Role of Vitamin D Supplementation in Chronic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Petrana Martinekova; Mahmoud Obeidat; Mihaela Topala; Szilárd Váncsa; Dániel Sándor Veres; Ádám Zolcsák; Miheller Pál; László Földvári-Nagy; Peter Banovcin; Bálint Erőss; Péter Hegyi; Krisztina Hagymasi

doi:10.1093/nutrit/nuaf117

. 2025 Jul 11;83(11):2043–2054. doi: 10.1093/nutrit/nuaf117

Role of Vitamin D Supplementation in Chronic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Petrana Martinekova ^1,², Mahmoud Obeidat ³, Mihaela Topala ^4,⁵, Szilárd Váncsa ^6,^7,⁸, Dániel Sándor Veres ^9,¹⁰, Ádám Zolcsák ^11,¹², Miheller Pál ^13,¹⁴, László Földvári-Nagy ^15,¹⁶, Peter Banovcin ^17,¹⁸, Bálint Erőss ^19,^20,²¹, Péter Hegyi ^22,^23,²⁴, Krisztina Hagymasi ^25,^26,^✉

¹ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

² Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic

³ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

⁴ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

⁵ Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania

⁶ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

⁷ Institute of Pancreatic Diseases, Semmelweis University, Budapest 1083, Hungary

⁸ Institute for Translational Medicine, University of Pécs, Medical School, Pécs 7623, Hungary

⁹ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

¹⁰ Department of Biophysics and Radiation Biology, Semmelweis University, Budapest 1094, Hungary

¹¹ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

¹² Department of Biophysics and Radiation Biology, Semmelweis University, Budapest 1094, Hungary

¹³ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

¹⁴ Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest 1082, Hungary

¹⁵ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

¹⁶ Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest 1088, Hungary

¹⁷ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

¹⁸ Gastroenterology Clinic, University Hospital in Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 036 59, Slovak Republic

¹⁹ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

²⁰ Institute of Pancreatic Diseases, Semmelweis University, Budapest 1083, Hungary

²¹ Institute for Translational Medicine, University of Pécs, Medical School, Pécs 7623, Hungary

²² Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

²³ Institute of Pancreatic Diseases, Semmelweis University, Budapest 1083, Hungary

²⁴ Institute for Translational Medicine, University of Pécs, Medical School, Pécs 7623, Hungary

²⁵ Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary

²⁶ Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest 1082, Hungary

^✉

Corresponding Author: Krisztina Hagymasi, Department of Surgery, Transplantation, and Gastroenterology; Semmelweis University, H-1082 Budapest, Üllői út 78, Hungary (hagymasi.krisztina@semmelweis.hu).

PMCID: PMC12512233 PMID: 40644459

Abstract

Context

Vitamin D deficiency is highly prevalent in chronic liver disease. Although international societies recommend vitamin D supplementation in cases of proven deficiency, the impact of vitamin D on chronic liver disease remains uncertain.

Objective

Our aim was to evaluate the effects of vitamin D supplementation in patients with chronic liver disease by conducting a systematic review and meta-analysis of randomized controlled trials (RCTs).

Data Sources

We systematically searched PubMed, EMBASE and the Cochrane Library on July 2, 2024.

Data Extraction

Our primary outcomes involved survival, controlled attenuation parameter (CAP), liver stiffness measurement (LSM), and effects on changes in liver enzymes. Secondary outcomes included lipid profile and homeostasis model assessment of insulin resistance (HOMA-IR), among others. The pooled risk ratio (RR), mean difference (MD), and corresponding 95% CIs were calculated using the random-effects model.

Data Analysis

Forty-six RCTs were included, comprising 4084 patients. When we compared the vitamin D group with the control, the RR for overall survival was 1.14 (95% CI, 0.85-1.54; 4 RCTs) at 6 months and 0.99 (95% CI, 0.83-1.17; 4 RCTs) at the 12-month follow-up. Vitamin D supplementation did not result in a lower CAP (MD, −23.50 dB/m; 95% CI, −81.72 to 34.72; 3 RCTs) and LSM (MD, −0.65 kPa; 95% CI, −1.98 to 0.68; 3 RCTs). A significant reduction in HOMA-IR was observed in the vitamin D group (MD, −0.31; 95% CI, −0.62 to −0.01; 15 RCTs). Alanine aminotransferase (ALT) (MD, −4.98 IU/L; 95% CI, −8.28 to −1.68; 24 RCTs), aspartate aminotransferase (AST) (MD, −3.33 IU/L; 95% CI, −6.25 to −0.40; 23 RCTs), gamma-glutamyl transferase (GGT) (MD, −5.14 IU/L; −6.40; −3.88; 11 RCTs), triglycerides (MD, −7.59 mg/dL; 95% CI, −15.09 to −0.81), and insulin (MD −0.79 μIU/L; 95% CI, −1.36 to −0.21) were significantly reduced in the patients with vitamin D supplementation.

Conclusion

Our results showed significantly reduced ALT, AST, GGT, triglycerides, insulin, and HOMA-IR in the vitamin D–supplemented group; however, the effect was modest. In addition, there were no differences in survival, CAP, or LSM. Further RCTs with adequate power are warranted to clarify the results.

Systematic Review Registration

PROSPERO registration No. CRD42022370312

Keywords: vitamin D, micronutrient, liver cirrhosis, chronic liver disease

KEY POINTS.

Basic science suggested a possible protective role of vitamin D in hepatic fibrogenesis. The beneficial effect of vitamin D supplementation on liver steatosis and fibrosis was not shown based on the result of our study but further research is warranted.
Insulin resistance, determined by HOMA-IR, was significantly reduced after vitamin D supplementation. While insulin levels were reduced in vitamin D patients, there was no evidence of a difference in fasting plasma glucose levels.
There was a significant reduction in ALT, AST, and GGT in vitamin D-supplemented patients. The inclusion of eligible participants with liver enzymes above the normal range may ascertain the effect.

INTRODUCTION

The burden of chronic liver disease, which leads to significant mortality rates, is a global concern. Ye et al demonstrated an increasing trend in global cirrhosis-related mortality of 47.15% from 1990 to 2017.¹ The most pronounced increase was detected in countries with a middle or high sociodemographic index and Eastern Europe, where unfavorable trends in cirrhosis-related mortality are driven by lifestyle-modifiable etiologies such as alcohol-related liver disease (ALD) or non-alcoholic fatty liver disease (NAFLD).

The nuclear vitamin D receptor (VDR) has been detected in various tissues and cells, involving skeletal muscle, liver, pancreas, or immune cells.² The circulating form of vitamin D, calcifediol (25-hydroxycholecalciferol, 25OHD), can be used by many cells to locally produce its active metabolite owing to the presence of a 1α-hydroxylase enzyme (CYP27B1).³ Due to the potential of vitamin D to regulate the expression of numerous genes, intensive research on its extra-skeletal properties has been conducted over the last 2 decades.

Vitamin D deficiency is common in chronic liver disease, despite its endogenous cutaneous production.⁴ There are multifactorial causes, including patient lifestyle (sedentarism, lack of optimal nutritional intake) and the effect of disease (intestinal edema in portal hypertension, hepatic dysfunction, maldigestion, malabsorption, hypercatabolic state).⁵^,⁶ The association of vitamin D deficiency with liver dysfunction, complications, and mortality, including its role in hepatic fibrogenesis, has been previously described.^7–11

The European Association for the Study of Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), and the European Society for Clinical Nutrition and Metabolism (ESPEN) recommend vitamin D supplementation in patients with chronic liver disease when a deficiency is detected in order to reach the desired levels of 25-hydroxyvitamin D (above 30 ng/mL or 75 nmol/L ).^12–14 Nonetheless, it remains unclear whether vitamin D supplementation in deficient chronic liver disease patients yields any impact, as demonstrated by previously published meta-analysis.¹⁵ However, additional randomized controlled trials (RCTs) have been published. Furthermore, a quantitative summary of the effect on liver steatosis or fibrosis has not been meta-analyzed beforehand. On the basis of the recommendations of international societies and the inconsistent results of vitamin D supplementation in this population, we aimed to assess and clarify the role of vitamin D in managing chronic liver disease.

METHODS

This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline (Supplementary Table S1) and the Cochrane Handbook.¹⁶^,¹⁷ The pre-established protocol was registered in advance on PROSPERO (CRD42022370312), and we adhered to it.¹⁸

Eligibility Criteria

We followed the subsequent inclusion criteria: (1) human studies; (2) randomized controlled trials; and (3) fitting the PICO framework (Table 1).¹⁹ To increase comprehensiveness and decrease publication bias, we also included conference abstracts, as recommended by Scherer et al.²⁰

Table 1.

Detailed PICO Framework

P	Adult patients (≥18 years) with chronic liver disease, irrespective of stage and etiology
I	Standard of care + vitamin D supplementation in any form, dose, duration, route of administration, administered as monotherapy or in combination with calcium
C	Standard of care with or without placebo
O	*Primary:* Survival, CAP, LSM, ALT, AST, GGT, ALP, CRP, IL-6 *Secondary:* HOMA-IR, insulin, FPG, TC, TG, LDL, HDL, adiponectin, INR, albumin, and bilirubin *Surrogate:* virologic response, BMD, and sarcopenia
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMD, bone mineral density; CAP, controlled attenuation parameter; CRP, C-reactive protein; FPG, fasting plasma glucose; GGT, gamma-glutamyl transferase; HDL, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment for insulin resistance; IL-6, interleukin-6; INR, international normalized ratio; LDL, low-density lipoprotein cholesterol; LSM, liver stiffness measurement; TC, total cholesterol; TG, total triglycerides.

Open in a new tab

Information Sources and Search Strategy

A literature search was conducted on the November 8, 2022, in 3 electronic databases: MEDLINE (via PubMed), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), with no restrictions or filtering options. Forward and backward citation chasing of included articles was performed on January 5, 2023, to identify further relevant studies. In addition, the updated search was run on February 7, 2024, to reveal newly published articles. For a detailed search strategy, see Table S2.

Selection and Data Collection Process

After automatic and manual duplicate removal, 2 independent review authors (P.M. and M.T.) conducted a selection to identify studies potentially eligible for further assessment. Cohen’s kappa was used to describe the agreement during the selection. A third independent reviewer (M.O.) resolved disagreements in case of any discrepancy. Data from eligible studies were manually extracted and cross-checked by 2 independent investigators (P.M. and M.T.). Differences in extracted data were resolved by discussion.

Data Items

We collected the following data items: study characteristics (first author, year, geographical location, number of participating centers, study period, and sample size); demographics (etiology of chronic liver disease, age, sex, and body mass index [BMI]); details about the intervention and control groups separately (number of participants, age, sex, BMI, baseline vitamin D level, and the standard of care applied); intervention specifics (form of vitamin D supplements, dosage, brand, duration, monotherapy or in combination with calcium); and outcome measures as reported in each article. Primary and secondary outcomes were assessed at the end of the trial period, and the change (after treatment baseline values) was extracted if data for change were available.

Study Risk of Bias Assessment

Two authors (P.M. and M.T.) performed the risk of bias assessment independently using the Cochrane Collaboration RoB2 tool with disagreements resolved by consensus.²¹ The subsequent domains were critically evaluated: randomization process, deviation from the intended interventions, missing outcomes, outcome measurement, and selection of reported results. Each domain and each outcome were judged to have a high (red), unclear (yellow), or low (green) risk of bias.

Quality of Evidence

Each finding was evaluated according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework using the GRADEpro tool (software) to estimate the level of evidence.²²

Synthesis Method

The minimum number of studies required to perform a meta-analysis was set at 3. As we assumed considerable between-study heterogeneity in all cases, a random-effects model was used to pool effect sizes. When there were 2 treatment or control arms, we combined them to create a single pairwise comparison, as recommended by the Cochrane Handbook.¹⁷ We calculated the risk ratio (RR) with a 95% CI for dichotomous variables and mean differences (MDs) for continuous variables. Results were considered statistically significant if the pooled CIs did not contain the null or 1 value for MDs and RRs, respectively. We summarized the findings of the meta-analysis in forest plots. In addition to the between-study variance (τ²), between-study heterogeneity was described by Higgins and Thompson’s I² statistics.²³ Further details on the statistical analysis can be found in Supplementary File S1, synthesis methods and search key.

