Adverse Effects of Vitamin D Deficiency on Outcomes of Patients With Chronic Hepatitis B

doi:10.1016/j.cgh.2014.09.050

Clinical Gastroenterology and Hepatology

Volume 13, Issue 4, April 2015, Pages 783-790.e1

https://doi.org/10.1016/j.cgh.2014.09.050 Get rights and content

Background & Aims

Vitamin D is an immunomodulator that might be involved in the pathogenesis of viral hepatitis. We investigated the effects of vitamin D deficiency on long-term outcomes of patients with chronic hepatitis B (CHB).

Methods

We performed a prospective cohort study of 426 patients with CHB (65% male; mean age, 41 ± 13 years), who were enrolled from 1997 through 2000. Serum levels of 25-hydroxycholecalciferol (25(OH)D₃) were measured on study enrollment (baseline). Patients were followed for 159 ± 46 months until last clinic visit or death; approximately 33% received antiviral therapy during the follow-up period. The primary outcome was a clinical event (hepatocellular carcinoma, complications of cirrhosis, or death).

Results

At baseline, the patients’ mean serum level of hepatitis B virus DNA was 5.0 ± 2.1 log₁₀ IU/mL; their mean level of 25(OH)D₃ was 24.3 ± 9.4 ng/mL, and 348 patients (82%) had vitamin D deficiency (<32 ng/mL). Serum levels of 25(OH)D₃ did not correlate with cirrhosis or viral load. Ninety-seven patients (22.8%) developed clinical events by a mean time of 118 ± 60 months after study enrollment. Patients who developed clinical events had lower baseline serum levels of 25(OH)D₃ (23.2 ± 10.4 ng/mL) than patients who did not (28.2 ± 9.3 ng/mL, P < .001). Low baseline serum 25(OH)D₃ was an independent factor associated with clinical events after adjustment for sex, age, and cirrhosis. The adjusted hazard ratio of vitamin D deficiency for clinical events was 1.90 (95% confidence interval [CI], 1.06–2.43; P = .04). The 15-year cumulative incidence rate of clinical events among patients with vitamin D deficiency was 25.5% (95% CI, 23.1%–27.9%), compared with 11.1% (95% CI, 7.4%–14.8%) in patients with normal serum levels of 25(OH)D₃.

Conclusions

Vitamin D deficiency is common among patients with CHB and is associated with adverse clinical outcomes.

Section snippets

Study Population

Consecutive chronic hepatitis B patients of Chinese ethnicity recruited at the Hepatitis Clinic, Prince of Wales Hospital from December 1997 to July 2000 were studied.13, 14 Patients with HCC at baseline, Child class C cirrhosis, hepatic decompensation, autoimmune hepatitis, coinfection with hepatitis C virus and human immunodeficiency virus, or other serious concurrent illness (eg, alcoholism, uncontrolled diabetes, or cancer) were excluded. The study protocol was approved by the local ethics

Patient Characteristics

Four hundred twenty-six patients including 278 men (65%) with a mean age of 41 ± 13 years were recruited. At baseline, 49 patients (11%) had clinical cirrhosis; 157 (37%) had positive HBeAg. The baseline serum HBV DNA level was 5.0 ± 2.1 log IU/mL, with 116 patients (27%) <2000 IU/mL. The serum 25(OH)D₃ level was 24.3 ± 9.4 ng/mL, and 348 patients (82%) had vitamin D deficiency (<32 ng/mL). Ninety-six patients (22.5%) did not have baseline 25(OH)D₃ collected in June to August of the year; 43

Discussion

This is the one of the first long-term prospective cohort studies demonstrating the adverse effect of vitamin D deficiency on clinical outcomes of CHB patients. Vitamin D deficiency is common among CHB patients, with a prevalence of 82%. The increased risk of HCC, hepatic event, and mortality among patients with vitamin D deficiency might be related to a less optimal viral suppression. Although serum 25(OH)D₃ level was influenced by gender and age, it was not affected by viral load and the

