Summary of main results

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 significant effect on all‐cause mortality, liver‐related mortality, or serious or non‐serious adverse events because the results were imprecise. Neither did vitamin D seem beneficial in increasing the number of people with sustained virological response or decreasing the number of people with acute cellular rejection in liver transplant recipients. Analyses of three trials in people with chronic hepatitis C suggested that we are uncertain as to whether vitamin D₃ might be beneficial in increasing the number of people with rapid and early virological response because the results were imprecise (Abu‐Mouch 2011; Atsukawa 2016; Vosoghinia 2016). Vitamin D status of participants with chronic liver diseases was significantly increased after supplementation with vitamin D. We found no significant changes in biochemical indices after supplementation. There was insufficient evidence on the effect of vitamin D supplementation on liver‐related morbidity and health‐related quality of life in people with chronic liver diseases.

The results of our systematic review should be interpreted with great caution because all included trials were at high risk of bias. Due to the small number of included trials and selective outcome reporting, we were unable to conduct subgroup analyses according to the different forms of vitamin D. The number of people and outcome data were insufficient which adds to our risk of making both type I and type II errors due to paucity of data (Keus 2010). Our Trial Sequential Analysis CI revealed that we have insufficient information for making valid conclusions.

Although vitamin D deficiency is considered common in people with a variety of liver diseases (Chen 2014; Iruzubieta 2014; Elangovan 2017), we found no convincing evidence that vitamin D supplementation has therapeutic impact in chronic liver diseases.

Overall completeness and applicability of evidence

Our published protocol described our plan to analyse the effect of vitamin D on chronic liver diseases in randomised trials in adults (Bjelakovic 2015). We included all eligible randomised trials up to January 2017. We found only a small number of randomised trials with a small number of participants. All trials were at high risk of bias. We found significant statistical heterogeneity in some of our analyses. This decreases the precision and power of our analyses (Higgins 2011; Turner 2013). Our analyses revealed that outcome reporting was missing on approximately 6% of trial participants. Accordingly, our 'best‐worst case' and 'worst‐best case' analyses revealed that our results were compatible with both a large beneficial effect and a large detrimental effect of vitamin D on mortality. Although these extreme sensitivity analyses are unlikely analyses, they reveal how missing participants can substantially change our findings of great benefit into a null effect or maybe even harm. Therefore, we advise critical application of our findings.

Quality of the evidence

Our review followed the overall plan of a published, peer‐reviewed Cochrane protocol (Bjelakovic 2015). We were unable to find earlier meta‐analyses of trials of vitamin D on chronic liver diseases in the literature. We conducted a thorough review in accordance with Cochrane methodology (Higgins 2011) and implemented findings of methodological studies (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b; Lundh 2017).

We repeatedly searched several databases and contacted authors of trials and industry producing vitamin D supplements. Therefore, we believe that we have not overlooked important randomised clinical trials. As stated below, we may have missed trials only reported to regulatory authorities. However, such trials are often neutral or negative. We found no significant evidence of publication bias (Johnson 2007). However, only about every second trial is reported (Gluud 2008), so we cannot exclude reporting biases. We have also performed Trial Sequential Analysis, based on the estimation of the diversity‐adjusted required information size to avoid an undue risk of random errors in a cumulative meta‐analysis and to prevent premature statements of superiority of vitamin D or of lack of effect (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2011a; Thorlund 2011b; TSA 2017; Wetterslev 2017).

We used GRADE to construct a 'Summary of findings' table. The GRADE assessments showed that the quality if the evidence was very low for all‐cause mortality, liver‐related mortality, serious adverse events (hypercalcaemia, myocardial infarction, thyroiditis), failure of sustained virological response, glossitis, or acute cellular rejection in liver transplant recipients. We applied the results of Trial Sequential Analysis for rating imprecision. If there was insufficient evidence to reach a conclusion, that is, if the Trial Sequential Analysis indicated that the required information size had not been reached, we downgraded the quality of the evidence. We also used risk of attrition bias for rating imprecision, significant between‐trial heterogeneity for rating inconsistency, and design errors for rating indirectness.

Potential biases in the review process

Certain limitations of this review warrant consideration. As with all systematic reviews, our findings and interpretations are limited by the quality and quantity of available evidence on the effects of vitamin D on chronic liver diseases. Despite extensive speculations in the literature and a number of epidemiological studies that claimed possible beneficial effects of vitamin D in people with chronic liver diseases, only few randomised trials assessed such effects. The duration of supplementation and duration of follow‐up were short in some of the included trials. This may make it difficult to detect any effects, beneficial or harmful. All 15 included trials were at high risk of bias. Instead of reporting clinical outcomes, most of the trials based their analysis on surrogate outcomes. Many of the included trials were not adequately powered. These factors corrupt the validity of our results (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b). Adverse events were insufficiently reported. It has been pointed out that adverse events are very often neglected in randomised trials (Ioannidis 2009). In a number of trials in people with chronic hepatitis C, vitamin D was administered in combination with pegylated‐interferon and ribavirin, which made it difficult to judge its beneficial or harmful effects, or to which intervention one should assign any of the observed adverse events. Significant between‐trial heterogeneity was present in some of our meta‐analyses. This may emphasise the inconsistency of our findings and may additionally question our review findings.

