone (n = 176) until week 48. 25-OH vitamin D concentration was measured at baseline in frozen serum. RESULTS A total of 461 patients could be analysed for virologic response at W24, and 285 (119 non-responders at W24 + 166 responders who continued dual therapy until W48) for the impact of SVR. There were 487 patients who could be analysed for fibrosis progression. Metavir fibrosis scores (centralised analysis) were: F1 30%, F2 34%, F3 27% and F4 9%. Median 25-OH vitamin D concentrations were similar in virologic responders (13.5 ng/ml) and in non-responders at W24 (12.6 ng/ml), as well as in patients with SVR (12.8 ng/ml) and without SVR (12.8 ng/ml, 3.99) at W72. Median 25-OH vitamin D concentrations were: F1: 14.30 ng/ml, F2: 13.50 ng/ml, F3: 13.30 ng/ml and F4: 12.80 ng/ml. CONCLUSION In this study, 25-OH vitamin D level has no impact on the efficacy of antiviral therapy in naïve genotype 1 HCV-infected patients.
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Affiliation(s)
- Arthur Belle
- Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Emmanuel Gizard
- Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Guillaume Conroy
- Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Anthony Lopez
- Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Magali Bouvier-Alias
- National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France
| | | | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France
| | - Jean-Pierre Bronowicki
- Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
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14
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Drori A, Shabat Y, Ben Ya'acov A, Danay O, Levanon D, Zolotarov L, Ilan Y. Extracts from Lentinula edodes (Shiitake) Edible Mushrooms Enriched with Vitamin D Exert an Anti-Inflammatory Hepatoprotective Effect. J Med Food 2016; 19:383-9. [DOI: 10.1089/jmf.2015.0111] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Ariel Drori
- Liver Unit, Department of Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
| | - Yehudit Shabat
- Liver Unit, Department of Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
| | - Ami Ben Ya'acov
- Liver Unit, Department of Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
| | - Ofer Danay
- Migal, Galilee Research Institute, Kiryat Shmone, Israel
| | - Dan Levanon
- Migal, Galilee Research Institute, Kiryat Shmone, Israel
| | - Lidya Zolotarov
- Liver Unit, Department of Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
| | - Yaron Ilan
- Liver Unit, Department of Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
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15
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Atsukawa M, Tsubota A, Shimada N, Yoshizawa K, Abe H, Asano T, Ohkubo Y, Araki M, Ikegami T, Okubo T, Kondo C, Osada Y, Nakatsuka K, Chuganji Y, Matsuzaki Y, Iwakiri K, Aizawa Y. Effect of native vitamin D3 supplementation on refractory chronic hepatitis C patients in simeprevir with pegylated interferon/ribavirin. Hepatol Res 2016; 46:450-458. [PMID: 26289410 DOI: 10.1111/hepr.12575] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 02/08/2023]
Abstract
AIM Protease inhibitors with pegylated interferon (PEG IFN)/ribavirin improve a sustained virological response (SVR) rate to approximately 90% in chronic hepatitis C genotype 1b patients with IL28B rs8099917 genotype TT, but yield only approximately 50% in those with the unfavorable non-TT. Among such treatment-refractory patients, serum vitamin D levels could influence the SVR rate. This randomized controlled trial was conducted to assess the effect of native vitamin D supplementation in simeprevir with PEG IFN/ribavirin for 1b patients with non-TT. METHODS Patients were randomly assigned to receive simeprevir (100 mg/day) for 12 weeks plus PEG IFN/ribavirin for 24 weeks (control group, n = 58), or vitamin D (2000 IU/day) for 16 weeks including a lead-in phase plus PEG IFN/ribavirin for 24 weeks (vitamin D group, n = 57). The primary end-point was sustainably undetectable viremia 24 weeks after the end of treatment (SVR). RESULTS SVR rates were 37.9% in the control group and 70.2% in the vitamin D group. In subgroup analysis, SVR rates of prior null responders were 11.8% and 54.5%, respectively. SVR rates for advanced fibrosis were 28.6% and 65.4%. SVR rates for patients with vitamin D3 deficiency at the baseline were 25.0% in the control group and 66.7% in the vitamin D group. Overall, the SVR rate was significantly higher in patients with high serum 25(OH)D3 levels at the beginning of combination therapy than in those with low serum 25(OH)D3 levels. CONCLUSION Native vitamin D3 supplementation improved SVR rates in simeprevir with PEG IFN/ribavirin for chronic hepatitis C genotype 1b patients with refractory factors.