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Long-term use of tenofovir disoproxil fumarate increases fracture risk in elderly patients with chronic hepatitis B
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The use of tenofovir disoproxil fumarate (TDF) is associated with a reduction in bone mineral density and an increase in bone metabolism biomarkers. However, data on clinical bone fractures remain limited. We evaluated the impact of TDF compared to entecavir on the risk of fracture in elderly patients with chronic hepatitis B (CHB).
Patients with CHB aged ≥60 years receiving entecavir or TDF between January 2008 and December 2022 were identified using a territory-wide database in Hong Kong. The risk of incident fracture in entecavir- and TDF-treated patients before and after month 24 were compared after propensity score matching.
A total of 41,531 patients with CHB (mean age 69.8±7.8 years, 61.6% male) receiving entecavir (n = 39,897 [96.1%]) and TDF (n = 1,634 [3.9%]) were analysed. At a median follow-up of 25.3 (9.1–58.5) months, 1,733 (4.2%) patients developed incident fracture. Patients with incident fracture were more likely to have diabetes, hypertension, congestive heart failure, rheumatoid arthritis, osteoporosis, and a history of fracture. Compared with propensity score-matched entecavir-treated patients, the risk of incident fracture in TDF-treated patients was comparable in the first 24 months (weighted subdistribution hazard ratio [sHR] 0.99, 95% CI 0.56–1.73, p = 0.960) but increased after month 24 (weighted sHR 1.80, 95% CI 1.11–2.93, p = 0.019). The 24-, 60-, and 96-month cumulative incidences (95% CI) of fracture in TDF-treated and entecavir-treated patients were 2.3% (1.6%–3.4%) vs. 2.6% (1.9%–3.5%), 6.4% (5.0%–8.2%) vs. 4.7% (3.8%–6.0%), and 10.2% (8.3%–12.6%) vs. 6.8% (5.4%–8.5%), respectively.
The risk of fracture increased with TDF treatment for ≥24 months in elderly patients with CHB. Selection of nucleos(t)ide analogues should be individualised based on age and comorbidities.
Previous literature suggested that the use of tenofovir disoproxil fumarate (TDF) is associated with a decrease in bone mineral density. However, data on the impact of TDF on long-term incident clinical fracture remains scarce. In this real-world territory-wide study of 41,531 treated patients with chronic hepatitis B in Hong Kong, patients who received TDF were at a higher risk of fracture after 2 years of treatment than those who received entecavir. Given the ageing population of patients with chronic hepatitis B and the rising prevalence of comorbidities, our findings support the current treatment guidelines that recommend selecting antiviral treatment based on age and comorbidities.
Vitamin D role in hepatitis B: focus on immune system and genetics mechanism
2022, Heliyon
Citation Excerpt :
Some studies have declared vitamin D deficiency reduces the therapeutic effects in infectious patients. Vitamin D inhibits virus replication [105, 106, 107, 108]; it has an effective role in platelet and albumin levels and reducing ALT enzyme levels in patients with acute hepatitis [109, 110, 111, 112]. In a research study, severe vitamin D deficiency in patients with autoimmune hepatitis has led to disease progression and lack of response to treatment.
According to the World Health Organization (WHO) report, viral hepatitis has been a problem in human society. Vitamins play a significant role in preventing the hepatocarcinoma and liver cirrhosis. In this report, we will first focus on the vitamin D function in the immune system reactions, and then investigate its role in the viral infections and the signaling pathway of hepatitis B virus.
The existence of the cytochrome P450 (CYP) 27B1 enzyme, which is involved in vitamin D synthesis in immune system cells, has drawn researchers ' attention to the field of immune system. Toll like receptor (TLR) play a significant role in the immune system, and are one of the primary receptors of the innate immune system. In addition, the synthesis of inflammatory cytokines, such as Interferon γ (IFNγ) and Interleukin-2 (IL-2) is one of the key roles of T helper type 1 (Th1) cells; these cells can suppress two cited cytokines via vitamin D. In the chronic phase of hepatitis B, Cytotoxic T lymphocytes (CTLs) cells have weaker performance than the acute phase of the disease. The association between vitamin D physiologies with viral infections is also confirmed by genetic studies, carried out on genetic variations of vitamin D receptor (VDR) R-encoding disease susceptibility gene. Vitamin D affects different phases of the disease. Therefore, further experiments in this area are proposed.
IL-10 and IL-28B gene variants as predictors of sustained response to peginterferon and ribavirin therapy in chronic HCV infection
2022, Cytokine
Objectives: Interleukin-10 (IL-10) plays an important role in the immunity to hepatitis C virus (HCV). Insofar as IL-10 variants are associated with altered levels of IL-10, previous studies that examined the association of IL-10 polymorphisms with the susceptibility to and progression of chronic HCV, and response to anti-viral treatment were inconsistent. We investigated the association between common IL-10 variants in the intron and the promotor region with HCV and associated features.
Methods: Study subjects comprised 120 patients infected with HCV-1b, and treated with Peg-IFN/RBV. Genotyping of six IL-10 promoter variants in the intron region (rs1878672, rs1554286, rs1518111) and promotor region (rs1800872, rs1800871, rs1800896) were done by real-time PCR.
