Vitamin D supplementation for chronic liver diseases

Review question

Is vitamin D supplementation beneficial or harmful for people with chronic liver diseases?

Background

The available evidence on vitamin D and chronic liver diseases is inconclusive. Many observational studies (a study of a group of people where the researcher has no control of treatments and conditions because of ethical concerns or logistical constraints) suggest that chronic liver diseases are associated with low vitamin D levels in the blood. Therefore, improving vitamin D levels could have beneficial effects on chronic liver diseases. Results of randomised clinical trials (trials where people are randomly assigned into one of two or more treatment groups) testing the effect of vitamin D supplementation for chronic liver diseases are contradictory. The aim of this systematic review (a summary of results of available healthcare trials) was to analyse the benefits and harms of the different forms of vitamin D in people with chronic liver diseases.

Study characteristics

Fifteen trials provided data for this review; 1034 adult participants were randomly assigned to vitamin D compared with placebo or no treatment. Nine trials were conducted in high-income countries, and six trials in middle-income countries. All trials were at high risk of bias (that is overestimation of benefits and underestimation of harms). The age range of the participants was 18 years to 84 years and on average 42% were women. Six trials included participants with chronic hepatitis C, four trials included participants with liver cirrhosis, four trials included participants with non-alcoholic fatty liver disease, and one trial included liver transplant recipients. Most of included trials reported the baseline vitamin D status of participants. Vitamin D administration lasted on average six months and most trials used the cholecalciferol (vitamin D3) form.

Funding

Six trials appeared to be free of industry sponsorship or other type of for-profit support that may bias the results of the trials. Eight trials may not have been free of for-profit bias as they did not provide any information on clinical trial support or sponsorship. One trial was funded by industry.

Key results

This review suggests that vitamin D has no beneficial or harmful effects on chronic liver diseases. However, there were too few trials on the individual diagnosis of chronic liver diseases and there were too few participants in the individual trials as well as in our meta-analysis. Therefore, neither benefits nor harms can be excluded.

Quality of the evidence

All trials were judged to be at high risk of bias (that is, possibly an overestimation of benefits and underestimation of harms).

Currentness of evidence

This evidence is up to date as of January 2017.

Authors' conclusions: 

We are uncertain as to whether vitamin D supplements in the form of vitamin D3, vitamin D2, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D have important effect on all-cause mortality, liver-related mortality, or on serious or non-serious adverse events because the results were imprecise. There is no evidence on the effect of vitamin D supplementation on liver-related morbidity and health-related quality of life. Our conclusions are based on few trials with an insufficient number of participants and on lack of data on clinically important outcomes. In addition, the analysed trials are at high risk of bias with significant intertrial heterogeneity. The overall quality of evidence is very low.

Read the full abstract...
Background: 

Vitamin D deficiency is often reported in people with chronic liver diseases. Therefore, improving vitamin D status could have a beneficial effect on people with chronic liver diseases.

Objectives: 

To assess the beneficial and harmful effects of vitamin D supplementation in people with chronic liver diseases.

Search strategy: 

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science. We also searched databases of ongoing trials and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. All searches were up to January 2017.

Selection criteria: 

Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)).

Data collection and analysis: 

We used standard methodological procedures expected by The Cochrane Collaboration. We contacted authors of the trials to ask for missing information. We conducted random-effects and fixed-effect meta-analyses. For dichotomous outcomes, we calculated risk ratios (RRs), and for continuous outcomes, we calculated mean differences (MD), both with 95% confidence intervals (CI) and Trial Sequential Analyses-adjusted CIs. We calculated Peto odds ratio (OR) for rare events. We considered risk of bias in domains to assess the risk of systematic errors. We conducted Trial Sequential Analyses to control the risk of random errors. We assessed the quality of the evidence with GRADE.

Main results: 

We included 15 randomised clinical trials with 1034 participants randomised. All trials had a parallel group design. Nine trials were conducted in high-income countries and six trials in middle-income countries. All trials were at high risk of bias. Six trials included participants with chronic hepatitis C, four trials included participants with liver cirrhosis, four trials included participants with non-alcoholic fatty liver disease, and one trial included liver transplant recipients. All included trials reported the baseline vitamin D status of participants. Participants in six trials had baseline 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), while participants in the remaining nine trials were vitamin D insufficient (less than 20 ng/mL). All trials administered vitamin D orally. Mean duration of vitamin D supplementation was 0.5 years and follow-up was 0.6 years. Eleven trials (831 participants; 40% women; mean age 52 years) tested vitamin D3, one trial (18 men; mean age 61 years) with three intervention groups tested vitamin D2 and 25-dihydroxyvitamin D in separate groups, and three trials (185 participants; 55% women; mean age 55 years) tested 1,25-dihydroxyvitamin D. Seven trials used placebo, and eight trials used no intervention in the control group.

The effect of vitamin D on all-cause mortality at the end of follow-up is uncertain because the results were imprecise (Peto OR 0.70, 95% CI 0.09 to 5.38; I2 = 32%; 15 trials; 1034 participants; very low quality evidence). Trial Sequential Analysis on all-cause mortality was performed based on a mortality rate in the control group of 10%, a relative risk reduction of 28% in the experimental intervention group, a type I error of 2.5%, and type II error of 10% (90% power). There was no diversity. The required information size was 6396 participants. The cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit or harm after the 15th trial, and the Trial Sequential Analyses-adjusted CI was 0.00 to 2534.

The effect of vitamin D on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) and on serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants), myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants), and thyroiditis (RR 0.33 95% CI 0.01 to 7.91; 1 trial; 68 participants) is uncertain because the results were imprecise. The evidence on all these outcomes is of very low quality. The effect of vitamin D3 on non-serious adverse events such as glossitis (RR 3.70, 95% CI 0.16 to 87.6; 1 trial; 65 participants; very low quality of evidence) is uncertain because the result was imprecise.

Due to few data, we did not conduct Trial Sequential Analysis on liver-related mortality, and serious and non-serious adverse events.

We found no data on liver-related morbidity and health-related quality of life in the randomised trials included in this review.

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