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Affiliation(s)
- Masanori Atsukawa
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo
| | | | | | - Hiroshi Abe
- Jikei University School of Medicine Katsushika Medical Center
| | - Toru Asano
- Tokyo Metropolitan Bokutoh Hospital, Tokyo
| | | | | | | | - Tomomi Okubo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai
| | - Chisa Kondo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai
| | | | | | | | | | | | - Yoshio Aizawa
- Jikei University School of Medicine Katsushika Medical Center
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16
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Wu MP, Zhang JW, Huang P, Han YP, Zhang Y, Peng ZH, Wang J, Zhu P, Su J, Yu RB, Li J, Yue M. Genetic variations in vitamin D receptor were associated with the outcomes of hepatitis C virus infection among Chinese population. J Hum Genet 2016; 61:129-135. [PMID: 26446365 DOI: 10.1038/jhg.2015.117] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Revised: 09/03/2015] [Accepted: 09/07/2015] [Indexed: 02/06/2023]
Abstract
Vitamin D has been considered as an immune modulator, and exerted the effect through the vitamin D receptor (VDR). This study investigated the associations of single-nucleotide polymorphisms (SNPs) of VDR with the outcomes of Hepatitis C virus (HCV) infection. Three SNPs (rs2228570, rs757343 and rs739837) were genotyped by TaqMan assay among Chinese population, including 538 HCV spontaneous clearance subjects, 834 persistent infection subjects and 1030 uninfected subjects. Binary logistic analyses were used to control the effects of confounding factors. The results showed that subjects with the rs757343 A allele and rs739837 A allele had the significantly reduced risk of HCV susceptibility (all PBonferroni<0.05 in dominant/additive model). In the stratified analysis, the protection of rs757343 A allele and rs739837 A allele against HCV infection remained effective in some subgroups. In addition, patients carrying rs739837 CA genotype were less prone to develop persistent infection (PBonferroni=0.033) and such effect still work in several subgroups in the stratified analysis. Furthermore, haplotype analysis indicated that when compared with the most frequent GC haplotype, the haplotype carrying AA (odds ratio (OR)=0.66, 95% confidence interval (CI)=0.56-0.78) and GA (OR=0.64, 95% CI=0.47-0.85) suggested a protective effect. Our findings indicated that the polymorphisms of VDR are associated with the outcomes of HCV infection among Chinese population.
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Affiliation(s)
- Meng-ping Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Jiangsu, China
| | - Jin-wei Zhang
- Department of Anesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Jiangsu, China
| | - Peng Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Jiangsu, China
| | - Ya-ping Han
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Jiangsu, China
| | - Yun Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Jiangsu, China
- Institute of Epidemiology and Microbiology, Huadong Research Institute for Medicine and Biotechnics, Jiangsu, China
| | - Zhi-hang Peng
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Jiangsu, China
| | - Jie Wang
- School of Nursing, Nanjing Medical University, Jiangsu, China
| | - Ping Zhu
- Department of Medical Affairs, The First Affiliated Hospital of Nanjing Medical University, Jiangsu, China
| | - Jing Su
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Jiangsu, China
| | - Rong-bin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Jiangsu, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Jiangsu, China
| | - Ming Yue
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Jiangsu, China
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17