Results: Compared to G/G, carriage of IL-10 rs1800896 (-1082A/G) A/A genotype was more frequent in patients with sustained virological response (SVR). The decline in viral load over the first 12 weeks of treatment was more pronounced in rs1800896 A/A genotype carriers, compared to G/G genotype carriers, and was irrespective of the treatment dosage. Carriage of rs1800896 A/A genotype was positively associated with improvement in viral load decline, which was simultaneous, with and without carriage of the common favourable IL-28B variant. Carriage of both IL-10 rs1800896 G/G and IL-28B non-favourable genotype was associated with twice the risk of getting slow decline of viral load during treatment. Haploview analysis identified ACGCTA and CCGCTG haplotypes to be linked with excellent PegIFN/RBV cure rate, and complete HCV eradication. On the other hand, ACGCTG and CCGCTA haplotypes were associated with resistance to PegIFN/RBV treatment.
Conclusion: IL-10 rs1800896 variant markedly influences the clinical outcome of HCV infection, and is a determinant of the response to HCV treatment.
Vitamin D signaling inhibits HBV activity by directly targeting the HBV core promoter
2021, Journal of Biological Chemistry
Clinical and epidemiological studies support a role for vitamin D in suppressing hepatitis B virus (HBV). This antiviral role of vitamin D is widely attributed to vitamin D receptor (VDR)/retinoid X receptor–mediated regulation of host immunomodulatory genes through vitamin D response elements (VDREs) in their promoters. Here, we investigated the ability of calcitriol (1α,25-dihydroxyvitamin D3, metabolically activated vitamin D) to directly regulate HBV activity through this signaling pathway. We observed that calcitriol selectively inhibited only the HBV core promoter without affecting the HBV-PreS1, HBV-PreS2/S, or HBx promoters. We then identified a VDRE cluster in the HBV core promoter that is highly conserved across most HBV genotypes. Disruption of this VDRE cluster abrogated calcitriol-mediated suppression of the HBV core promoter. Furthermore, we showed that VDR interacts directly with the VDRE cluster in the HBV core promoter independent of retinoid X receptor. This demonstrates that calcitriol inhibits HBV core promoter activity through a noncanonical calcitriol-activated VDR pathway. Finally, we observed that calcitriol suppressed expression of the canonical HBV core promoter transcripts, pregenomic RNA, and precore RNA in multiple HBV cell culture models. In addition, calcitriol inhibited the secretion of hepatitis B “e” antigen and hepatitis B surface antigen (HBV-encoded proteins linked to poor disease prognosis), without affecting virion secretion. Our findings identify VDR as a novel regulator of HBV core promoter activity and also explain at least in part the correlation of vitamin D levels to HBV activity observed in clinical studies. Furthermore, this study has implications on the potential use of vitamin D along with anti-HBV therapies, and lays the groundwork for studies on vitamin D-mediated regulation of viruses through VDREs in virus promoters.
Response to letter to the editor “The association of vitamin D with hepatitis B virus replication: Just the bystander?”
2021, Journal of the Formosan Medical Association
Estimating the proportion of people with chronic hepatitis B virus infection eligible for hepatitis B antiviral treatment worldwide: a systematic review and meta-analysis
2021, The Lancet Gastroenterology and Hepatology
Citation Excerpt :
13 403 records were unique, after removal of duplicates, and of these, 465 were selected for full-text screening. Review of the full-text articles led to the exclusion of 303, and the inclusion of 162 articles in the analysis (figures 1 and 2).12–173 Of the 162 studies included (table 1), 50 (31%) were published in 2007–11, and 112 (69%) were published in 2012–18.
In 2016, of the estimated 257 million people living with chronic hepatitis B virus (HBV) infection worldwide, only a small proportion was diagnosed and treated. The insufficiency of information on the proportion of people infected with HBV who are eligible for treatment limits the interpretation of global treatment coverage. We aimed to estimate the proportion of people with chronic HBV infection who were eligible for antiviral treatment worldwide, based on the WHO 2015 guidelines.
In this systematic review and meta-analysis, we searched Medline, EMBASE, and the Cochrane databases from Jan 1, 2007, to Jan 31, 2018, for studies describing HBsAg-positive people in the population or health-care facilities. We extracted information from published studies using a standardised form to estimate the frequency of cirrhosis, abnormal alanine aminotransferase (ALT), HBV DNA exceeding 2000 IU/mL or 20 000 IU/mL, presence of HBeAg, and eligibility for treatment as per WHO and other guidelines as reported in the studies. We pooled proportions through meta-analysis with random effects. The study was registered with PROSPERO, CRD42020132345.
Of the 13 497 studies, 162 were eligible and included in our analysis. These studies included 145 789 participants. The pooled estimate of the proportion of cirrhosis was 9% (95% CI 8–10), ranging from 6% (4–8) in community settings to 10% (9–11) in clinic settings. Examining the proportion of participants who had characteristics used to determine eligibility in the WHO guidelines, 1750 (10·1%) of 17 394 had HBV DNA exceeding 20 000 IU/mL, and 20 425 (30·8%) of 66 235 had ALT above the upper limit of normal. 32 studies reported eligibility for treatment according to WHO or any other guidelines, with a pooled estimate of eligibility at 19% (95% CI 18–20), ranging from 12% (6–18) for studies in community settings to 25% (19–30) in clinic settings.
Many studies described people with HBV infection, but few reported information in a way that allowed assessment of eligibility for treatment. Although about one in ten of the 257 million people with HBV infection (26 million) might be in urgent need of treatment because of cirrhosis, a larger proportion (12–25%) is eligible for treatment in accordance with different guidelines. Future studies describing people with HBV infection should report on treatment eligibility, according to broadly agreed definitions.
WHO and US Centers for Disease Control and Prevention.