Most of included trials used vitamin D₃, three trials tested 1,25‐dihydroxyvitamin D, one trial tested vitamin D₂, and one trial tested 25‐dihydroxyvitamin D. We were unable to perform subgroup analyses comparing different forms of vitamin D used for supplementation.

We did not search files of regulatory agencies such as Food and Drug Administration and European Medicine Agency. This may bias our selection of trials. We did not conduct searches after observational studies on harms. This may bias our findings towards benefits of the interventions with less focus on harms (Storebø 2015).

Different types of bias can influence the results of our meta‐analyses including selective reporting of some results in trial publications (Chan 2004; Williamson 2005; Furukawa 2007). Outcome reporting in the included trials was insufficient and inconsistent. There are several possible explanations for selective reporting of outcomes in randomised trials. Trials in which the outcome was not reported may not have measured outcomes of interest. Researchers may not have reported unexpected results or results may have not satisfied sponsors (Lesser 2007). Pharmaceutical companies provided vitamin D in one of the 15 included trials. This number may be higher because this information was not available in seven trials. It could be that researchers have selectively omitted to report some of the outcomes. We are well aware of the difficulties in collecting data on outcomes in clinical trials that focus on safety and efficacy evaluations. The worst result of outcome reporting bias and suppression of some significant or non‐significant findings could be the use of harmful interventions. The results of meta‐analyses may underestimate the true effects of interventions when there is exaggerated outcome reporting bias. One would wish that results of randomised clinical trials are reported in greater details (Nordic Trial Alliance 2015). In some of the trials, instead of full reporting, we found partial or qualitative reporting. The huge human efforts of investigators and the high cost of randomised clinical trials should be justified with more rigour in their reporting. In spite of the large investment in the reviewed trials, a number of questions remain unanswered.

Other types of bias, such as academic bias, bias from trials with deficiencies in the trial design (Schulz 1995; Moher 1998; Kjaergard 2001), and small trial bias (Siersma 2007), could probably influence our results. Meta‐analysis of randomised trials increases the power and precision of the estimated intervention effect, but this effect may be influenced by systematic errors or random errors and can lead to a report of false significant results (Gluud 2006; Wetterslev 2008). It is probable that the results of our meta‐analysis are influenced by random errors and systematic errors.

A number of design errors may influence our results. First, abuse of surrogate outcomes. In most trials, the authors used non‐validated surrogate outcomes such as biochemical indices, liver steatosis, or bone mineral density, assuming that normal levels are beneficial. The ideal primary outcome in randomised clinical trials is one that is relevant to the person's quality of life or course of disease. Relying on non‐validated potential surrogate outcomes is potentially dangerous when assessing new therapies (Gluud 2007; Garattini 2016). We lack validated surrogate outcome measures in hepatology. Some trials included in this review examined early, rapid, or sustained virological response as a surrogate outcome for successful treatment. Improved early, rapid, or sustained virological response do not definitely mean significant improvement in clinical outcomes (Gluud 2007; Jakobsen 2017). The use of new interventions in hepatology should not be justified until these have been confirmed to be beneficial on clinical outcomes (Gluud 2006; Jakobsen 2017). These issues could be resolved with the development and application of agreed sets of outcomes, known as core outcome sets (www.comet‐initiative.org). The increase in the number of hepato‐biliary randomised trials will never be considered a sufficient valuable source for data if aspects of trial design, such as sample size, completeness of data reporting, duration of follow‐up, and bias risk, are not improved.

Agreements and disagreements with other studies or reviews

Efforts in evaluating the benefits and harms of vitamin D supplementation in people with chronic liver diseases resulted in neutral results. It is likely that vitamin D deficiency is not a pathogenetic mechanism contributing to liver damage. There is also the possibility that vitamin D deficiency is the consequence but not the cause of chronic liver diseases. Inflammatory processes involved in the pathogenesis of chronic liver diseases, as well as other chronic diseases, reduce serum vitamin D levels, which can explain their low vitamin D status (Autier 2014). Life style could also be related to vitamin D status (Skaaby 2016). Vitamin D supplementation had neutral effect on mortality which can be a result that included randomised clinical trials focused on a group of people with well‐compensated liver diseases at low risk of mortality.