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Omori-Mizuno Y, Nakayama N, Inao M, Funyu J, Asabe S, Tomita K, Nishikawa K, Hosoda Y, Tanaka M, Hashimoto Y, Yakabi K, Koshima Y, Mochida S. Randomized study comparing vitamin D3 and 1α-Hydroxyvitamin D3 in combination with pegylated interferon/ribavirin therapy for chronic hepatitis C. J Gastroenterol Hepatol 2015; 30:1384-90. [PMID: 25778685 DOI: 10.1111/jgh.12949] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/01/2015] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIM An intention-to-treat prospective randomized study was carried out to compare the potentiation of antiviral efficacies between cholecalciferol, non-activated vitamin D3 supplement, and alfacalcidol, activated 1α-Hydroxyvitamin D3 [1α (OH)-vitamin D3]. METHODS Chronic hepatitis patients with genotype 1b hepatitis C virus (HCV) infection showing serum HCV-RNA levels greater than 5 Log IU/mL received oral administration of cholecalciferol (2000 IU/day) or alfacalcidol (0.5 μg/day) for 4 weeks, and then they were given pegylated interferon (Peg-IFN)-α2a plus ribavirin therapy in combination with either vitamin D3 for 48 or 72 weeks according to the response-guided manner. RESULTS A total of 36 patients were evaluated. Serum 25-hydroxyvitamin D3 [25(OH)-D3] levels were increased only in patients in the cholecalciferol group during the lead-in vitamin D administration, and the levels at 4 weeks were higher in these patients than in those in the alfacalcidol group (P < 0.001), while serum 1α,25-dihydroxyvitamin D3 [1α,25(OH)2 -D3] levels were not different between both groups. Rapid virological response was obtained in six (33%) patients in the cholecalciferol group; the ratio was higher than that in the alfacalcidol group (one patient; 6%, P < 0.05). Serum HCV-RNA level decline at 4 weeks of combined Peg-IFN-α2a plus ribavirin therapy compared with the baseline levels were greater in the cholecalciferol group (4.6 Log IU/mL) than in the alfacalcidol group (3.5 Log IU/mL) (P < 0.05), when four patients showing null response to the therapy was excluded. However, both complete early virological response and sustained viral response rates were not different between both groups. CONCLUSION Cholecalciferol produced superior potentiation of the antiviral activity than alfacalcidol only during the initial periods of combined Peg-IFN-α2a plus ribavirin therapy through upregulation of serum 25(OH)-D3 levels.
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Affiliation(s)
- Yoshie Omori-Mizuno
- Department of Gastroenterology & Hepatology, Saitama Medical University, Moroyama-Machi, Saitama, Japan
| | - Nobuaki Nakayama
- Department of Gastroenterology & Hepatology, Saitama Medical University, Moroyama-Machi, Saitama, Japan
| | - Mie Inao
- Department of Gastroenterology & Hepatology, Saitama Medical University, Moroyama-Machi, Saitama, Japan
| | - Junji Funyu
- Department of Internal Medicine, Chichibu Hospital, Chichibu, Saitama, Japan
| | - Shinichi Asabe
- Department of Gastroenterology, Siatama Medical Center, Jichi Medical University, Saitama, Saitama, Japan
| | - Kengo Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College Hospital, Tokorozawa, Saitama, Japan
| | - Kou Nishikawa
- Department of Gastroenterology, Ageo Chuo General Hospital, Ageo, Saitama, Japan
| | - Yasuo Hosoda
- Department of Gastroenterology, National Hospital Organization Saitama National Hospital, Wako, Saitama, Japan
| | - Masahiko Tanaka
- Department of Internal Medicine, Kan-etsu Hospital, Tsurugashima, Saitama, Japan
| | | | - Koji Yakabi
- Department of Gastroenterology & Hepatology, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan
| | - Yohei Koshima
- Department of Internal Medicine I, Saitama Red Cross Hospital, Saitama, Saitama, Japan
| | - Satoshi Mochida
- Department of Gastroenterology & Hepatology, Saitama Medical University, Moroyama-Machi, Saitama, Japan
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18