RESULTS

Search and Selection

Altogether, 10 990 studies were identified. After duplicate removal, 8757 articles remained; titles and abstracts were reviewed for these. Eighty-five studies were found eligible, 51 of them were finally selected (Figure 1). Three RCTs were published only as abstracts,^24–26 and 1 abstract was a post hoc analysis.²⁷^,²⁸

Figure 1. — PRISMA Flowchart of the Article Selection Process

Baseline Characteristics of Included Studies

Supplementary Table S3 yields baseline characteristics of relevant studies. Thirty-six of the included studies were performed in Asia,²⁴^,^26–65 5 in Europe,²⁵^,^66–69 4 in Africa,^70–73 and 1 in the USA.⁷⁴ The most used form of vitamin D supplementation was vitamin D3 (cholecalciferol, n = 33), followed by calcitriol (n = 7), vitamin D2 (ergocalciferol, n = 6), and calcifediol (n = 1).

In 20 RCTs patients suffered from NAFLD, 13 RCTs involved patients with chronic viral hepatitis C (CHC), 3 trials were performed on patients with chronic hepatitis B (CHB), and 1 trial included both CHC and CHB patients. Six studies involved patients with liver cirrhosis regardless of etiology, 1 was conducted on patients with alcohol-related liver cirrhosis,⁷⁴ 1 involved liver transplant recipients,⁶² and 1 included only patients with primary biliary cholangitis.⁵⁵ Of 46 included studies, 23 included only patients with proven vitamin D insufficiency/deficiency (<30 ng/mL), as depicted in Table S4.

Survival

Eight RCTs were included in the survival analysis divided into 6- and 12-month periods.²⁴^,²⁷^,⁴⁴^,⁵²^,⁶⁰^,⁶⁵^,⁷³^,⁷⁴ We found no evidence for improved or worse survival in vitamin D-supplemented patients with RR 1.14 (95% CI, 0.85-1.54) and 0.99 (95% CI, 0.83-1.17) at the 6- and 12-month follow-ups, respectively (Figure 2). Additionally, we did not find differences between the chronic hepatitis and cirrhosis groups (Figure S5.26).

Figure 2. — Forest Plot Showing Survival in Vitamin D and Control Groups at 6- and 12-Month Follow-Up. Abbreviation: RR, risk ratio.

Liver Steatosis (CAP) and Liver Fibrosis (LSM)

Three RCTs with 411 participants with NAFLD were included in this analysis. Patients receiving vitamin D supplementation showed no significant effects on steatosis assessement by controlled attenuation parameter (CAP) (MD, −23.50 dB/m; 95% CI, −81.72 to 34.72) or fibrosis assessed by liver stiffness measurement (LSM) (MD, −0.65 kPa; 95% CI, −1.98 to 0.68); however, a small sample size may impact these findings (Figure 3A and 3B). A summary of additional findings on liver fibrosis and steatosis is presented in Table 2.

Figure 3. — (A) Forest Plot Showing the Change in the Controlled Attenuated Parameter (CAP) Representing Liver Steatosis and (B) Forest Plot Showing the Change in the Liver Stiffness Measurement (LSM) Representing Liver Fibrosis. Abbreviations: MD, mean difference. If the study is indicated with **, then the change value is an estimated change value of that study. β means that the mean and SD are the estimated mean and SD in that study. See Supplementary Material for raw data and synthesis methods

Table 2.

Summary of Further Findings on Liver Fibrosis and Steatosis

Author and year	Findings
Afsordeh et al 2019³⁰	8 wk of aerobic training statistically improved grade of fatty liver in both the AT+vitamin D group and AT group; meanwhile, vitamin D supplementation of 50 000 IU/wk alone did not improve the grade.
Alarfaj et al 2023⁷⁰	No significant differences in the degree of hepatic steatosis were observed between the vitamin D–supplemented and placebo arms.
Barchetta et al 2016⁶⁶	Cholecalciferol for 24 wk did not result in significant changes between the HFF, P3NP, and FLI groups.
Boonyagard et al 2020³³	No significant differences observed in steatosis grade and fibrosis stage assessed by Fibroscan^® after 5 mo of D2 supplementation.
Ebrahimpour-Koujan et al 2024³⁵	After 12 wk of intervention, serum hyaluronic acid (−28.7 ng/mL in vitamin D–supplemented vs −3.5 ng/mL in placebo, P = .04) and laminin (−10.6 ng/mL in vitamin D–supplemented and 4.9 ng/mL in placebo, P = .01) significantly differed between the groups, while there was no difference in collagen type IV levels (P = .09).
Geier et al 2018⁶⁷	Disease activity evaluated by NAFLD activity score improved in 3/3 vitamin D and 3/4 placebo patients. Absolute reduction of steatosis by at least 20% was observed in 2/3 vitamin D patients but in none of the placebo patients.
Hoseini et al 2020⁴⁰	Although the grade of fatty liver was reduced in AT+VD, AT, and vitamin D groups, the most pronounced reduction was observed when aerobic training was combined with vitamin D supplementation. Moreover, the grade of fatty liver significantly increased in the control group.
Hosseini et al 2018⁴¹	Single intramuscular dose of cholecalciferol + vitamin E 400 IU/d reduced the severity of liver steatosis by 1 grade in 8/37 (21.6%). The same standard of care + vitamin E 400 IU without vitamin D caused a grade reduction only in 1/38 (2.6%).
Komolmit et al 2017⁴⁷	6 wk of D2 supplementation significantly increased antifibrogenic MMP-2 and MMP-9 levels while reducing profibrogenic TGF-β.
Pilz et al 2016⁶⁹	Treatment with 2800 IU/d of cholecalciferol for 8 wk showed no difference in ELF score and levels of hyaluronic acid between the groups.
Sharifi et al 2014⁵⁶	No significant differences in grade of hepatic steatosis observed between the vitamin D–supplemented and placebo arms.
Sriphoosanaphan et al 2021⁵⁸	6 wk of vitamin D in CHC patients after curative treatment with DAAs does not improve serum fibrogenesis markers (MMP-9, P3NP, TGF-β) and may not facilitate the healing process of the remaining hepatic fibrosis.
Yaghooti et al 2021⁶⁴	Treatment with calcitriol 0.25 μg/d for 17 wk did not result in better HSI or APRI when compared to the placebo group.

Open in a new tab

Abbreviations: APRI, AST-to-Platelet Ratio Index; AT, aerobic training; CHC, chronic hepatitis C; DAA, direct antiviral agent; D2, ergocalciferol; ELF, enhanced liver fibrosis; FLI, fatty liver index; HFF, hepatic fat fraction; HSI, hepatic steatosis index; IU, international units; MMP, matrix metalloproteinase; P3NP, procollagen 3 N-terminal peptide; TGF-β, tumor growth factor β.

Liver Enzymes

The effect of vitamin D supplementation on liver enzymes is illustrated in Figure 4. In the vitamin D group, a significant decrease in ALT was observed with a small change of MD, −4.98 IU/L (95% CI, −8.28 to −1.68). A similar result was found for AST (MD, −3.33; 95% CI, −6.25 to −0.40) and gamma-glutamyl transferase (GGT) (MD, −5.14 IU/L; 95% CI, −6.40 to −3.88). The results for ALP were marginally significant (MD, −7.53; 95% CI, −15.77 to 0.72). No subgroup differences were observed if studies included only vitamin D–deficient patients (P = .46 for ALT, P = .14 for AST, P = .69 for GGT), however, in patients who underwent vitamin D-supplementation for ≥3 months showed a more pronounced decrease in the vitamin D-supplemented group for ALT (P = .02) and AST (P = .04) but not for ALP (P = .83). The results remained significant when excluding high-risk biased studies in cases of AST, ALT, and GGT. Further details regarding subgroups and individual analyses can be found in Supplementary file S2.

Glucose and Lipid Metabolism

Fifteen RCTs with 1426 participants investigated the effect of vitamin D on HOMA-IR. All but 1 study²⁹ involved only patients with NAFLD. Vitamin D–supplemented patients showed decreased HOMA-IR (MD, −0.31; 95% CI, −0.62 to −0.01), indicating an improvement (Figure 5). The length of the vitamin D supplementation (≥ or <3 months) did not result in differences between the subgroups (P = .88). Additionally, no difference was observed with subgrouping for the presence of vitamin D insufficiency/deficiency or sufficiency (P = .47), as visualized in Figure S3.3.

Figure 5. — Forest Plot Showing HOMA-IR Change in Vitamin D and Control Groups by Length of Intervention. Abbreviations: MD, mean difference. If the study is indicated with **, then the change value is an estimated change value in that study. The β means that the mean and SD are the estimated mean and SD in that study. See the raw data and the synthesis methods in the Supplementary Material.

Fasting insulin levels decreased modestly in vitamin D–supplemented patients (MD, −0.79 μIU/L; 95% CI, −1.36 to −0.21), whereas FPG did not vary significantly between the groups. No difference was observed in adiponectin, low density lipoprotein (LDL), and TC. Meanwhile, modestly increased high-density lipoprotein (HDL) (MD, 1.65 mg/dL; 95% CI, 0.08 to 3.23) and lowered triglyceride (TG; MD −7.59 mg/dL; 95% CI, −15.09 to −0.81) were found in the vitamin D–supplemented group (Supplementary File S4). The result remained statistically significant for TG when excluding high-risk biased studies.

Additional Outcomes

Inflammatory Markers.

We did not observe a difference in C-reactive protein (CRP) with an MD change of −0.77 mg/L (95% CI, −1.80 to 0.26). In addition, there was no significant difference in interleukin-6 (IL-6) between the groups with an MD change of −1.42 pg/mL (95% CI, −4.51 to 1.69) (Supplementary File S5). The study by Yang et al⁶³ was excluded from the analyses for CRP (estimated change value, −40.22 mg/dL; 95% CI, −42.19 to −38.25) and IL-6 (estimated change value −76.80; 95% CI, −86.79 to −66.81) as they differed in magnitude, which suggested that not only the mean but the individual data of the patients probably highly differed.

Bone Mineral Density and Sarcopenia.

Due to insufficient data and differences in reporting bone mineral density (BMD), we were unable to meta-analyze this outcome. Five RCTs evaluated the effect of vitamin D supplementation on BMD, and 2 studies investigated the effect on skeletal muscles (Supplementary File S5).

Virologic Response.

The meta-analysis showed no statistical significance for sustained virologic response in vitamin D–supplemented patients (RR, 1.29; 95% CI, 0.96-1.74) (Supplementary file S6). Moreover, Wang et al⁶¹ detected no differences in quantitative hepatitis B (HB) antigen or hepatitis B virus (HBV) DNA levels in patients in the vitamin D and control groups.

International normalized ratio, Albumin, Bilirubin.

No significant differences were observed for the international normalized ratio (INR) (MD, −0.08; 95% CI, −0.59 to 0.43), albumin (MD, 0.01; 95% CI, −0.11 to 0.13 g/dL), and bilirubin (MD, −0.18; 95% CI, −0.62 to 0.26 mg/dL) (Supplementary File S5).

Adverse Events.

Details of adverse events are provided in Table S6.

Subgroup Analyses

When at least 3 studies for each group were present, we performed additional subgroup analyses based on the length of the intervention (<3 or ≥3 months) and the presence of vitamin D insufficiency/deficiency or sufficiency (<30 or ≥30 ng/mL). No analyses were possible for the form of vitamin D and the etiology of chronic liver disease due to a paucity of data. Subgroup analyses demonstrated that longer interventions led to significant differences in ALT and AST (P = .02 and .04, respectively). However, such differences were not found (P > .05) for ALP, HOMA-IR, FPG, TC, LDL, HDL, and TG.

Surprisingly, subgrouping based on the presence of vitamin D insufficiency/deficiency (<30 ng/mL) did not yield significant results (P > .05) for ALT, AST, GGT, HOMA-IR, insulin, FPG, TC, LDL, HDL, TG, and CRP. Excluding high-risk bias studies from the analyses did not have an impact on the findings for any outcome except HDL. Detailed subgroup analysis figures are available in Supplementary Files S2-S5.