Four trials in the present review included people with liver cirrhosis. We found no evidence that vitamin D supplementation may decrease mortality in people with liver cirrhosis. This finding is contrary to earlier claims in the literature that vitamin D deficiency is associated with increased mortality in people with advanced cirrhosis (Putz‐Bankuti 2012; Wang 2013; Stokes 2014; Finkelmeier 2015; Paternostro 2017). It seems that vitamin D status in people with liver cirrhosis is not only related to liver dysfunction (Lim 2012). Earlier it was thought that people with cholestatic liver disease were more likely to be vitamin D deficient. It is now evident that people with liver cirrhosis, non‐alcoholic fatty liver disease, and chronic hepatitis C are also at risk for low vitamin D levels. Vitamin D deficiency in these people is likely to be multifactorial in aetiology including decreased intake and absorption, altered activity of hepatic 25‐hydroxylase, and insufficient exposure to sunlight (Lim 2012). Trials including people with liver cirrhosis reported biochemical indices after vitamin D supplementation. There was no significant difference between supplemented and control group in most of the recorded values.

Our review did not confirm suggestions that vitamin D supplementation can be beneficial as an adjuvant to other drugs such as interferon or ribavirin (Luong 2012). Meta‐analysis of six trials that included participants with chronic hepatitis C revealed no effect of vitamin D₃ on sustained virological response, and beneficial effect on rapid and early virological response. One study suggested no effect of vitamin D supplementation in people with advanced chronic hepatitis C (Corey 2012). Oliveira and colleagues observed no association between vitamin D and the degree of liver fibrosis in people with chronic hepatitis C (Oliveira 2017). Our results are contrary to the result of one meta‐analysis that found a positive relationship between high vitamin D status and sustained virological response in people with hepatitis C virus infection (Villar 2013), and in agreement with the results of another meta‐analysis by Kitson and colleagues that found that baseline vitamin D status was not associated with sustained virological response in people with chronic hepatitis C (Kitson 2014). However, due to paucity of data, we warn that our results may be deeply influenced by systematic and random errors. We found no randomised trials that tested vitamin D supplementation in people with chronic hepatitis B. Farnik and colleagues found that low vitamin D levels were associated with increased hepatitis B virus replication in people with chronic hepatitis B (Farnik 2013), while Mahamid and colleagues showed a correlation between normal vitamin D levels and spontaneous hepatitis B surface antigen seroclearance (Mahamid 2013). Hoan and colleagues observed vitamin D deficiency in the majority of hepatitis B‐infected people (Hoan 2016). However, whether vitamin D deficiency is the cause or is a consequence of chronic hepatitis is still unknown (Bitetto 2011).

Non‐alcoholic fatty liver disease has become the most common form of chronic liver disease in high‐income countries (Sayiner 2016; Younossi 2016). There is a growing interest to explore the relationship between vitamin D deficiency and severity of non‐alcoholic fatty liver disease. Four trials included in our review administered vitamin D₃ to participants with non‐alcoholic fatty liver disease. We were unable to extract data on clinically important outcomes from these trials. We found no significant effect of vitamin D₃ on surrogate outcomes such as liver function tests. Two meta‐analysis of case‐control and cross‐sectional studies found that people with non‐alcoholic fatty liver disease were more likely to be vitamin D deficient than people in the control groups, suggesting that vitamin D may play a role in the development of non‐alcoholic fatty liver disease (Eliades 2013; Wang 2015). However, we found that vitamin D supplementation may not be beneficial in this population.

We lack sufficient evidence on the effect of vitamin D supplementation on liver‐related morbidity and health‐related quality of life.

Although two included randomised trials analysed the influence of vitamin D supplementation on bone mineral density in people with liver cirrhosis, we were unable to extract relevant data from published reports, and the authors did not respond to our request for additional information. One systematic review and meta‐analysis concluded that vitamin D supplementation for osteoporosis prevention in community‐dwelling adults without specific risk factors for vitamin D deficiency seemed to be inappropriate (Reid 2014). In the same way, another updated systematic evidence review for the US Preventive Service Task Force found no benefit from vitamin D supplementation for prevention of cancer and cardiovascular disease (Fortmann 2013). Bolland and colleagues found that vitamin D did not reduce skeletal, vascular, or cancer outcomes (Bolland 2014).

It seems that health claims are again ahead of the evidence. Great enthusiasm for vitamin D as a cure for a myriad of diseases, reinforced by observational studies showing that healthy people have higher vitamin D status, has not been supported by the evidence obtained from randomised clinical trials. It is very likely that low vitamin D status is not the cause but rather the consequence of chronic diseases (Grey 2010; Guallar 2010; Harvey 2012; Kupferschmidt 2012; Autier 2014). We have now some evidence that vitamin D status is a biomarker of health status (Skaaby 2016). It is likely that less healthy people are obese, less active, and more sunlight‐deprived than healthier people, and therefore have lower vitamin D status (Lucas 2005; Bolland 2006; Grey 2010; Autier 2016; Skaaby 2016). It seems that the cautionary tale of antioxidant supplements is reiterated (Garattini 2016). Current evidence does not support the use of vitamin D supplementation to prevent or cure chronic liver diseases. Results of ongoing randomised trials will help us further in resolving the vitamin D enigma. Until then, it is prudent to get vitamin D from sun exposure and from a balanced diet.