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Atsukawa M, Tsubota A, Shimada N, Yoshizawa K, Abe H, Asano T, Ohkubo Y, Araki M, Ikegami T, Kondo C, Itokawa N, Nakagawa A, Arai T, Matsushita Y, Nakatsuka K, Furihata T, Chuganji Y, Matsuzaki Y, Aizawa Y, Iwakiri K. Influencing factors on serum 25-hydroxyvitamin D3 levels in Japanese chronic hepatitis C patients. BMC Infect Dis 2015; 15:344. [PMID: 26286329 PMCID: PMC4543479 DOI: 10.1186/s12879-015-1020-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Accepted: 07/13/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Serum 25-hydroxyvitamin D3 levels are generally lower in chronic hepatitis C patients than in healthy individuals. The purpose of this study is to clarify the factors which affect serum 25-hydroxyvitamin D3 levels using data obtained from Japanese chronic hepatitis C patients. METHODS The subjects were 619 chronic hepatitis C patients. Serum 25-hydroxyvitamin D3 levels were measured by using double-antibody radioimmunoassay between April 2009 and August 2014. Serum 25-hydroxyvitamin D3 levels of 20 ng/mL or less were classified as vitamin D deficiency, and those with serum 25-hydroxyvitamin D3 levels of 30 ng/mL or more as vitamin D sufficiency. The relationship between patient-related factors and serum 25-hydroxyvitamin D3 levels was analyzed. RESULTS The cohort consisted of 305 females and 314 males, aged between 18 and 89 years (median, 63 years). The median serum 25-hydroxyvitamin D3 level was 21 ng/mL (range, 6-61 ng/mL). On the other hand, the median serum 25-hydroxyvitamin D3 level in the healthy subjects was 25 ng/mL (range, 7-52), being significantly higher than that those in 80 chronic hepatitis C patients matched for age, gender, and season (p = 1.16 × 10(-8)). In multivariate analysis, independent contributors to serum 25-hydroxyvitamin D3 deficiency were as follows: female gender (p = 2.03 × 10(-4), odds ratio = 2.290, 95 % confidence interval = 1.479-3.545), older age (p = 4.30 × 10(-4), odds ratio = 1.038, 95 % confidence interval = 1.017-1.060), cold season (p = 0.015, odds ratio = 1.586, 95 % confidence interval = 1.095-2.297), and low hemoglobin level (p = 0.037, odds ratio = 1.165, 95 % confidence interval = 1.009-1.345). By contrast, independent contributors to serum 25-hydroxyvitamin D3 sufficiency were male gender (p = 0.001, odds ratio = 3.400, 95 % confidence interval = 1.635-7.069), warm season (p = 0.014, odds ratio = 1.765, 95 % confidence interval = 1.117-2.789) and serum albumin (p = 0.016, OR = 2.247, 95 % CI = 1.163-4.342). CONCLUSIONS Serum 25-hydroxyvitamin D3 levels in chronic hepatitis C Japanese patients were influenced by gender, age, hemoglobin level, albumin and the season of measurement.
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Affiliation(s)
- Masanori Atsukawa
- Nippon Medical School Chiba Hokusoh Hospital, 1715, Inzai, Chiba, Japan.
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences, Jikei University School of Medicine, 3-25-8, Minato-ku, Tokyo, Japan.
| | - Noritomo Shimada
- Chiba Tokushukai Hospital, 2-11-1 Takanedai, Funabashi, Chiba, Japan.
| | - Kai Yoshizawa
- Machida Municipal Hospital, 2-15-41 Asahi-cho, Machida, Tokyo, Japan.
| | - Hiroshi Abe
- Jikei University School of Medicine Katsusika Medical Center, 6-41-2 Aoto, Katsushika, Tokyo, Japan.
| | - Toru Asano
- Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Koutoubashi, Sumida, Tokyo, Japan.
| | - Yusuke Ohkubo
- Saiseikai Yokohamashi Tobu Hospital, 3-6-1 shimosueyoshi, Tsurumi, Kanagawa, Japan.
| | - Masahiro Araki
- Ibaraki Central Hospital, Kasama, 6528, Koihuchi, Ibaraki, Japan.
| | - Tadashi Ikegami
- Tokyo Medical University, Ibaraki Medical Center, 3-20-1 amichochuo, Inashiki, Ibaraki, Japan.
| | - Chisa Kondo
- Nippon Medical School Chiba Hokusoh Hospital, 1715, Inzai, Chiba, Japan.
| | - Norio Itokawa
- Nippon Medical School Chiba Hokusoh Hospital, 1715, Inzai, Chiba, Japan.
| | - Ai Nakagawa
- Nippon Medical School Chiba Hokusoh Hospital, 1715, Inzai, Chiba, Japan.