Risk of Bias and Certainty of Evidence

Most studies resulted in an overall high risk of bias (n = 21), followed by moderate (n = 13) and low (n = 12) risk. The high risk of bias was mainly due to deviations from the intended interventions as a result of inadequate blinding (Supplementary File S7). However, the overall risk of bias differed among the outcomes accounting for results from low-moderate in the case of glucose and lipid metabolism to high in the case of survival. The quality of evidence was very low based on the GRADE assessment (Table S7).

Publication Bias and Heterogeneity

No publication bias was detected for ALT, GGT, HOMA-IR, FPG, insulin, LDL, and TG. Egger’s tests suggested a potential publication bias for AST (P = .0946), HDL (P = .0963), and TC (P = .0291) (Supplementary File S2-S6). The visual inspection of funnel plots did not confirm potential publication bias but rather indicated high heterogeneity; therefore, we believe that publication bias is unlikely, but even if present, it is not relevant based on the data.

DISCUSSION

We comprehensively assessed the role of vitamin D in chronic liver disease. Current evidence showed no statistical difference between vitamin D supplementation and the standard of care in terms of liver steatosis and fibrosis. Clinically negligible but statistically significant reductions in ALT, AST, GGT, TG, insulin, and HOMA-IR were observed in the vitamin D–supplemented group. On the contrary, we did not find sufficient evidence that supplementation affects survival, CRP, IL-6, LDL, TC, adiponectin, FPG, or liver function tests (INR, albumin, bilirubin).

Vitamin D deficiency, especially severe vitamin D deficiency, has been associated with increased mortality in patients with chronic liver disease.⁷⁵^,⁷⁶ Furthermore, a recent meta-analysis by Yang et al confirmed the association between severe vitamin D deficiency (25OHD < 10 ng/mL) and mortality risk in patients with liver cirrhosis (RR, 1.79; 95% CI, 1.44-2.22).⁷⁷ Mayr et al reported that cirrhotic ICU patients with vitamin D levels >20 ng/mL at admission had better survival than those with moderate or severe vitamin D deficiency.⁷⁸ Nonetheless, our study failed to demonstrate prolonged survival in the vitamin D–supplemented group for either 6 or 12 months of follow-up. Half of the studies involved only patients with at least moderate vitamin D deficiency (<20 ng/mL).²⁴^,⁴⁴^,⁵²^,⁷⁴ The severity of chronic liver disease could modify the effect of vitamin D supplementation on survival; however, we did not find differences between the chronic hepatitis and cirrhosis patient groups. Six of 8 RCTs included patients with liver cirrhosis. While 4 of these patients reported being in the decompensated stage of liver cirrhosis,²⁴^,⁴⁴^,⁵²^,⁷³ 1 study was performed on patients with liver cirrhosis irrespective of the compensation,²⁷ and no details were given in another report.⁷⁴ Compensation for liver disease is the crucial factor regarding mortality, as the 28-day mortality in decompensated cirrhosis can reach from 5% up to 20% depending on the presence of acute or chronic liver failure.⁷⁹ Our analysis recognized the study of Mohamed et al⁷³ in which the vitamin D–supplemented group showed better survival. Interestingly, only patients with decompensated liver cirrhosis and spontaneous bacterial peritonitis (SBP) were included in this trial. Yang et al also observed a lower incidence of SBP in vitamin D–supplemented patients (5.8% vs 30%, P < .01).⁶³ Further research may help to explain the role of vitamin D in immunity and ascertain its effect on decompensated cirrhotic patients with SBP. Cathelicidin is recognized as 1 of the factors responsible for the antimicrobial effects of vitamin D.⁸⁰ As infections contribute to the high mortality observed in liver diseases, further translational insight into the vitamin D–cathelicidin axis may benefit the current understanding.

Emerging evidence suggests a protective effect of vitamin D against liver fibrogenesis. Although the mechanisms of action on hepatic fibrogenesis remain uncertain, vitamin D has shown antifibrotic properties based on its regulation of hepatic stellate cells (HSCs) via the VDR. Quiescent HSCs are activated upon stimulation by growth factors and cytokines, consequently playing an important profibrogenic role.¹¹^,⁸¹ Komolmit et al detected reduced levels of profibrotic TGF-β, while some antifibrotic metalloproteinases were significantly increased compared with those in the placebo arm.⁴⁷ On the other hand, neither 6 weeks nor 4 months of vitamin D supplementation resulted in statistical differences between the groups in the remaining RCTs.⁵⁶^,⁵⁸ Vitamin D has been shown to alleviate hepatic fibrosis in cholecalciferol-treated mice through its effect on histidine-rich calcium-binding protein.⁸² A study by Ding et al demonstrated that VDR-knockout mice develop spontaneous liver fibrosis.⁸³ In addition, it has been shown that a noncalcemic vitamin D derivate, calcipotriol, could prevent thioacetamide-induced liver cirrhosis in a mouse model.⁸⁴ Our meta-analysis did not demonstrate a reduction in steatosis or fibrosis measured non-invasively by CAP and LSM in NAFLD. The current EASL guideline recommends liver biopsy as a reference to evaluate nonalcoholic steatohepatitis and liver fibrosis resolution; therefore, these findings must be interpreted with caution.⁸⁵ Given the small sample size and the tendency observed, additional RCTs should be performed. In addition, the length of vitamin D supplementation and adequate time for the outcome assessment must be considered, especially for outcomes such as liver steatosis or fibrosis. Lukenda Zanko et al observed the superiority of vitamin D supplementation in the improvement of CAP and LSM, which gradually decreased over the 6-month to 12-month period in the vitamin D–supplemented group but worsened in the placebo.⁶⁸ Fibrosis progression and resolution develop over months, years, or even decades, suggesting longer intervention and follow-up time may be required to elicit the effect of vitamin D on fibrogenesis.⁸⁶

Insulin resistance is an important pathophysiological factor contributing to the development and progression of NAFLD. In addition, insulin resistance has been found to influence the course of disease in patients with CHC.⁸⁷ Our meta-analysis of 15 RCTs with 1426 participants showed a modest effect of vitamin D on insulin resistance measured by HOMA-IR. This finding is concurrent with a previously published meta-analysis, in which vitamin D improved insulin resistance with the pooled MD −1.06 (95% CI, −1.66 to −0.45; P = .0006).⁸⁸ Interestingly, a double-blind trial of 54 participants with NAFLD and concomitant vitamin D deficiency/insufficiency compared the effect of calcitriol (1 μg/d) and cholecalciferol (50 000 IU/wk) and found that calcitriol reduced HOMA-IR 1.8 times more than cholecalciferol.⁸⁹ Due to data limitations, we were unable to compare different forms of vitamin D. Similarly, the present data indicate that insulin levels were significantly reduced in the supplemented group. Although the dogma implies that hyperinsulinemia is a secondary consequence of insulin resistance in the past, current evidence has questioned this belief.⁹⁰^,⁹¹ Nevertheless, we found no difference in adiponectin levels, another contributing factor of insulin resistance described in the literature. Meta-analysis of RCTs conducted on adults with diabetes mellitus type 2 and an umbrella review of meta-analysis in adults investigated the effect of vitamin D on lipid metabolism, for which the same improvement of HDL and reduction of TG was found.⁹²^,⁹³

In populations at risk for vitamin D deficiency, recommended doses vary widely. The majority of the included RCTs used cholecalciferol as the preferred form, although higher absorption rates of calcifediol have been described.⁹⁴ Recent guidelines recommend against ergocalciferol supplementation, which was chosen in 5 of the studies included in our analysis.⁹⁵ Indeed, a tailored approach to vitamin D supplementation is needed, based on the specific mechanisms underlying the deficiency.⁹⁶ Pludowski et al recommended using calcifediol in patients with chronic liver disease.⁹⁶ However, data on the effects of calcifediol are scarce, as this study shows that only 1 RCT used solely this form. Surprisingly, it has been proposed that the oral route of administration may be preferable for vitamin D deficiency in the loading phase, whereas both oral and parenteral routes may be equivalent in maintenance treatment.⁹⁷ This finding is contradicted by the conclusions of 2 other studies, in which the intramuscular route was more effective in restoring vitamin D levels.⁹⁸^,⁹⁹ It remains unanswered how much these findings reflect the needs of chronic liver disease.

Strengths and Limitations

Several strengths of the present study must be acknowledged. A rigorous methodology was strictly applied at each step. We included only RCTs to reduce confounding and increase the level of evidence. In addition, we performed a subgroup analysis for the length of the intervention and etiological factors, whereas subgrouping by a form of vitamin D was not possible due to the low number of studies in different groups. In comparison with the previous meta-analysis,¹⁵ we were able to include 19 additional trials with 2105 more participants and we assessed the effect of vitamin D supplementation on liver steatosis and fibrosis, while similar eligibility criteria were applied. Moreover, in this article we present dynamic changes in multiple outcomes rather than simple comparisons between the groups and we performed additional subgroup analyses.

On the other hand, limitations should also be considered. The results are based on the limited number of trials performed mainly in Asia (78%); therefore, the conclusions might not be extrapolatable to the general population. Furthermore, differences in the applied interventions in terms of duration, doses, and follow-up also contributed to the high heterogeneity, which was not reduced when subgrouping for the length of the intervention or vitamin D insufficiency/deficiency. However, a limited number of studies for each tested association may weaken the conclusions and limit the feasibility of meaningful subgroup analyses. Although patients with ALD or cholestatic liver diseases have significantly lower vitamin D serum concentrations than individuals with other causes of liver cirrhosis,⁷⁵ only 2 studies included solely this specific population.

Implications for Practice and Research

Rapid application of scientific results is paramount.¹⁰⁰^,¹⁰¹ As the burden of liver diseases indicates progressive trends in lifestyle-modifiable diseases and liver disorders steadily contribute to premature deaths, it is necessary to translate mechanistic knowledge into bedside care. Vitamin D supplements are recommended to patients by individual societies; therefore, this meta-analysis provides a bridge to understanding the role of vitamin D in the selected population. Vitamin D may be a cost-effective and simple tool to modestly improve some outcomes in patients with chronic liver disease. The present work showed a more pronounced decrease in liver enzymes of vitamin D–supplemented patients. On the other hand, it should be noted that the magnitude of liver enzyme elevation does not necessarily reflect the severity of liver disease and prognosis, especially in chronic liver disease.¹⁰² Even though nutritional interventions improve health outcomes, the possible role of a single micronutrient seems to be small. Further RCTs with adequate power and appropriate sample size are warranted to clarify the topic, particularly to evaluate the effects of prolonged vitamin D supplementation (≥6 months) on liver steatosis and fibrosis in chronic liver disease. More studies should be conducted on the survival outcomes based on the disease severity.

CONCLUSION

This meta-analysis showed that additional use of vitamin D may result in modest improvements in ALT, AST, GGT, HOMA-IR, insulin, TG, and HDL. However, it did not lead to significant differences in survival, CRP, IL-6, TC, LDL, adiponectin, FPG, INR, albumin, and bilirubin. Vitamin D neither improved nor worsened CAP and LSM, and its effect on liver steatosis or fibrosis should be further investigated.

Supplementary Material

nuaf117_Supplementary_Data

nuaf117_supplementary_data.zip^{(20.2MB, zip)}

Acknowledgments

We express our gratitude to Maryam Saleh, a medical student at Semmelweis University, for her help in translating articles written in Persian.

Contributor Information

Petrana Martinekova, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic.

Mahmoud Obeidat, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary.

Mihaela Topala, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania.

Szilárd Váncsa, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Institute of Pancreatic Diseases, Semmelweis University, Budapest 1083, Hungary; Institute for Translational Medicine, University of Pécs, Medical School, Pécs 7623, Hungary.

Dániel Sándor Veres, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest 1094, Hungary.

Ádám Zolcsák, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest 1094, Hungary.

Miheller Pál, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest 1082, Hungary.

László Földvári-Nagy, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest 1088, Hungary.

Peter Banovcin, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Gastroenterology Clinic, University Hospital in Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 036 59, Slovak Republic.