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: Conflicts of interest These authors disclose the following: Grace Wong has served as an advisory committee member for Otsuka and Gilead and has also served as a speaker for Bristol-Myers Squibb, Echosens, Furui and Otsuka. Henry Chan is a consultant for Abbott, Bristol-Myers Squibb, Furui, Gilead, Merck, Novartis, and Roche, has received honoraria for lectures for Abbott, Bristol-Myers Squibb, Echosens, Gilead, Glaxo-Smith-Kline, Merck, Novartis, and Roche, and has received an unrestricted grant from Roche for hepatitis B research. Vincent Wong has served as an advisory committee member for Roche, Novartis, Gilead, and Otsuka and has also served as a speaker for Bristol-Myers Squibb, Roche, Novartis, Abbott Diagnostics, and Echosens. The remaining authors disclose no conflicts.

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Original articlePancreas, biliary tract, and liverAdverse Effects of Vitamin D Deficiency on Outcomes of Patients With Chronic Hepatitis B

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Population

Patient Characteristics

Discussion

Clin Gastroenterol Hepatol

J Hepatol

Lancet

Gastroenterology

J Hepatol

Hepatitis B virus infection

N Engl J Med

Hepatocellular carcinoma and hepatitis B virus

Semin Liver Dis

Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy

World J Gastroenterol

Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma

Aliment Pharmacol Ther

Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis

Hepatology

Meta-analysis: reduction in hepatic events following interferon-alfa therapy of chronic hepatitis B

Aliment Pharmacol Ther

Clinical practice: vitamin D insufficiency

N Engl J Med

Reduced bone mineral density and altered bone turnover markers in patients with non-cirrhotic chronic hepatitis B or C infection

World J Gastroenterol

Prevalence of vitamin D deficiency in chronic liver disease

Dig Dis Sci

Low vitamin D serum concentration is associated with high levels of hepatitis B virus replication in chronically infected patients

Hepatology

Original article
Pancreas, biliary tract, and liver
Adverse Effects of Vitamin D Deficiency on Outcomes of Patients With Chronic Hepatitis B