| | - Taeang Arai
- Nippon Medical School Chiba Hokusoh Hospital, 1715, Inzai, Chiba, Japan.
| | | | | | - Tomomi Furihata
- Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
| | - Yoshimichi Chuganji
- Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Koutoubashi, Sumida, Tokyo, Japan.
| | - Yasushi Matsuzaki
- Tokyo Medical University, Ibaraki Medical Center, 3-20-1 amichochuo, Inashiki, Ibaraki, Japan.
| | - Yoshio Aizawa
- Jikei University School of Medicine Katsusika Medical Center, 6-41-2 Aoto, Katsushika, Tokyo, Japan.
| | - Katsuhiko Iwakiri
- Nippon Medical School Chiba Hokusoh Hospital, 1715, Inzai, Chiba, Japan.
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Refaat B, El-Shemi AG, Ashshi A, Azhar E. Vitamin D and chronic hepatitis C: effects on success rate and prevention of side effects associated with pegylated interferon-α and ribavirin. Int J Clin Exp Med 2015; 8:10284-10303. [PMID: 26379820 PMCID: PMC4565203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 07/01/2015] [Indexed: 06/05/2023]
Abstract
Chronic hepatitis C (CHC) is one of the most common causes of liver diseases worldwide, affecting 3% of the world population and 3 to 4 million people acquire new infection annually. Despite the recent introduction of novel antiviral drugs for the treatment of CHC, these drugs are expensive and the access to them is not an option for many patients. Hence, the traditional therapy by pegylated interferon-α (Peg-IFN-α) and ribavirin may still have a role in the clinical management of CHC especially in developing countries. However, this standard therapy is associated with several severe extra-hepatic side effects and the most common adverse events are hematological abnormalities and thyroid disorders and they could result in dose reduction and/or termination of therapy. Vitamin D has been shown to be a key regulatory element of the immune system, and its serum concentrations correlate with the severity of liver damage and the development of liver fibrosis/cirrhosis. Furthermore, supplementation with vitamin D with Peg-IFN-α based therapy for the treatment of CHC could be beneficial in increase the response rate to Peg-INF-α based therapy. Vitamin D has also been shown to regulate the thyroid functions and the process of erythropoiesis. This review appraises the data to date researching the role of vitamin D during the treatment of CHC and the potential role of vitamin D in preventing/treating Peg-IFN-α induced thyroiditis and anemia during the course of treatment.
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Affiliation(s)
- Bassem Refaat
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura UniversityAl Abdeyah, Makkah, PO Box 7607, KSA
| | - Adel Galal El-Shemi
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura UniversityAl Abdeyah, Makkah, PO Box 7607, KSA
- Department of Pharmacology, Faculty of Medicine, Assiut UniversityEgypt
| | - Ahmed Ashshi
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura UniversityAl Abdeyah, Makkah, PO Box 7607, KSA
| | - Esam Azhar
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz UniversityJeddah, KSA
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz UniversityJeddah, Saudi Arabia
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Kondo Y, Kimura O, Shimosegawa T. Significant biomarkers for the management of hepatocellular carcinoma. Clin J Gastroenterol 2015; 8:109-115. [PMID: 25855582 DOI: 10.1007/s12328-015-0568-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 03/30/2015] [Indexed: 02/07/2023]
Abstract
Surveillance of hepatocellular carcinoma (HCC) is important for early detection. Imaging tests including computed tomography, magnetic resonance imaging and ultrasonography with or without various kinds of contrast medium are important options for detecting HCC. In addition to the imaging tests, various kinds of biomarkers including alpha-fetoprotein (AFP), lectin-bound AFP (AFP-L3) and protein induced by vitamin K absence or antagonist II (PIVKA-II) have been widely used to detect HCC and analyze treatment response. Recently, various kinds of novel biomarkers (proteins and miRNA) have been found to predict the malignancy potential of HCC and treatment response to specific therapies. Moreover, various combinations of well-established biomarkers and novel biomarkers have been tested to improve sensitivity and specificity. In practical terms, biomarkers that can be analyzed using peripheral blood samples might be more useful than immunohistochemical techniques. It has been reported that quantification of cytokines in peripheral blood and the analysis of peripheral immune subsets could be good biomarkers for managing HCC. Here, we describe the usefulness of and update well-established and novel biomarkers for the management of HCC.