Bálint Erőss, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Institute of Pancreatic Diseases, Semmelweis University, Budapest 1083, Hungary; Institute for Translational Medicine, University of Pécs, Medical School, Pécs 7623, Hungary.

Péter Hegyi, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Institute of Pancreatic Diseases, Semmelweis University, Budapest 1083, Hungary; Institute for Translational Medicine, University of Pécs, Medical School, Pécs 7623, Hungary.

Krisztina Hagymasi, Centre for Translational Medicine, Semmelweis University, Budapest 1085, Hungary; Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest 1082, Hungary.

Author Contributions

P.M.: conceptualization, project administration, data curation, methodology, writing—original draft; M.O.: conceptualization, methodology, project administration, writing—original draft; M.T.: conceptualization, data curation, writing—review and editing; S.V.: conceptualization, writing—review and editing; D.S.V.: conceptualization, formal analysis, data curation, visualization, writing—review and editing; A.Z.: conceptualization, formal analysis, data curation, visualization, writing—review and editing; M.P.: conceptualization, writing—review and editing; L. F.-N.: conceptualization, writing—review and editing; P.B.: conceptualization, writing—review and editing; B.E.: conceptualization, supervision, writing—review and editing; P.H.: conceptualization, supervision, writing—review and editing; K.H.: conceptualization, supervision, project administration, writing—original draft. All authors have read and agreed to the published version of the manuscript.

Supplementary Material

Supplementary Material is available at Nutrition Reviews online.

Funding

None declared.

Conflicts of Interest

None declared.

Data Availability

The datasets can be found in the full-text articles included in the systematic review and meta-analysis.

References

1. Ye F, Zhai M, Long J, et al. The burden of liver cirrhosis in mortality: results from the global burden of disease study. Front Public Health. 2022;10:909455. 10.3389/fpubh.2022.909455 [DOI] [PMC free article] [PubMed] [Google Scholar]
2. Pike JW, Meyer MB, Lee SM, Onal M, Benkusky NA. The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. J Clin Invest. 2017;127:1146-1154. 10.1172/jci88887 [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor? Arch Biochem Biophys. 2012;523:123-133. 10.1016/j.abb.2012.04.001 [DOI] [PubMed] [Google Scholar]
4. Llibre-Nieto G, Lira A, Vergara M, et al. Micronutrient deficiencies in patients with decompensated liver cirrhosis. Nutrients. 2021;13:1249. 10.3390/nu13041249 [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Lim LY, Chalasani N. Vitamin d deficiency in patients with chronic liver disease and cirrhosis. Curr Gastroenterol Rep. 2012;14:67-73. 10.1007/s11894-011-0231-7 [DOI] [PubMed] [Google Scholar]
6. Pop TL, Sîrbe C, Benţa G, Mititelu A, Grama A. The role of vitamin D and Vitamin D binding protein in chronic liver diseases. Int J Mol Sci. 2022;23:10705. 10.3390/ijms231810705 [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Paternostro R, Wagner D, Reiberger T, et al. Low 25-OH-vitamin D levels reflect hepatic dysfunction and are associated with mortality in patients with liver cirrhosis. Wien Klin Wochenschr. 2017;129:8-15. 10.1007/s00508-016-1127-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Ravaioli F, Pivetti A, Di Marco L, et al. Role of vitamin D in liver disease and complications of advanced chronic liver disease. Int J Mol Sci. 2022;23:9016. 10.3390/ijms23169016 [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Sun J, Zhang YG. Vitamin D receptor influences intestinal barriers in health and disease. Cells. 2022;11:1129. 10.3390/cells11071129 [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Triantos C, Kalafateli M, Aggeletopoulou I, et al. Vitamin D-related immunomodulation in patients with liver cirrhosis. Eur J Gastroenterol Hepatol. 2020;32:867-876. 10.1097/meg.0000000000001597 [DOI] [PubMed] [Google Scholar]
11. Udomsinprasert W, Jittikoon J. Vitamin D and liver fibrosis: molecular mechanisms and clinical studies. Biomed Pharmacother. 2019;109:1351-1360. 10.1016/j.biopha.2018.10.140 [DOI] [PubMed] [Google Scholar]
12. Merli M, Berzigotti A, Shira Zelber-Sagi S, et al. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol. 2019;70:172-193. 10.1016/j.jhep.2018.06.024 [DOI] [PMC free article] [PubMed] [Google Scholar]
13. Lai JC, Tandon P, Bernal W, et al. Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American Association for the study of liver diseases. Hepatology. 2021;74:1611-1644. 10.1002/hep.32049 [DOI] [PMC free article] [PubMed] [Google Scholar]
14. Bischoff SC, Bernal W, Dasarathy S, et al. ESPEN practical guideline: clinical nutrition in liver disease. Clin Nutr. 2020;39:3533-3562. 10.1016/j.clnu.2020.09.001 [DOI] [PubMed] [Google Scholar]
15. Bjelakovic M, Nikolova D, Bjelakovic G, Gluud C. Vitamin D supplementation for chronic liver diseases in adults. Cochrane Database Syst Rev. 2021;8:CD011564. 10.1002/14651858.CD011564.pub3 [DOI] [PMC free article] [PubMed] [Google Scholar]
16. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372:n71. 10.1136/bmj.n71 [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Higgins JES, Li T. Chapter 23: including variants on randomized trials. In: Higgins JPT, Thomas J, Chandler J, et al. , eds. Cochrane Handbook for Systematic Reviews of Interventions Version 6.3. Cochrane; 2022. Available from www.training.cochrane.org/handbook. [Google Scholar]
18. Booth A, Clarke M, Dooley G, et al. PROSPERO at one year: an evaluation of its utility. Syst Rev. 2013;2:4. 10.1186/2046-4053-2-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Munn Z, Stern C, Aromataris E, Lockwood C, Jordan Z. What kind of systematic review should I conduct? A proposed typology and guidance for systematic reviewers in the medical and health sciences. BMC Med Res Methodol. 2018;18:5. 10.1186/s12874-017-0468-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
20. Scherer RW, Saldanha IJ. How should systematic reviewers handle conference abstracts? A view from the trenches. Syst Rev. 2019;8:264. 10.1186/s13643-019-1188-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
21. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366:l4898. 10.1136/bmj.l4898 [DOI] [PubMed] [Google Scholar]
22. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383-394. 10.1016/j.jclinepi.2010.04.026 [DOI] [PubMed] [Google Scholar]
23. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539-1558. 10.1002/sim.1186 [DOI] [PubMed] [Google Scholar]
24. Harun M, Rashid. Effect of vitamin D treatment in patients with decompensated cirrhosis of liver—report from a Tertiary Centre, Bangladesh. Hepatol Int. 2020; 14:S407. https://doi.org/Doi: 10.1007/s12072-020-10030-4 [Google Scholar]
25. Mihai C, Dranga M, Drug V, Prelipcean CC. Vitamin D and B12 supplementation and sustained virologic response in chronic hepatitis C patients treated with pegylated interferon and ribavirin. Gastroenterology. 2014;146:S-982. 10.1016/S0016-5085(14)63568-X [DOI] [Google Scholar]
26. Atthakitmongkol T, Chotiyaputta W, Lertwattanarak R, Sritippayawan S, Tanwandee T. Vitamin D and calcium supplementation prevent bone loss in vitamin d-deficient chronic hepatitis B patients treated with tenofovir disoproxil fumarate: a randomized controlled study. Gastroenterology. 2023;164:S-1360-S-1361. 10.1016/S0016-5085(23)04168-9 [DOI] [Google Scholar]
27. Grover I, Sharma S, Madhu D, et al. Effect of vitamin d supplementation on clinical outcomes in patients with cirrhosis: a post hoc analysis of a randomized controlled trial. Hepatology. 2021;74(Suppl. 1):1213A-1214A. 10.1002/hep.32188 [DOI] [Google Scholar]
28. Grover I, Gunjan D, Singh N, et al. Effect of vitamin D supplementation on vitamin D level and bone mineral density in patients with cirrhosis: a randomized clinical trial. Am J Gastroenterol. 2021;116:2098-2104. 10.14309/ajg.0000000000001272 [DOI] [PubMed] [Google Scholar]
29. Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol. 2011;17:5184-5190. 10.3748/wjg.v17.i47.5184 [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Afsordeh Kolsoum RR, Aliakbar A. Effect of aerobic training and vitamin D supplements on fatty liver and lipid profiles in women with fatty liver. Pejouhesh dar Pezeshki (Res Med). 2019;43:8-14. [Google Scholar]
31. Atsukawa M, Tsubota A, Shimada N, et al. Effect of native vitamin D3 supplementation on refractory chronic hepatitis C patients in simeprevir with pegylated interferon/ribavirin. Hepatol Res. 2016;46:450-458. 10.1111/hepr.12575 [DOI] [PubMed] [Google Scholar]
32. Behera MK, Shukla SK, Dixit VK, et al. Effect of vitamin D supplementation on sustained virological response in genotype 1/4 chronic hepatitis C treatment-naïve patients from India. Indian J Med Res. 2018;148:200-206. 10.4103/ijmr.IJMR_1295_15 [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Boonyagard S, Techathuvanan K. Impact of vitamin D replacement on liver enzymes in non-alcoholic fatty liver disease patients: a randomized, double-blind, placebo-controlled trial. J Med Assoc Thailand. 2020;103:A105-A112. 10.35755/jmedassocthai.2020.S08.12052 [DOI] [Google Scholar]
34. Dabbaghmanesh MH, Danafar F, Eshraghian A, Omrani GR. Vitamin D supplementation for the treatment of non-alcoholic fatty liver disease: a randomized double blind placebo controlled trial. Diabetes Metab Syndr. 2018;12:513-517. 10.1016/j.dsx.2018.03.006 [DOI] [PubMed] [Google Scholar]
35. Ebrahimpour-Koujan S, Sohrabpour AA, Giovannucci E, Vatannejad A, Esmaillzadeh A. Effects of vitamin D supplementation on liver fibrogenic factors, vitamin D receptor and liver fibrogenic microRNAs in metabolic dysfunction-associated steatotic liver disease (MASLD) patients: an exploratory randomized clinical trial. Nutr J. 2024;23:24. 10.1186/s12937-024-00911-x [DOI] [PMC free article] [PubMed] [Google Scholar]
36. Foroughi M, Maghsoudi Z, Askari G. The effect of vitamin D supplementation on blood sugar and different indices of insulin resistance in patients with non-alcoholic fatty liver disease (NAFLD). Iran J Nurs Midwifery Res. 2016;21:100-104. 10.4103/1735-9066.174759 [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Foroughi M, Maghsoudi Z, Ghiasvand R, Iraj B, Askari G. Effect of vitamin D supplementation on C-reactive protein in patients with nonalcoholic fatty liver. Int J Prev Med. 2014;5:969-975. [PMC free article] [PubMed] [Google Scholar]
38. Guo XF, Wang C, Yang T, et al. The effects of fish oil plus vitamin D(3) intervention on non-alcoholic fatty liver disease: a randomized controlled trial. Eur J Nutr. 2022;61:1931-1942. 10.1007/s00394-021-02772-0 [DOI] [PubMed] [Google Scholar]
39. Hajiaghamohammadi A, Shafikhani AA, Bastani A, Gaemi N. Effect of vitamin D replacement on liver enzymes in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol Res. 2019;8:2907-2910. 10.17554/j.issn.2224-3992.2019.08.819 [DOI] [Google Scholar]
40. Hoseini Z, Behpour N, Hoseini R. Co-treatment with vitamin D supplementation and aerobic training in elderly women with Vit D deficiency and NAFLD: a single-blind controlled trial. Hepat Mon. 2020;20:e96437. 10.5812/hepatmon.96437 [DOI] [Google Scholar]
41. Hosseini S, Aliashrafi S, Ebrahimi-Mameghani M. The effect of a single intramuscular injection of cholecalciferol on the serum levels of vitamin D, adiponectin, insulin resistance, and liver function in women with non-alcoholic fatty liver disease (NAFLD): a randomized, controlled clinical trial. Iran Red Cresc Med J. 2024;20:1-12. 10.5812/ircmj.60746 [DOI] [Google Scholar]
42. Hussain M, Iqbal J, Malik SA, et al. Effect of vitamin D supplementation on various parameters in non-alcoholic fatty liver disease patients. Pak J Pharm Sci. 2019;32:1343-1348. [PubMed] [Google Scholar]
43. Jeong JY, Jun DW, Park SJ, et al. Effects of vitamin D supplements in patients with chronic hepatitis C: a randomized, multi-center, open label study. Korean J Intern Med. 2020;35:1074-1083. 10.3904/kjim.2018.273 [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Jha AK, Jha SK, Kumar A, Dayal VM, Jha SK. Effect of replenishment of vitamin D on survival in patients with decompensated liver cirrhosis: a prospective study. World J Gastrointest Pathophysiol. 2017;8:133-141. 10.4291/wjgp.v8.i3.133 [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Khan J, Adil N, Naseer A, Asif M, Sabir A, Fatima S. Comparison of frequency of rapid virological response in patients of hepatitis C being treated with 25-OH vitamin D along with sofosbuvir/ribavirin with those treated with sofosbuvir/ribavirin only. Pak J Med Health Sci. 2022;16:342-343. 10.53350/pjmhs22166342 [DOI] [Google Scholar]
46. Komolmit P, Charoensuk K, Thanapirom K, et al. 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. 10.1371/journal.pone.0174608 [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Komolmit P, Kimtrakool S, Suksawatamnuay S, et al. Vitamin D supplementation improves serum markers associated with hepatic fibrogenesis in chronic hepatitis C patients: a randomized, double-blind, placebo-controlled study. Sci Rep. 2017;7:8905. 10.1038/s41598-017-09512-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Lorvand Amiri H, Agah S, Tolouei Azar J, Hosseini S, Shidfar F, Mousavi SN. Effect of daily calcitriol supplementation with and without calcium on disease regression in non-alcoholic fatty liver patients following an energy-restricted diet: randomized, controlled, double-blind trial. Clin Nutr. 2017;36:1490-1497. 10.1016/j.clnu.2016.09.020 [DOI] [PubMed] [Google Scholar]
49. Lorvand Amiri H, Agah S, Mousavi SN, Hosseini AF, Shidfar F. Regression of non-alcoholic fatty liver by vitamin D supplement: a double-blind randomized controlled clinical trial. Arch Iran Med. 2016;19:631-638. [PubMed] [Google Scholar]
50. Shidfar F, Mousavi SN, Amiri HL, Agah S, Hoseini S, Hajimiresmail SJ. Reduction of some atherogenic indices in patients with non-alcoholic fatty liver by Vitamin D and calcium co-supplementation: a double blind randomized controlled clinical trial. Iran J Pharm Res. 2019;18:496-505. [PMC free article] [PubMed] [Google Scholar]
51. Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients. World J Gastroenterol. 2012;18:800-805. 10.3748/wjg.v18.i8.800 [DOI] [PMC free article] [PubMed] [Google Scholar]
52. Okubo T, Atsukawa M, Tsubota A, et al. Effect of vitamin D supplementation on skeletal muscle volume and strength in patients with decompensated liver cirrhosis undergoing branched chain amino acids supplementation: a prospective, randomized, controlled pilot trial. Nutrients. 2021;13:1874. 10.3390/nu13061874 [DOI] [PMC free article] [PubMed] [Google Scholar]
53. Sakpal M, Satsangi S, Mehta M, et al. Vitamin D supplementation in patients with nonalcoholic fatty liver disease: a randomized controlled trial. JGH Open. 2017;1:62-67. 10.1002/jgh3.12010 [DOI] [PMC free article] [PubMed] [Google Scholar]
54. Shiomi S, Masaki K, Habu D, et al. Calcitriol for bone disease in patients with cirrhosis of the liver. J Gastroenterol Hepatol. 1999;14:547-552. 10.1046/j.1440-1746.1999.01913.x [DOI] [PubMed] [Google Scholar]
55. Shiomi S, Masaki K, Habu D, et al. Calcitriol for bone loss in patients with primary biliary cirrhosis. J Gastroenterol. 1999;34:241-245. 10.1007/s005350050250 [DOI] [PubMed] [Google Scholar]
56. Sharifi N, Amani R, Hajiani E, Cheraghian B. Does vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trial. Endocrine. 2014;47:70-80. 10.1007/s12020-014-0336-5 [DOI] [PubMed] [Google Scholar]
57. Sharifi N, Amani R, Hajiani E, Cheraghian B. Women may respond different from men to vitamin D supplementation regarding cardiometabolic biomarkers. Exp Biol Med. 2016;241:830-838. 10.1177/1535370216629009 [DOI] [PMC free article] [PubMed] [Google Scholar]
58. Sriphoosanaphan S, Thanapirom K, Kerr SJ, et al. Effect of vitamin D supplementation in patients with chronic hepatitis C after direct-acting antiviral treatment: a randomized, double-blind, placebo-controlled trial. PeerJ. 2021; 9:e10709. 10.7717/peerj.10709 [DOI] [PMC free article] [PubMed] [Google Scholar]
59. Taghvaei T, Akha O, Mouodi M, Tirgar Fakheri H, Kashi Z, Maleki. I. Effects of vitamin d supplementation on patients with non-alcoholic fatty liver disease (nafld). Acta Med Mediterr. 2018;34:415-422. 10.19193/0393-6384_2018_2_66 [DOI] [Google Scholar]
60. Vosoghinia H, Esmaeilzadeh A, Ganji A, et al. Vitamin D in standard HCV regimen (PEG-interferon plus ribavirin), its effect on the early virologic response rate: a clinical trial. Razavi Int J Med. 2016;4:e36632. 10.17795/rijm36632 [DOI] [Google Scholar]
61. Wang CC, Tzeng IS, Su WC, et al. The association of vitamin D with hepatitis B virus replication: bystander rather than offender. J Formos Med Assoc. 2020;119:1634-1641. 10.1016/j.jfma.2019.12.004 [DOI] [PubMed] [Google Scholar]
62. Xing T, Qiu G, Zhong L, Ling L, Huang L, Peng Z. Calcitriol reduces the occurrence of acute cellular rejection of liver transplants: a prospective controlled study. Pharmazie. 2013;68:821-826. [PubMed] [Google Scholar]
63. Yang Z, Haijun C, Yejin X, Dehe Z, Jing Z, Shengnan L. Efficacy of vitamin D adjuvant therapy for prevention of spontaneous bacterial peritonitis in patients with decompensated cirrhosis of hepatitis B. Chin J Clin Infect Dis. 2023;16:215-219. 10.3760/cma.j.issn.1674-2397.2023.03.009 [DOI] [Google Scholar]
64. Yaghooti H, Ghanavati F, Seyedian SS, Cheraghian B, Mohammadtaghvaei N. The efficacy of calcitriol treatment in non-alcoholic fatty liver patients with different genotypes of vitamin D receptor FokI polymorphism. BMC Pharmacol Toxicol. 2021;22:18. 10.1186/s40360-021-00485-y [DOI] [PMC free article] [PubMed] [Google Scholar]
65. Yokoyama S, Takahashi S, Kawakami Y, et al. Effect of vitamin D supplementation on pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b: a randomized controlled trial. J Viral Hepat. 2014;21:348-356. 10.1111/jvh.12146 [DOI] [PubMed] [Google Scholar]
66. Barchetta I, Del Ben M, Angelico F, et al. No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. BMC Med. 2016;14:92. 10.1186/s12916-016-0638-y [DOI] [PMC free article] [PubMed] [Google Scholar]
67. Geier A, Eichinger M, Stirnimann G, et al. Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study. Scand J Gastroenterol. 2018;53:1114-1120. 10.1080/00365521.2018.1501091 [DOI] [PubMed] [Google Scholar]
68. Lukenda Zanko V, Domislovic V, Trkulja V, et al. Vitamin D for treatment of non-alcoholic fatty liver disease detected by transient elastography: a randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2020;22:2097-2106. 10.1111/dom.14129 [DOI] [PubMed] [Google Scholar]
69. Pilz S, Putz-Bankuti C, Gaksch M, et al. Effects of vitamin D supplementation on serum 25-hydroxyvitamin D concentrations in cirrhotic patients: a randomized controlled trial. Nutrients. 2016;8:278. 10.3390/nu8050278 [DOI] [PMC free article] [PubMed] [Google Scholar]
70. Alarfaj SJ, Bahaa MM, Yassin HA, et al. A randomized placebo-controlled, double-blind study to investigate the effect of a high oral loading dose of cholecalciferol in non-alcoholic fatty liver disease patients, new insights on serum STAT-3 and hepassocin. Eur Rev Med Pharmacol Sci. 2023;27:7607-7619. 10.26355/eurrev_202308_33413 [DOI] [PubMed] [Google Scholar]
71. Esmat G, El Raziky M, Elsharkawy A, et al. Impact of vitamin D supplementation on sustained virological response in chronic hepatitis C genotype 4 patients treated by pegylated interferon/ribavirin. J Interferon Cytokine Res. 2015;35:49-54. 10.1089/jir.2014.0060 [DOI] [PubMed] [Google Scholar]
72. Mohamed AA, Halim AA, Mohamed S, et al. The effect of high oral loading dose of cholecalciferol in non-alcoholic fatty liver disease patients. A randomized placebo controlled trial. Front Pharmacol. 2023;14:1149967. 10.3389/fphar.2023.1149967 [DOI] [PMC free article] [PubMed] [Google Scholar]
73. Mohamed AA, Al-Karmalawy AA, El-Kholy AA, et al. Effect of vitamin D supplementation in patients with liver cirrhosis having spontaneous bacterial peritonitis: a randomized controlled study. Eur Rev Med Pharmacol Sci. 2021;25:6908-6919. 10.26355/eurrev_202111_27239 [DOI] [PubMed] [Google Scholar]
74. Mobarhan SA, Russell RM, Recker RR, Posner DB, Iber FL, Miller P. Metabolic bone disease in alcoholic cirrhosis: a comparison of the effect of vitamin D2, 25-hydroxyvitamin D, or supportive treatment. Hepatology. 1984;4:266-273. 10.1002/hep.1840040216 [DOI] [PubMed] [Google Scholar]
75. Finkelmeier F, Kronenberger B, Zeuzem S, Piiper A, Waidmann O. Low 25-hydroxyvitamin D levels are associated with infections and mortality in patients with cirrhosis. PLoS One. 2015;10:e0132119. 10.1371/journal.pone.0132119 [DOI] [PMC free article] [PubMed] [Google Scholar]
76. Kim TH, Yun SG, Choi J, et al. Differential impact of serum 25-hydroxyvitamin D3 levels on the prognosis of patients with liver cirrhosis according to MELD and child-pugh scores. J Korean Med Sci. 2020;35:e129. 10.3346/jkms.2020.35.e129 [DOI] [PMC free article] [PubMed] [Google Scholar]
77. Yang F, Ren H, Gao Y, Zhu Y, Huang W. The value of severe vitamin D deficiency in predicting the mortality risk of patients with liver cirrhosis: a meta-analysis. Clin Res Hepatol Gastroenterol. 2019;43:722-729. 10.1016/j.clinre.2019.03.001 [DOI] [PubMed] [Google Scholar]
78. Mayr U, Fahrenkrog-Petersen L, Batres-Baires G, et al. Vitamin D deficiency is highly prevalent in critically ill patients and a risk factor for mortality: a prospective observational study comparing noncirrhotic patients and patients with cirrhosis. J Intensive Care Med. 2020;35:992-1001. 10.1177/0885066618803844 [DOI] [PubMed] [Google Scholar]
79. Moreau R, Tonon M, Krag A, et al. EASL Clinical Practice Guidelines on acute-on-chronic liver failure. J Hepatol. 2023;79:461-491. 10.1016/j.jhep.2023.04.021 [DOI] [PubMed] [Google Scholar]
80. Chung C, Silwal P, Kim I, Modlin RL, Jo EK. Vitamin D-cathelicidin axis: at the crossroads between protective immunity and pathological inflammation during infection. Immune Netw. 2020;20:e12. 10.4110/in.2020.20.e12 [DOI] [PMC free article] [PubMed] [Google Scholar]
81. Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells. 2019;8:1419. 10.3390/cells8111419 [DOI] [PMC free article] [PubMed] [Google Scholar]
82. Lu W, Li X, Liu N, et al. Vitamin D alleviates liver fibrosis by inhibiting histidine-rich calcium binding protein (HRC). Chem Biol Interact. 2021;334:109355. 10.1016/j.cbi.2020.109355 [DOI] [PubMed] [Google Scholar]
83. Ding N, Yu RT, Subramaniam N, et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell. 2013;153:601-613. 10.1016/j.cell.2013.03.028 [DOI] [PMC free article] [PubMed] [Google Scholar]
84. Wahsh E, Abu-Elsaad N, El-Karef A, Ibrahim T. The vitamin D receptor agonist, calcipotriol, modulates fibrogenic pathways mitigating liver fibrosis in-vivo: an experimental study. Eur J Pharmacol. 2016;789:362-369. 10.1016/j.ejphar.2016.07.052 [DOI] [PubMed] [Google Scholar]
85. Wahsh E, Berzigotti A, Tsochatzis E, Boursier J, et al. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol. 2021;75:659-689. 10.1016/j.jhep.2021.05.025 [DOI] [PubMed] [Google Scholar]
86. Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. J Hepatol. 2012;56:1171-1180. 10.1016/j.jhep.2011.09.024 [DOI] [PubMed] [Google Scholar]
87. Patel S, Jinjuvadia R, Patel R, Liangpunsakul S. Insulin resistance is associated with significant liver fibrosis in chronic hepatitis C patients: a systemic review and meta-analysis. J Clin Gastroenterol. 2016;50:80-84. 10.1097/mcg.0000000000000400 [DOI] [PMC free article] [PubMed] [Google Scholar]
88. Sindhughosa DA, Wibawa IDN, Mariadi IK, Somayana G. Additional treatment of vitamin D for improvement of insulin resistance in non-alcoholic fatty liver disease patients: a systematic review and meta-analysis. Sci Rep. 2022;12:7716. 10.1038/s41598-022-11950-x [DOI] [PMC free article] [PubMed] [Google Scholar]
89. Mahmoudi L, Asadi S, Al-Mousavi Z, Niknam R. A randomized controlled clinical trial comparing calcitriol versus cholecalciferol supplementation to reduce insulin resistance in patients with non-alcoholic fatty liver disease. Clin Nutr. 2021;40:2999-3005. 10.1016/j.clnu.2020.11.037 [DOI] [PubMed] [Google Scholar]
90. Abdul-Ghani M, DeFronzo RA. Insulin resistance and hyperinsulinemia: the egg and the chicken. J Clin Endocrinol Metab. 2021;106:e1897-e1899. 10.1210/clinem/dgaa364 [DOI] [PMC free article] [PubMed] [Google Scholar]
91. Janssen J. Hyperinsulinemia and its pivotal role in aging, obesity, type 2 diabetes, cardiovascular disease and cancer. Int J Mol Sci. 2021;22:7797. 10.3390/ijms22157797 [DOI] [PMC free article] [PubMed] [Google Scholar]
92. Lu Q, Liang Q, Xi Y. The effects of vitamin D supplementation on serum lipid profiles in people with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Front Nutr. 2024;11:1419747. 10.3389/fnut.2024.1419747 [DOI] [PMC free article] [PubMed] [Google Scholar]
93. Radkhah N, Zarezadeh M, Jamilian P, Ostadrahimi A. The effect of vitamin D supplementation on lipid profiles: an umbrella review of meta-analyses. Adv Nutr. 2023;14:1479-1498. 10.1016/j.advnut.2023.08.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
94. Quesada-Gomez JM, Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporos Int. 2018;29:1697-1711. 10.1007/s00198-018-4520-y [DOI] [PubMed] [Google Scholar]
95. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2020 Update. Endocr Pract. 2020;26:1-46. 10.4158/gl-2020-0524suppl [DOI] [PubMed] [Google Scholar]
96. Pludowski P, Holick MF, Grant WB, et al. Vitamin D supplementation guidelines. J Steroid Biochem Mol Biol. 2018;175:125-135. 10.1016/j.jsbmb.2017.01.021 [DOI] [PubMed] [Google Scholar]
97. Bilezikian JP, Formenti AM, Adler RA, et al. Vitamin D: dosing, levels, form, and route of administration: does one approach fit all? Rev Endocr Metab Disord. 2021;22:1201-1218. 10.1007/s11154-021-09693-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
98. Tellioglu A, Basaran S, Guzel R, Seydaoglu G. Efficacy and safety of high dose intramuscular or oral cholecalciferol in vitamin D deficient/insufficient elderly. Maturitas. 2012;72:332-338. 10.1016/j.maturitas.2012.04.011 [DOI] [PubMed] [Google Scholar]
99. Masood MQ, Khan A, Awan S, et al. Comparision of vitamin D replacement strategies with high-dose intramuscular or oral cholecalciferol: a prospective intervention study. Endocr Pract. 2015;21:1125-1133. 10.4158/ep15680.Or [DOI] [PubMed] [Google Scholar]
100. Hegyi P, Petersen OH, Holgate S, et al. Academia Europaea position paper on translational medicine: the cycle model for translating scientific results into community benefits. J Clin Med. 2020;9:1532. 10.3390/jcm9051532 [DOI] [PMC free article] [PubMed] [Google Scholar]
101. Hegyi P, Erőss B, Izbéki F, Párniczky A, Szentesi A. Accelerating the translational medicine cycle: the Academia Europaea pilot. Nat Med. 2021;27:1317-1319. 10.1038/s41591-021-01458-8 [DOI] [PubMed] [Google Scholar]
102. Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67:6-19. 10.1136/gutjnl-2017-314924 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