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Affiliation(s)
- Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo, Aoba, Sendai City, Miyagi, 980-8574, Japan,
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21
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Vitamin D Deficiency in HIV Infection: Not Only a Bone Disorder. BIOMED RESEARCH INTERNATIONAL 2015; 2015:735615. [PMID: 26000302 PMCID: PMC4426898 DOI: 10.1155/2015/735615] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 02/18/2015] [Accepted: 03/02/2015] [Indexed: 01/01/2023]
Abstract
Hypovitaminosis D is a worldwide disorder, with a high prevalence in the general population of both Western and developing countries. In HIV patients, several studies have linked vitamin D status with bone disease, neurocognitive impairment, depression, cardiovascular disease, high blood pressure, metabolic syndrome, type 2 diabetes mellitus, infections, autoimmune diseases like type 1 diabetes mellitus, and cancer. In this review, we focus on the most recent epidemiological and experimental data dealing with the relationship between vitamin D deficiency and HIV infection. We analysed the extent of the problem, pathogenic mechanisms, clinical implications, and potential benefits of vitamin D supplementation in HIV-infected subjects.
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Abstract
BACKGROUND Vitamin D is a fat-soluble sterol derivative that is predominantly synthesized in the liver and has multiple functions. The accumulative data showed that the clinical manifestations and prognosis of chronic liver diseases are associated with serum vitamin D levels. DATA SOURCES A PubMed and Google Scholar search using terms: "vitamin D", "25(OH)D", "liver disease", "viral hepatitis", "non-alcoholic fatty liver disease", "liver fibrosis", "cirrhosis", "hepatocellular carcinoma" and "autoimmune liver disease" was performed, and relevant articles published in English between January 2000 and March 2014 were reviewed. Full-text publications relevant to the field were selected and relevant articles from reference lists were also included. RESULTS The insufficiency or deficiency of vitamin D is common in various kinds of chronic liver diseases including viral hepatitis B and C. Serum 25-hydroxyvitamin D and vitamin D receptors are possibly interrelated with the incidence, treatment and prognosis of diseases. Though the evidence of vitamin D supplementation in viral hepatitis and associated liver diseases is still limited, there is great potential to apply this adjuvant therapy to improve the treatments. CONCLUSIONS Although the exact role and mechanisms of vitamin D have not been fully elucidated in chronic liver diseases, it is potentially beneficial in the treatment of chronic liver diseases. Further mechanistic studies are needed to validate its clinical application.
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Affiliation(s)
- En-Qiang Chen
- Center of Infectious Diseases, West China Hospital; and Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
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Escota GV, Cross S, Powderly WG. Vitamin D and calcium abnormalities in the HIV-infected population. Endocrinol Metab Clin North Am 2014; 43:743-67. [PMID: 25169565 DOI: 10.1016/j.ecl.2014.05.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The prevalence of vitamin D deficiency among HIV-infected persons is substantial and comparable to the general population. The factors associated with vitamin D deficiency are similar for both populations but additional factors (ie, use of certain antiretroviral agents) also contribute to vitamin D deficiency among HIV-infected persons. The adverse outcomes associated with vitamin D deficiency considerably overlap with non-AIDS defining illnesses (NADIs) that are increasingly becoming widespread in the aging HIV-infected population. However, there is scant evidence to support any causal inference. Further studies are warranted as efforts to identify and address modifiable risk factors contributing to NADIs continue.
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Affiliation(s)
- Gerome V Escota
- Division of Infectious Diseases, Washington University School of Medicine, 660 South Euclid, St Louis, MO 63110, USA
| | - Sara Cross
- Division of Infectious Diseases, University of Tennessee Health Sciences Center, 956 Court Avenue, E336 Coleman Building, Memphis, TN 38163, USA
| | - William G Powderly
- Division of Infectious Diseases, Washington University School of Medicine, 660 South Euclid, St Louis, MO 63110, USA.
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