nuaf117_Supplementary_Data

nuaf117_supplementary_data.zip^{(20.2MB, zip)}

Data Availability Statement

The datasets can be found in the full-text articles included in the systematic review and meta-analysis.

[nuaf117-B1] 1. Ye F, Zhai M, Long J, et al. The burden of liver cirrhosis in mortality: results from the global burden of disease study. Front Public Health. 2022;10:909455. 10.3389/fpubh.2022.909455 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B2] 2. Pike JW, Meyer MB, Lee SM, Onal M, Benkusky NA. The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. J Clin Invest. 2017;127:1146-1154. 10.1172/jci88887 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B3] 3. Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor? Arch Biochem Biophys. 2012;523:123-133. 10.1016/j.abb.2012.04.001 [DOI] [PubMed] [Google Scholar]

[nuaf117-B4] 4. Llibre-Nieto G, Lira A, Vergara M, et al. Micronutrient deficiencies in patients with decompensated liver cirrhosis. Nutrients. 2021;13:1249. 10.3390/nu13041249 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B5] 5. Lim LY, Chalasani N. Vitamin d deficiency in patients with chronic liver disease and cirrhosis. Curr Gastroenterol Rep. 2012;14:67-73. 10.1007/s11894-011-0231-7 [DOI] [PubMed] [Google Scholar]

[nuaf117-B6] 6. Pop TL, Sîrbe C, Benţa G, Mititelu A, Grama A. The role of vitamin D and Vitamin D binding protein in chronic liver diseases. Int J Mol Sci. 2022;23:10705. 10.3390/ijms231810705 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B7] 7. Paternostro R, Wagner D, Reiberger T, et al. Low 25-OH-vitamin D levels reflect hepatic dysfunction and are associated with mortality in patients with liver cirrhosis. Wien Klin Wochenschr. 2017;129:8-15. 10.1007/s00508-016-1127-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B8] 8. Ravaioli F, Pivetti A, Di Marco L, et al. Role of vitamin D in liver disease and complications of advanced chronic liver disease. Int J Mol Sci. 2022;23:9016. 10.3390/ijms23169016 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B9] 9. Sun J, Zhang YG. Vitamin D receptor influences intestinal barriers in health and disease. Cells. 2022;11:1129. 10.3390/cells11071129 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B10] 10. Triantos C, Kalafateli M, Aggeletopoulou I, et al. Vitamin D-related immunomodulation in patients with liver cirrhosis. Eur J Gastroenterol Hepatol. 2020;32:867-876. 10.1097/meg.0000000000001597 [DOI] [PubMed] [Google Scholar]

[nuaf117-B11] 11. Udomsinprasert W, Jittikoon J. Vitamin D and liver fibrosis: molecular mechanisms and clinical studies. Biomed Pharmacother. 2019;109:1351-1360. 10.1016/j.biopha.2018.10.140 [DOI] [PubMed] [Google Scholar]

[nuaf117-B12] 12. Merli M, Berzigotti A, Shira Zelber-Sagi S, et al. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol. 2019;70:172-193. 10.1016/j.jhep.2018.06.024 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B13] 13. Lai JC, Tandon P, Bernal W, et al. Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American Association for the study of liver diseases. Hepatology. 2021;74:1611-1644. 10.1002/hep.32049 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B14] 14. Bischoff SC, Bernal W, Dasarathy S, et al. ESPEN practical guideline: clinical nutrition in liver disease. Clin Nutr. 2020;39:3533-3562. 10.1016/j.clnu.2020.09.001 [DOI] [PubMed] [Google Scholar]

[nuaf117-B15] 15. Bjelakovic M, Nikolova D, Bjelakovic G, Gluud C. Vitamin D supplementation for chronic liver diseases in adults. Cochrane Database Syst Rev. 2021;8:CD011564. 10.1002/14651858.CD011564.pub3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B16] 16. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372:n71. 10.1136/bmj.n71 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B17] 17. Higgins JES, Li T. Chapter 23: including variants on randomized trials. In: Higgins JPT, Thomas J, Chandler J, et al. , eds. Cochrane Handbook for Systematic Reviews of Interventions Version 6.3. Cochrane; 2022. Available from www.training.cochrane.org/handbook. [Google Scholar]

[nuaf117-B18] 18. Booth A, Clarke M, Dooley G, et al. PROSPERO at one year: an evaluation of its utility. Syst Rev. 2013;2:4. 10.1186/2046-4053-2-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B19] 19. Munn Z, Stern C, Aromataris E, Lockwood C, Jordan Z. What kind of systematic review should I conduct? A proposed typology and guidance for systematic reviewers in the medical and health sciences. BMC Med Res Methodol. 2018;18:5. 10.1186/s12874-017-0468-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B20] 20. Scherer RW, Saldanha IJ. How should systematic reviewers handle conference abstracts? A view from the trenches. Syst Rev. 2019;8:264. 10.1186/s13643-019-1188-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B21] 21. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366:l4898. 10.1136/bmj.l4898 [DOI] [PubMed] [Google Scholar]

[nuaf117-B22] 22. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383-394. 10.1016/j.jclinepi.2010.04.026 [DOI] [PubMed] [Google Scholar]

[nuaf117-B23] 23. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539-1558. 10.1002/sim.1186 [DOI] [PubMed] [Google Scholar]

[nuaf117-B24] 24. Harun M, Rashid. Effect of vitamin D treatment in patients with decompensated cirrhosis of liver—report from a Tertiary Centre, Bangladesh. Hepatol Int. 2020; 14:S407. https://doi.org/Doi: 10.1007/s12072-020-10030-4 [Google Scholar]

[nuaf117-B25] 25. Mihai C, Dranga M, Drug V, Prelipcean CC. Vitamin D and B12 supplementation and sustained virologic response in chronic hepatitis C patients treated with pegylated interferon and ribavirin. Gastroenterology. 2014;146:S-982. 10.1016/S0016-5085(14)63568-X [DOI] [Google Scholar]

[nuaf117-B26] 26. Atthakitmongkol T, Chotiyaputta W, Lertwattanarak R, Sritippayawan S, Tanwandee T. Vitamin D and calcium supplementation prevent bone loss in vitamin d-deficient chronic hepatitis B patients treated with tenofovir disoproxil fumarate: a randomized controlled study. Gastroenterology. 2023;164:S-1360-S-1361. 10.1016/S0016-5085(23)04168-9 [DOI] [Google Scholar]

[nuaf117-B27] 27. Grover I, Sharma S, Madhu D, et al. Effect of vitamin d supplementation on clinical outcomes in patients with cirrhosis: a post hoc analysis of a randomized controlled trial. Hepatology. 2021;74(Suppl. 1):1213A-1214A. 10.1002/hep.32188 [DOI] [Google Scholar]

[nuaf117-B28] 28. Grover I, Gunjan D, Singh N, et al. Effect of vitamin D supplementation on vitamin D level and bone mineral density in patients with cirrhosis: a randomized clinical trial. Am J Gastroenterol. 2021;116:2098-2104. 10.14309/ajg.0000000000001272 [DOI] [PubMed] [Google Scholar]

[nuaf117-B29] 29. Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol. 2011;17:5184-5190. 10.3748/wjg.v17.i47.5184 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B30] 30. Afsordeh Kolsoum RR, Aliakbar A. Effect of aerobic training and vitamin D supplements on fatty liver and lipid profiles in women with fatty liver. Pejouhesh dar Pezeshki (Res Med). 2019;43:8-14. [Google Scholar]

[nuaf117-B31] 31. Atsukawa M, Tsubota A, Shimada N, et al. Effect of native vitamin D3 supplementation on refractory chronic hepatitis C patients in simeprevir with pegylated interferon/ribavirin. Hepatol Res. 2016;46:450-458. 10.1111/hepr.12575 [DOI] [PubMed] [Google Scholar]

[nuaf117-B32] 32. Behera MK, Shukla SK, Dixit VK, et al. Effect of vitamin D supplementation on sustained virological response in genotype 1/4 chronic hepatitis C treatment-naïve patients from India. Indian J Med Res. 2018;148:200-206. 10.4103/ijmr.IJMR_1295_15 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B33] 33. Boonyagard S, Techathuvanan K. Impact of vitamin D replacement on liver enzymes in non-alcoholic fatty liver disease patients: a randomized, double-blind, placebo-controlled trial. J Med Assoc Thailand. 2020;103:A105-A112. 10.35755/jmedassocthai.2020.S08.12052 [DOI] [Google Scholar]

[nuaf117-B34] 34. Dabbaghmanesh MH, Danafar F, Eshraghian A, Omrani GR. Vitamin D supplementation for the treatment of non-alcoholic fatty liver disease: a randomized double blind placebo controlled trial. Diabetes Metab Syndr. 2018;12:513-517. 10.1016/j.dsx.2018.03.006 [DOI] [PubMed] [Google Scholar]

[nuaf117-B35] 35. Ebrahimpour-Koujan S, Sohrabpour AA, Giovannucci E, Vatannejad A, Esmaillzadeh A. Effects of vitamin D supplementation on liver fibrogenic factors, vitamin D receptor and liver fibrogenic microRNAs in metabolic dysfunction-associated steatotic liver disease (MASLD) patients: an exploratory randomized clinical trial. Nutr J. 2024;23:24. 10.1186/s12937-024-00911-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B36] 36. Foroughi M, Maghsoudi Z, Askari G. The effect of vitamin D supplementation on blood sugar and different indices of insulin resistance in patients with non-alcoholic fatty liver disease (NAFLD). Iran J Nurs Midwifery Res. 2016;21:100-104. 10.4103/1735-9066.174759 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B37] 37. Foroughi M, Maghsoudi Z, Ghiasvand R, Iraj B, Askari G. Effect of vitamin D supplementation on C-reactive protein in patients with nonalcoholic fatty liver. Int J Prev Med. 2014;5:969-975. [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B38] 38. Guo XF, Wang C, Yang T, et al. The effects of fish oil plus vitamin D(3) intervention on non-alcoholic fatty liver disease: a randomized controlled trial. Eur J Nutr. 2022;61:1931-1942. 10.1007/s00394-021-02772-0 [DOI] [PubMed] [Google Scholar]

[nuaf117-B39] 39. Hajiaghamohammadi A, Shafikhani AA, Bastani A, Gaemi N. Effect of vitamin D replacement on liver enzymes in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol Res. 2019;8:2907-2910. 10.17554/j.issn.2224-3992.2019.08.819 [DOI] [Google Scholar]

[nuaf117-B40] 40. Hoseini Z, Behpour N, Hoseini R. Co-treatment with vitamin D supplementation and aerobic training in elderly women with Vit D deficiency and NAFLD: a single-blind controlled trial. Hepat Mon. 2020;20:e96437. 10.5812/hepatmon.96437 [DOI] [Google Scholar]

[nuaf117-B41] 41. Hosseini S, Aliashrafi S, Ebrahimi-Mameghani M. The effect of a single intramuscular injection of cholecalciferol on the serum levels of vitamin D, adiponectin, insulin resistance, and liver function in women with non-alcoholic fatty liver disease (NAFLD): a randomized, controlled clinical trial. Iran Red Cresc Med J. 2024;20:1-12. 10.5812/ircmj.60746 [DOI] [Google Scholar]

[nuaf117-B42] 42. Hussain M, Iqbal J, Malik SA, et al. Effect of vitamin D supplementation on various parameters in non-alcoholic fatty liver disease patients. Pak J Pharm Sci. 2019;32:1343-1348. [PubMed] [Google Scholar]

[nuaf117-B43] 43. Jeong JY, Jun DW, Park SJ, et al. Effects of vitamin D supplements in patients with chronic hepatitis C: a randomized, multi-center, open label study. Korean J Intern Med. 2020;35:1074-1083. 10.3904/kjim.2018.273 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B44] 44. Jha AK, Jha SK, Kumar A, Dayal VM, Jha SK. Effect of replenishment of vitamin D on survival in patients with decompensated liver cirrhosis: a prospective study. World J Gastrointest Pathophysiol. 2017;8:133-141. 10.4291/wjgp.v8.i3.133 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B45] 45. Khan J, Adil N, Naseer A, Asif M, Sabir A, Fatima S. Comparison of frequency of rapid virological response in patients of hepatitis C being treated with 25-OH vitamin D along with sofosbuvir/ribavirin with those treated with sofosbuvir/ribavirin only. Pak J Med Health Sci. 2022;16:342-343. 10.53350/pjmhs22166342 [DOI] [Google Scholar]

[nuaf117-B46] 46. Komolmit P, Charoensuk K, Thanapirom K, et al. 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. 10.1371/journal.pone.0174608 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B47] 47. Komolmit P, Kimtrakool S, Suksawatamnuay S, et al. Vitamin D supplementation improves serum markers associated with hepatic fibrogenesis in chronic hepatitis C patients: a randomized, double-blind, placebo-controlled study. Sci Rep. 2017;7:8905. 10.1038/s41598-017-09512-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B48] 48. Lorvand Amiri H, Agah S, Tolouei Azar J, Hosseini S, Shidfar F, Mousavi SN. Effect of daily calcitriol supplementation with and without calcium on disease regression in non-alcoholic fatty liver patients following an energy-restricted diet: randomized, controlled, double-blind trial. Clin Nutr. 2017;36:1490-1497. 10.1016/j.clnu.2016.09.020 [DOI] [PubMed] [Google Scholar]

[nuaf117-B49] 49. Lorvand Amiri H, Agah S, Mousavi SN, Hosseini AF, Shidfar F. Regression of non-alcoholic fatty liver by vitamin D supplement: a double-blind randomized controlled clinical trial. Arch Iran Med. 2016;19:631-638. [PubMed] [Google Scholar]

[nuaf117-B50] 50. Shidfar F, Mousavi SN, Amiri HL, Agah S, Hoseini S, Hajimiresmail SJ. Reduction of some atherogenic indices in patients with non-alcoholic fatty liver by Vitamin D and calcium co-supplementation: a double blind randomized controlled clinical trial. Iran J Pharm Res. 2019;18:496-505. [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B51] 51. Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients. World J Gastroenterol. 2012;18:800-805. 10.3748/wjg.v18.i8.800 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B52] 52. Okubo T, Atsukawa M, Tsubota A, et al. Effect of vitamin D supplementation on skeletal muscle volume and strength in patients with decompensated liver cirrhosis undergoing branched chain amino acids supplementation: a prospective, randomized, controlled pilot trial. Nutrients. 2021;13:1874. 10.3390/nu13061874 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B53] 53. Sakpal M, Satsangi S, Mehta M, et al. Vitamin D supplementation in patients with nonalcoholic fatty liver disease: a randomized controlled trial. JGH Open. 2017;1:62-67. 10.1002/jgh3.12010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B54] 54. Shiomi S, Masaki K, Habu D, et al. Calcitriol for bone disease in patients with cirrhosis of the liver. J Gastroenterol Hepatol. 1999;14:547-552. 10.1046/j.1440-1746.1999.01913.x [DOI] [PubMed] [Google Scholar]

[nuaf117-B55] 55. Shiomi S, Masaki K, Habu D, et al. Calcitriol for bone loss in patients with primary biliary cirrhosis. J Gastroenterol. 1999;34:241-245. 10.1007/s005350050250 [DOI] [PubMed] [Google Scholar]

[nuaf117-B56] 56. Sharifi N, Amani R, Hajiani E, Cheraghian B. Does vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trial. Endocrine. 2014;47:70-80. 10.1007/s12020-014-0336-5 [DOI] [PubMed] [Google Scholar]

[nuaf117-B57] 57. Sharifi N, Amani R, Hajiani E, Cheraghian B. Women may respond different from men to vitamin D supplementation regarding cardiometabolic biomarkers. Exp Biol Med. 2016;241:830-838. 10.1177/1535370216629009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B58] 58. Sriphoosanaphan S, Thanapirom K, Kerr SJ, et al. Effect of vitamin D supplementation in patients with chronic hepatitis C after direct-acting antiviral treatment: a randomized, double-blind, placebo-controlled trial. PeerJ. 2021; 9:e10709. 10.7717/peerj.10709 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B59] 59. Taghvaei T, Akha O, Mouodi M, Tirgar Fakheri H, Kashi Z, Maleki. I. Effects of vitamin d supplementation on patients with non-alcoholic fatty liver disease (nafld). Acta Med Mediterr. 2018;34:415-422. 10.19193/0393-6384_2018_2_66 [DOI] [Google Scholar]

[nuaf117-B60] 60. Vosoghinia H, Esmaeilzadeh A, Ganji A, et al. Vitamin D in standard HCV regimen (PEG-interferon plus ribavirin), its effect on the early virologic response rate: a clinical trial. Razavi Int J Med. 2016;4:e36632. 10.17795/rijm36632 [DOI] [Google Scholar]

[nuaf117-B61] 61. Wang CC, Tzeng IS, Su WC, et al. The association of vitamin D with hepatitis B virus replication: bystander rather than offender. J Formos Med Assoc. 2020;119:1634-1641. 10.1016/j.jfma.2019.12.004 [DOI] [PubMed] [Google Scholar]

[nuaf117-B62] 62. Xing T, Qiu G, Zhong L, Ling L, Huang L, Peng Z. Calcitriol reduces the occurrence of acute cellular rejection of liver transplants: a prospective controlled study. Pharmazie. 2013;68:821-826. [PubMed] [Google Scholar]

[nuaf117-B63] 63. Yang Z, Haijun C, Yejin X, Dehe Z, Jing Z, Shengnan L. Efficacy of vitamin D adjuvant therapy for prevention of spontaneous bacterial peritonitis in patients with decompensated cirrhosis of hepatitis B. Chin J Clin Infect Dis. 2023;16:215-219. 10.3760/cma.j.issn.1674-2397.2023.03.009 [DOI] [Google Scholar]

[nuaf117-B64] 64. Yaghooti H, Ghanavati F, Seyedian SS, Cheraghian B, Mohammadtaghvaei N. The efficacy of calcitriol treatment in non-alcoholic fatty liver patients with different genotypes of vitamin D receptor FokI polymorphism. BMC Pharmacol Toxicol. 2021;22:18. 10.1186/s40360-021-00485-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B65] 65. Yokoyama S, Takahashi S, Kawakami Y, et al. Effect of vitamin D supplementation on pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b: a randomized controlled trial. J Viral Hepat. 2014;21:348-356. 10.1111/jvh.12146 [DOI] [PubMed] [Google Scholar]

[nuaf117-B66] 66. Barchetta I, Del Ben M, Angelico F, et al. No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. BMC Med. 2016;14:92. 10.1186/s12916-016-0638-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B67] 67. Geier A, Eichinger M, Stirnimann G, et al. Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study. Scand J Gastroenterol. 2018;53:1114-1120. 10.1080/00365521.2018.1501091 [DOI] [PubMed] [Google Scholar]

[nuaf117-B68] 68. Lukenda Zanko V, Domislovic V, Trkulja V, et al. Vitamin D for treatment of non-alcoholic fatty liver disease detected by transient elastography: a randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2020;22:2097-2106. 10.1111/dom.14129 [DOI] [PubMed] [Google Scholar]

[nuaf117-B69] 69. Pilz S, Putz-Bankuti C, Gaksch M, et al. Effects of vitamin D supplementation on serum 25-hydroxyvitamin D concentrations in cirrhotic patients: a randomized controlled trial. Nutrients. 2016;8:278. 10.3390/nu8050278 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B70] 70. Alarfaj SJ, Bahaa MM, Yassin HA, et al. A randomized placebo-controlled, double-blind study to investigate the effect of a high oral loading dose of cholecalciferol in non-alcoholic fatty liver disease patients, new insights on serum STAT-3 and hepassocin. Eur Rev Med Pharmacol Sci. 2023;27:7607-7619. 10.26355/eurrev_202308_33413 [DOI] [PubMed] [Google Scholar]

[nuaf117-B71] 71. Esmat G, El Raziky M, Elsharkawy A, et al. Impact of vitamin D supplementation on sustained virological response in chronic hepatitis C genotype 4 patients treated by pegylated interferon/ribavirin. J Interferon Cytokine Res. 2015;35:49-54. 10.1089/jir.2014.0060 [DOI] [PubMed] [Google Scholar]

[nuaf117-B72] 72. Mohamed AA, Halim AA, Mohamed S, et al. The effect of high oral loading dose of cholecalciferol in non-alcoholic fatty liver disease patients. A randomized placebo controlled trial. Front Pharmacol. 2023;14:1149967. 10.3389/fphar.2023.1149967 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B73] 73. Mohamed AA, Al-Karmalawy AA, El-Kholy AA, et al. Effect of vitamin D supplementation in patients with liver cirrhosis having spontaneous bacterial peritonitis: a randomized controlled study. Eur Rev Med Pharmacol Sci. 2021;25:6908-6919. 10.26355/eurrev_202111_27239 [DOI] [PubMed] [Google Scholar]

[nuaf117-B74] 74. Mobarhan SA, Russell RM, Recker RR, Posner DB, Iber FL, Miller P. Metabolic bone disease in alcoholic cirrhosis: a comparison of the effect of vitamin D2, 25-hydroxyvitamin D, or supportive treatment. Hepatology. 1984;4:266-273. 10.1002/hep.1840040216 [DOI] [PubMed] [Google Scholar]

[nuaf117-B75] 75. Finkelmeier F, Kronenberger B, Zeuzem S, Piiper A, Waidmann O. Low 25-hydroxyvitamin D levels are associated with infections and mortality in patients with cirrhosis. PLoS One. 2015;10:e0132119. 10.1371/journal.pone.0132119 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B76] 76. Kim TH, Yun SG, Choi J, et al. Differential impact of serum 25-hydroxyvitamin D3 levels on the prognosis of patients with liver cirrhosis according to MELD and child-pugh scores. J Korean Med Sci. 2020;35:e129. 10.3346/jkms.2020.35.e129 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B77] 77. Yang F, Ren H, Gao Y, Zhu Y, Huang W. The value of severe vitamin D deficiency in predicting the mortality risk of patients with liver cirrhosis: a meta-analysis. Clin Res Hepatol Gastroenterol. 2019;43:722-729. 10.1016/j.clinre.2019.03.001 [DOI] [PubMed] [Google Scholar]

[nuaf117-B78] 78. Mayr U, Fahrenkrog-Petersen L, Batres-Baires G, et al. Vitamin D deficiency is highly prevalent in critically ill patients and a risk factor for mortality: a prospective observational study comparing noncirrhotic patients and patients with cirrhosis. J Intensive Care Med. 2020;35:992-1001. 10.1177/0885066618803844 [DOI] [PubMed] [Google Scholar]

[nuaf117-B79] 79. Moreau R, Tonon M, Krag A, et al. EASL Clinical Practice Guidelines on acute-on-chronic liver failure. J Hepatol. 2023;79:461-491. 10.1016/j.jhep.2023.04.021 [DOI] [PubMed] [Google Scholar]

[nuaf117-B80] 80. Chung C, Silwal P, Kim I, Modlin RL, Jo EK. Vitamin D-cathelicidin axis: at the crossroads between protective immunity and pathological inflammation during infection. Immune Netw. 2020;20:e12. 10.4110/in.2020.20.e12 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B81] 81. Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells. 2019;8:1419. 10.3390/cells8111419 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B82] 82. Lu W, Li X, Liu N, et al. Vitamin D alleviates liver fibrosis by inhibiting histidine-rich calcium binding protein (HRC). Chem Biol Interact. 2021;334:109355. 10.1016/j.cbi.2020.109355 [DOI] [PubMed] [Google Scholar]

[nuaf117-B83] 83. Ding N, Yu RT, Subramaniam N, et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell. 2013;153:601-613. 10.1016/j.cell.2013.03.028 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B84] 84. Wahsh E, Abu-Elsaad N, El-Karef A, Ibrahim T. The vitamin D receptor agonist, calcipotriol, modulates fibrogenic pathways mitigating liver fibrosis in-vivo: an experimental study. Eur J Pharmacol. 2016;789:362-369. 10.1016/j.ejphar.2016.07.052 [DOI] [PubMed] [Google Scholar]

[nuaf117-B85] 85. Wahsh E, Berzigotti A, Tsochatzis E, Boursier J, et al. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol. 2021;75:659-689. 10.1016/j.jhep.2021.05.025 [DOI] [PubMed] [Google Scholar]

[nuaf117-B86] 86. Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. J Hepatol. 2012;56:1171-1180. 10.1016/j.jhep.2011.09.024 [DOI] [PubMed] [Google Scholar]

[nuaf117-B87] 87. Patel S, Jinjuvadia R, Patel R, Liangpunsakul S. Insulin resistance is associated with significant liver fibrosis in chronic hepatitis C patients: a systemic review and meta-analysis. J Clin Gastroenterol. 2016;50:80-84. 10.1097/mcg.0000000000000400 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B88] 88. Sindhughosa DA, Wibawa IDN, Mariadi IK, Somayana G. Additional treatment of vitamin D for improvement of insulin resistance in non-alcoholic fatty liver disease patients: a systematic review and meta-analysis. Sci Rep. 2022;12:7716. 10.1038/s41598-022-11950-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B89] 89. Mahmoudi L, Asadi S, Al-Mousavi Z, Niknam R. A randomized controlled clinical trial comparing calcitriol versus cholecalciferol supplementation to reduce insulin resistance in patients with non-alcoholic fatty liver disease. Clin Nutr. 2021;40:2999-3005. 10.1016/j.clnu.2020.11.037 [DOI] [PubMed] [Google Scholar]

[nuaf117-B90] 90. Abdul-Ghani M, DeFronzo RA. Insulin resistance and hyperinsulinemia: the egg and the chicken. J Clin Endocrinol Metab. 2021;106:e1897-e1899. 10.1210/clinem/dgaa364 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B91] 91. Janssen J. Hyperinsulinemia and its pivotal role in aging, obesity, type 2 diabetes, cardiovascular disease and cancer. Int J Mol Sci. 2021;22:7797. 10.3390/ijms22157797 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B92] 92. Lu Q, Liang Q, Xi Y. The effects of vitamin D supplementation on serum lipid profiles in people with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Front Nutr. 2024;11:1419747. 10.3389/fnut.2024.1419747 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B93] 93. Radkhah N, Zarezadeh M, Jamilian P, Ostadrahimi A. The effect of vitamin D supplementation on lipid profiles: an umbrella review of meta-analyses. Adv Nutr. 2023;14:1479-1498. 10.1016/j.advnut.2023.08.012 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B94] 94. Quesada-Gomez JM, Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporos Int. 2018;29:1697-1711. 10.1007/s00198-018-4520-y [DOI] [PubMed] [Google Scholar]

[nuaf117-B95] 95. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2020 Update. Endocr Pract. 2020;26:1-46. 10.4158/gl-2020-0524suppl [DOI] [PubMed] [Google Scholar]

[nuaf117-B96] 96. Pludowski P, Holick MF, Grant WB, et al. Vitamin D supplementation guidelines. J Steroid Biochem Mol Biol. 2018;175:125-135. 10.1016/j.jsbmb.2017.01.021 [DOI] [PubMed] [Google Scholar]

[nuaf117-B97] 97. Bilezikian JP, Formenti AM, Adler RA, et al. Vitamin D: dosing, levels, form, and route of administration: does one approach fit all? Rev Endocr Metab Disord. 2021;22:1201-1218. 10.1007/s11154-021-09693-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B98] 98. Tellioglu A, Basaran S, Guzel R, Seydaoglu G. Efficacy and safety of high dose intramuscular or oral cholecalciferol in vitamin D deficient/insufficient elderly. Maturitas. 2012;72:332-338. 10.1016/j.maturitas.2012.04.011 [DOI] [PubMed] [Google Scholar]

[nuaf117-B99] 99. Masood MQ, Khan A, Awan S, et al. Comparision of vitamin D replacement strategies with high-dose intramuscular or oral cholecalciferol: a prospective intervention study. Endocr Pract. 2015;21:1125-1133. 10.4158/ep15680.Or [DOI] [PubMed] [Google Scholar]

[nuaf117-B100] 100. Hegyi P, Petersen OH, Holgate S, et al. Academia Europaea position paper on translational medicine: the cycle model for translating scientific results into community benefits. J Clin Med. 2020;9:1532. 10.3390/jcm9051532 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nuaf117-B101] 101. Hegyi P, Erőss B, Izbéki F, Párniczky A, Szentesi A. Accelerating the translational medicine cycle: the Academia Europaea pilot. Nat Med. 2021;27:1317-1319. 10.1038/s41591-021-01458-8 [DOI] [PubMed] [Google Scholar]

[nuaf117-B102] 102. Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67:6-19. 10.1136/gutjnl-2017-314924 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Role of Vitamin D Supplementation in Chronic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Petrana Martinekova

Mahmoud Obeidat

Mihaela Topala

Szilárd Váncsa

Dániel Sándor Veres

Ádám Zolcsák

Miheller Pál

László Földvári-Nagy

Peter Banovcin

Bálint Erőss

Péter Hegyi

Krisztina Hagymasi

Abstract

Context

Objective

Data Sources

Data Extraction

Data Analysis

Conclusion

Systematic Review Registration

KEY POINTS.

INTRODUCTION

METHODS

Eligibility Criteria

Table 1.

Information Sources and Search Strategy

Selection and Data Collection Process

Data Items

Study Risk of Bias Assessment

Quality of Evidence

Synthesis Method

RESULTS

Search and Selection

Figure 1.

Baseline Characteristics of Included Studies

Survival

Figure 2.

Liver Steatosis (CAP) and Liver Fibrosis (LSM)

Figure 3.

Table 2.

Liver Enzymes

Figure 4.

Glucose and Lipid Metabolism

Figure 5.

Additional Outcomes

Inflammatory Markers.

Bone Mineral Density and Sarcopenia.

Virologic Response.

International normalized ratio, Albumin, Bilirubin.

Adverse Events.

Subgroup Analyses

Risk of Bias and Certainty of Evidence

Publication Bias and Heterogeneity

DISCUSSION

Strengths and Limitations

Implications for Practice and Research

CONCLUSION

Supplementary Material

Acknowledgments

Contributor Information

Author Contributions

Supplementary Material

Funding

Conflicts of Interest

Data Availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases