Scolaris Content Display Scolaris Content Display

Cochrane Database of Systematic Reviews

Vitamin D supplementation for chronic liver diseases in adults

Información

DOI:
https://doi.org/10.1002/14651858.CD011564.pub3Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 25 agosto 2021see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:

  1. Grupo Cochrane de Hepatobiliar

Copyright:
  1. Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Cifras del artículo

Altmetric:

Citado por:

Citado 0 veces por enlace Crossref Cited-by

Contraer

Autores

  • Milica Bjelakovic

    Clinic of Gastroenterology and Hepatology, Clinical Centre Nis, Nis, Serbia

  • Dimitrinka Nikolova

    Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen, Denmark

  • Goran Bjelakovic

    Correspondencia a: Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia

    [email protected]

  • Christian Gluud

    Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen, Denmark

Contributions of authors

MB: took the lead in updating the review, performed data extraction, and drafted the review update.
DN: revised the protocol, performed data extraction, commented on and revised the review.
GB: initiated the review; drafted the protocol; performed the literature search, data extraction, and statistical analyses; updated and revised the review.
CG: revised the protocol, acted as arbiter for disagreements, and commented on and revised the review.

Sources of support

Internal sources

  • Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark

    Working place

External sources

  • Ministry of Education, Science and Technological Development of Republic of Serbia (Grant No: 451‐03‐9/2021‐14/200113), Serbia

    Salary

  • Medical Faculty, University of Nis, Internal project 66, Serbia

    No monetary support

  • Serbian Academy of Sciences and Arts ‐ branch in Nis Project O‐26‐20, Serbia

    No monetary support

Declarations of interest

MB: none known.
DN is the Managing Editor of the Cochrane Hepato‐Biliary Group. However, the peer review process was dealt with through staff within the Cochrane Central Editorial Service Team.
GB: none known.
CG: none known.

Acknowledgements

We thank Marija Bjelakovic and Marko Bjelakovic for their work on the review. They were co‐authors of previously published versions of this review (2015, Marija Bjelakovic; 2017, Marko Bjelakovic).

Cochrane Review Group funding acknowledgement: the Danish State is the largest single funder of the Cochrane Hepato‐Biliary Group through its investment in the Copenhagen Trial Unit, Centre for Clinical Intervention Research, the Capital Region, Rigshospitalet, Copenhagen, Denmark. Disclaimer: the views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or the Copenhagen Trial Unit.

Peer reviewers of the first review version: Sohail Mushtaq, UK; Tony Bruns, Germany
Peer review of this update: Maria G. Grammatikopoulou, Department of Nutritional Sciences & Dietetics, International Hellenic University, Greece (peer review of the update was manged by the Cochrane Central Editorial Service).
Contact Editor: Vanja Giljaca, UK
Cochrane Abdomen and Endocrine Network Associate Editor: Rachel Richardson, UK
Cochrane Abdomen and Endocrine Network and Sign‐off Editor: Cindy Farquhar, New Zealand
Copy‐editor: Lisa Winer, USA

Version history

Published

Title

Stage

Authors

Version

2021 Aug 25

Vitamin D supplementation for chronic liver diseases in adults

Review

Milica Bjelakovic, Dimitrinka Nikolova, Goran Bjelakovic, Christian Gluud

https://doi.org/10.1002/14651858.CD011564.pub3

2017 Nov 03

Vitamin D supplementation for chronic liver diseases in adults

Review

Goran Bjelakovic, Dimitrinka Nikolova, Marko Bjelakovic, Christian Gluud

https://doi.org/10.1002/14651858.CD011564.pub2

2015 Mar 04

Vitamin D supplementation for chronic liver diseases in adults

Protocol

Goran Bjelakovic, Dimitrinka Nikolova, Marija Bjelakovic, Christian Gluud

https://doi.org/10.1002/14651858.CD011564

Differences between protocol and review

  • We updated the Methods section of the protocol part of the review, as follows.

    • We removed the sentence "We included such studies only for assessment of harms." from the first two risk of bias domains.

    • Types of outcome measures. We modified and changed the order of outcomes. In addition, we merged secondary and exploratory outcomes due to updated editorial recommendations.

    • We added subgroup analysis according to participant's vitamin D status at entry, comparing participants with normal vitamin D levels at entry to those with decreased levels, and comparing different forms of vitamin D (vitamin D3, vitamin D2, 25‐dihydroxyvitamin D, and 1,25‐dihydroxyvitamin D).

    • We increased the number of biochemical indices to mirror the expanding number of outcomes assessed in the included trials.

    • Data synthesis. In our Trial Sequential Analysis, the diversity‐adjusted required information size was based on the event proportion in the control group; assumption of a plausible relative risk reduction of 20%; a risk of type I error of 1.25% for the first seven outcomes; a risk of type II error of 10%; and the observed diversity of the included trials in the meta‐analysis (Jakobsen 2014a; Wetterslev 2017). We reduced the relative risk reduction from 28% in our primary analysis to 20% in the current update given that the higher number seems unrealistic, and we could not find any evidence supporting it. The alpha level in our review update has decreased to 1.25% in order to account for multiplicity, assuming seven outcomes in the summary of findings table (Jakobsen 2014a).

    • We used Trial Sequential Analysis as sensitivity analysis to assess imprecision.

  • Milica Bjelakovic joined the team of authors during the preparation of the review update.

Notes

Cochrane Reviews can be expected to have a high percentage of overlap in the Methods section due to the use of standardised methods. In addition, overlap may be observed across some of our protocols and reviews, as they share at least three common authors.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Adult; Female; Humans; Male; Middle Aged;

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Study flow diagram.

Figuras y tablas -
Figure 1

Study flow diagram.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figuras y tablas -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figuras y tablas -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Ir a la figura de la revisiónAbrir en una pestaña nueva

All‐cause mortality.Trial Sequential Analysis was performed based on a mortality in the control group of 2%, a relative risk reduction of 20% in the experimental intervention group, a type I error of 1.25%, and a type II error of 10% (90% power). There was no diversity. The required information size was 63,116 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundary for benefit or harm after the 27th trial. The trial sequential monitoring boundaries were ignored due to little information (3.14%). The blue line represents the cumulative Z‐score of the meta‐analysis. The green dotted lines represent the conventional statistical boundaries.

Figuras y tablas -
Figure 4

All‐cause mortality.

Trial Sequential Analysis was performed based on a mortality in the control group of 2%, a relative risk reduction of 20% in the experimental intervention group, a type I error of 1.25%, and a type II error of 10% (90% power). There was no diversity. The required information size was 63,116 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundary for benefit or harm after the 27th trial. The trial sequential monitoring boundaries were ignored due to little information (3.14%). The blue line represents the cumulative Z‐score of the meta‐analysis. The green dotted lines represent the conventional statistical boundaries.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Rapid virological response.Trial Sequential Analysis was performed based on a failure of rapid virological response in the control group of 53%, a relative risk reduction (RRR) of 20% in the intervention group, a type I error of 1.25%, and a type II error of 10% (90% power). There was no diversity. The required information size was 1269 participants. The cumulative Z‐curve (blue line) crossed the conventional monitoring boundary for benefit but did not cross the trial sequential monitoring boundary for benefit (red down‐sloping line). The blue line represents the cumulative Z‐score of the meta‐analysis. The green dotted lines represent the conventional statistical boundaries. The red inward‐sloping lines represent the trial sequential monitoring boundaries.

Figuras y tablas -
Figure 5

Rapid virological response.

Trial Sequential Analysis was performed based on a failure of rapid virological response in the control group of 53%, a relative risk reduction (RRR) of 20% in the intervention group, a type I error of 1.25%, and a type II error of 10% (90% power). There was no diversity. The required information size was 1269 participants. The cumulative Z‐curve (blue line) crossed the conventional monitoring boundary for benefit but did not cross the trial sequential monitoring boundary for benefit (red down‐sloping line). The blue line represents the cumulative Z‐score of the meta‐analysis. The green dotted lines represent the conventional statistical boundaries. The red inward‐sloping lines represent the trial sequential monitoring boundaries.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Early virological response.Trial Sequential Analysis was performed based on failure of early virological response in the control group of 34%, a relative risk reduction of 20% in the intervention group, a type I error of 1.25%, and a type II error of 10% (90% power). The diversity was 88%. The required information size was 21,306 participants. The cumulative Z‐curve (blue line) crossed the conventional monitoring boundary for benefit. The trial sequential monitoring boundary was ignored due to little information (1.48%). The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries.

Figuras y tablas -
Figure 6

Early virological response.

Trial Sequential Analysis was performed based on failure of early virological response in the control group of 34%, a relative risk reduction of 20% in the intervention group, a type I error of 1.25%, and a type II error of 10% (90% power). The diversity was 88%. The required information size was 21,306 participants. The cumulative Z‐curve (blue line) crossed the conventional monitoring boundary for benefit. The trial sequential monitoring boundary was ignored due to little information (1.48%). The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Sustained virological response.Trial Sequential Analysis was performed based on failure of sustained virological response in the control group of 48%, a relative risk reduction (RRR) of 20% in the intervention group, a type I error of 1.25%, and a type II error of 10% (90% power). Diversity was 80%. The required information size was 7570 participants. The cumulative Z‐curve (blue line) crossed the conventional monitoring boundary for benefit. However, it did not cross any of the monitoring boundaries for benefit, harm, or futility. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries. The red inward‐sloping lines represent the trial sequential monitoring boundaries for benefit and harm.

Figuras y tablas -
Figure 7

Sustained virological response.

Trial Sequential Analysis was performed based on failure of sustained virological response in the control group of 48%, a relative risk reduction (RRR) of 20% in the intervention group, a type I error of 1.25%, and a type II error of 10% (90% power). Diversity was 80%. The required information size was 7570 participants. The cumulative Z‐curve (blue line) crossed the conventional monitoring boundary for benefit. However, it did not cross any of the monitoring boundaries for benefit, harm, or futility. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries. The red inward‐sloping lines represent the trial sequential monitoring boundaries for benefit and harm.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 1: 1.1 All‐cause mortality

Figuras y tablas -
Analysis 1.1

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 1: 1.1 All‐cause mortality

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 2: 1.1 All‐cause mortality according to vested interest

Figuras y tablas -
Analysis 1.2

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 2: 1.1 All‐cause mortality according to vested interest

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 3: All‐cause mortality according to vitamin D status at entry

Figuras y tablas -
Analysis 1.3

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 3: All‐cause mortality according to vitamin D status at entry

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 4: All‐cause mortality according to form of vitamin D

Figuras y tablas -
Analysis 1.4

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 4: All‐cause mortality according to form of vitamin D

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 5: All‐cause mortality (best‐worst‐case and worst‐best‐case scenarios)

Figuras y tablas -
Analysis 1.5

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 5: All‐cause mortality (best‐worst‐case and worst‐best‐case scenarios)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 6: Liver‐related mortality

Figuras y tablas -
Analysis 1.6

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 6: Liver‐related mortality

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 7: Serious adverse events

Figuras y tablas -
Analysis 1.7

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 7: Serious adverse events

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 8: Liver‐related morbidity

Figuras y tablas -
Analysis 1.8

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 8: Liver‐related morbidity

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 9: Health‐related quality of life

Figuras y tablas -
Analysis 1.9

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 9: Health‐related quality of life

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 10: Non‐serious adverse events

Figuras y tablas -
Analysis 1.10

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 10: Non‐serious adverse events

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 11: Failure of rapid virological response

Figuras y tablas -
Analysis 1.11

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 11: Failure of rapid virological response

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 12: Failure of early virological response

Figuras y tablas -
Analysis 1.12

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 12: Failure of early virological response

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 13: Failure of sustained virological response

Figuras y tablas -
Analysis 1.13

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 13: Failure of sustained virological response

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 14: Acute cellular rejection in liver transplant recipients

Figuras y tablas -
Analysis 1.14

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 14: Acute cellular rejection in liver transplant recipients

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 15: Vitamin D status (ng/mL)

Figuras y tablas -
Analysis 1.15

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 15: Vitamin D status (ng/mL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 16: Bone mineral density (g/cm)

Figuras y tablas -
Analysis 1.16

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 16: Bone mineral density (g/cm)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 17: Aspartate aminotransferase (IU/L)

Figuras y tablas -
Analysis 1.17

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 17: Aspartate aminotransferase (IU/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 18: Alanine aminotransferase (IU/L

Figuras y tablas -
Analysis 1.18

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 18: Alanine aminotransferase (IU/L

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 19: Alkaline phosphatases (IU/L)

Figuras y tablas -
Analysis 1.19

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 19: Alkaline phosphatases (IU/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 20: Gamma‐glutamyl transpeptidase (IU/L)

Figuras y tablas -
Analysis 1.20

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 20: Gamma‐glutamyl transpeptidase (IU/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 21: Bilirubin (mg/dL)

Figuras y tablas -
Analysis 1.21

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 21: Bilirubin (mg/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 22: Triglyceride (mg/dL)

Figuras y tablas -
Analysis 1.22

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 22: Triglyceride (mg/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 23: Cholesterol (mg/dL)

Figuras y tablas -
Analysis 1.23

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 23: Cholesterol (mg/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 24: LDL cholesterol (mg/dL)

Figuras y tablas -
Analysis 1.24

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 24: LDL cholesterol (mg/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 25: Albumin (g/L)

Figuras y tablas -
Analysis 1.25

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 25: Albumin (g/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 26: HDL cholesterol (mg/dL)

Figuras y tablas -
Analysis 1.26

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 26: HDL cholesterol (mg/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 27: Calcium (mg/dL)

Figuras y tablas -
Analysis 1.27

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 27: Calcium (mg/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 28: Glucose (mg/dL)

Figuras y tablas -
Analysis 1.28

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 28: Glucose (mg/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 29: Phosphorus (mg/dL)

Figuras y tablas -
Analysis 1.29

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 29: Phosphorus (mg/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 30: Adiponectin (µg/mL)

Figuras y tablas -
Analysis 1.30

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 30: Adiponectin (µg/mL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 31: Insulin (mIU/mL)

Figuras y tablas -
Analysis 1.31

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 31: Insulin (mIU/mL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 32: Parathyroid hormone (pg/mL)

Figuras y tablas -
Analysis 1.32

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 32: Parathyroid hormone (pg/mL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 33: C‐reactive protein (mg/L)

Figuras y tablas -
Analysis 1.33

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 33: C‐reactive protein (mg/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva
Summary of findings 1. Vitamin D compared with placebo or no intervention for chronic liver diseases in adults

Vitamin D compared with placebo or no intervention for chronic liver diseases in adults

Patient or population: people with chronic liver diseases
Setting: in‐ and outpatients
Intervention: vitamin D
Comparison: placebo or no intervention

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(trials)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo or no intervention

Risk with vitamin D

All‐cause mortality

Follow‐up: mean 7 months (1 to 18 months)

Study population

RR 0.86
(0.51 to 1.45)

1979
(27 RCTs)

⊕⊝⊝⊝
very low 1

21 per 1000

18 per 1000
(11 to 30)

Liver‐related mortality

Follow‐up: 12 months

Study population

RR 1.62
(0.08 to 34.66)

18
(1 RCT)

⊕⊝⊝⊝
very low 2

No information was available to calculate absolute effects.

‐

‐

Serious adverse events

Follow‐up: mean 10.5 months (6 to 12 months)

Study population

‐

‐

⊕⊝⊝⊝
very low 3

Several serious adverse events were reported: hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants); myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants); thyroiditis (RR 0.33, 95% CI 0.01 to 7.91; 1 trial; 68 participants); circular haemorrhoidal prolapse (RR 3.00, 95% CI 0.14 to 65.9; 1 trial; 20 participants); bronchopneumonia (RR 0.33, 95% CI 0.02 to 7.32; 1 trial; 20 participants).

Liver‐related morbidity

Study population

‐

(0 RCTs)

‐

‐

‐

Health‐related quality of life

Study population

‐

(0 RCTs)

‐

‐

‐

Non‐serious adverse events

Follow‐up: mean 7 months (3 to 12 months)

Study population

‐

‐

⊕⊝⊝⊝
very low 3

1 trial reported 1 single non‐serious adverse event, and another trial reported 16 single non‐serious adverse events, for a total of 17 types of non‐serious adverse events.

Failure of sustained virological response

Follow‐up: mean 16 months (6 to 18 months)

Study population

RR 0.65
(0.42 to 1.01)

630
(7 RCTs)

⊕⊝⊝⊝
very low4

484 per 1000

315 per 1000
(203 to 489)

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RCT: randomised clinical trial; RR: risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded because of risk of bias (1 level) (all trials were at high risk of bias); and imprecision (2 levels) (few events, and the optimal information size of 63,116 participants (based on a proportion of 2% in the control group, a relative risk reduction of 20%, an alpha of 1.25%, and a beta of 10%) was not met; wide CI which included both benefits and harms).
2Downgraded because of risk of bias (1 level) (the trial was at high risk of bias); and imprecision (2 levels) (very few events, and wide CI which included both benefits and harms).
3Downgraded because of risk of bias (1 level) (all trials were at high risk of bias); and imprecision (2 levels) (very few events, and wide CI which included both benefits and harms).
4Downgraded because of risk of bias (1 level) (all trials were at high risk of bias); imprecision (2 levels) (the optimal information size of 7570 participants (based on a proportion of 48% in the control group, a relative risk reduction of 20%, an alpha of 1.25%, and a beta of 10%) was not met); inconsistency (1 level) (considerable heterogeneity); and indirectness (3 levels)(sustained virological response is a surrogate outcome).

Figuras y tablas -
Summary of findings 1. Vitamin D compared with placebo or no intervention for chronic liver diseases in adults
Ir a la tabla de la revisión
Table 1. Characteristics of included trials (I)

Study ID

Protocol

Design

Groups

Bias
risk

Blinding

Participants
(n)

Women
(%)

Mean
age (years)

Abu‐Mouch 2011

Yes

Parallel group

2

High

NI

72

44

47

Atsukawa 2016

No

Parallel group

2

High

NI

115

50

64

Barchetta 2016

Yes

Parallel group

2

High

PL

65

35

59

Behera 2018

Yes

Parallel group

2

High

NI

60

40

41

Boonyagard 2016

No

Parallel group

2

High

PL

60

‐

‐

Dabbaghmanesh 2018

Yes

Parallel group

2

High

PL

106

59

45

Esmat 2015

No

Parallel group

2

High

NI

101

25

40

Foroughi 2016

Yes

Parallel group

2

High

PL

60

52

48

Geier 2018

Yes

Parallel group

2

High

PL

20

‐

44

Hosseini 2018

Yes

Parallel group

2

High

NI

82

100

34

Hussain 2019

No

Parallel group

2

High

PL

109

36

28

Jeong 2019

Yes

Parallel group

2

High

NI

148

49

52

Jha 2017

No

Parallel group

2

High

NI

101

24

45

Komolmit 2017a

Yes

Parallel group

2

High

PL

80

46

52

Komolmit 2017b

Yes

Parallel group

2

High

PL

58

38

50

Lorvand Amiri 2016

Yes

Parallel group

3

High

PL

120

38

41

Mobarhan 1984

No

Parallel group

3

High

NI

18

0

61

Nimer 2012

No

Parallel group

2

High

NI

50

58

47

Pilz 2016

Yes

Parallel group

2

High

PL

36

25

61

Sakpal 2017

No

Parallel group

2

High

NI

81

32

38

Sharifi 2014

No

Parallel group

2

High

PL

60

51

60

Shiomi 1999a

No

Parallel group

2

High

NI

76

66

61

Shiomi 1999b

No

Parallel group

2

High

NI

34

100

56

Taghvaei 2018

Yes

Parallel group

2

High

NI

40

50

42

Vosoghinia 2016

Yes

Parallel group

2

High

NI

68

13

42

Xing 2013

No

Parallel group

3

High

PL

75

17

48

Yokoyama 2014

No

Parallel group

2

High

NI

84

49

59

n: number of participants
NI: no intervention
PL: placebo

Figuras y tablas -
Table 1. Characteristics of included trials (I)
Ir a la tabla de la revisión
Table 2. Characteristics of included trials (II)

Study ID

Participants

Outcome measures

Sponsor

Country

Abu‐Mouch 2011

Chronic hepatitis C genotype 1

Sustained virological response

No information

Israel

Atsukawa 2016

Chronic hepatitis C genotype 1

Sustained virological response

No information

Japan

Barchetta 2016

NAFLD

Liver steatosis, liver function

No

Italy

Behera 2018

Chronic hepatitis C genotype 1, 4

Sustained virological response

No

India

Boonyagard 2016

NAFLD

Biochemical indices, HOMA, FibroScan measurement

No information

Thailand

Dabbaghmanesh 2018

NAFLD

Biochemical indices

No

Iran

Esmat 2015

Chronic hepatitis C genotype 4

Sustained virological response

No information

Egypt

Foroughi 2016

NAFLD

Liver steatosis, liver function

No

Iran

Geier 2018

NAFLD (NASH)

Liver steatosis, liver function

Yes

Switzerland

Hosseini 2018

NAFLD

Serum 25‐hydroxyvitamin D, adiponectin, HOMA‐IR, liver enzymes, and change in grade of NAFLD

No

Iran

Hussain 2019

NAFLD

Body weight, BMI, insulin resistance, dyslipidaemia, hepatic enzymes, CRP, and adiponectin

No information

Pakistan

Jeong 2019

Chronic hepatitis C genotype 1, 2, 3

Sustained virological response

No information

Republic of Korea

Jha 2017

Liver cirrhosis

Mortality

No information

India

Komolmit 2017a

Chronic hepatitis C

Serum levels of T‐helper cells associated cytokines

No

Thailand

Komolmit 2017b

Chronic hepatitis C

Serum fibrotic markers

No

Thailand

Lorvand Amiri 2016

NAFLD

Liver function, body fat

No

Iran

Mobarhan 1984

Liver cirrhosis

Bone mineral density

Yes

USA

Nimer 2012

Chronic hepatitis C genotype 2 or 3

Sustained virological response

No information

Israel

Pilz 2016

Liver cirrhosis

Vitamin D status, liver function

No

Austria

Sakpal 2017

NAFLD

Insulin resistance and serum ALT

No

India

Sharifi 2014

NAFLD

Liver function, insulin resistance index

No

Iran

Shiomi 1999a

Liver cirrhosis

Bone mineral density

No information

Japan

Shiomi 1999b

Primary biliary cirrhosis

Bone mineral density

No information

Japan

Taghvaei 2018

NAFLD

Biochemical indices, liver steatosis

No information

Iran

Vosoghinia 2016

Chronic hepatitis C genotype 1, 2, 3, 4

Early virological response

No

Iran

Xing 2013

Liver transplant recipients

Acute cellular rejection rate

No

China

Yokoyama 2014

Chronic hepatitis C genotype 1

Sustained virological response

No information

Japan

ALT: alanine aminotransferase
BMI: body mass index
CRP: C‐reactive protein
HOMA‐IR: homeostatic model assessment for insulin resistance
NAFLD: non‐alcoholic fatty liver disease
NASH: non‐alcoholic steatohepatitis

Figuras y tablas -
Table 2. Characteristics of included trials (II)
Ir a la tabla de la revisión
Table 3. Characteristics of included studies (III)

Study ID

Vitamin

Calcium
(mg)

Route

Regimen

Treatment
(weeks)

Follow‐up
(weeks)

Co‐intervention

D3
(IU)

D2
(IU)

25(OH)D
(IU)

1,25(OH)2D
(µg)

Abu‐Mouch 2011

2000

‐

‐

‐

‐

Orally

Daily

48

72

PEG‐IFN, RBV

Atsukawa 2016

2000

‐

‐

‐

‐

Orally

Daily

16

24

PEG‐IFN, RBV, SP

Barchetta 2016

2000

‐

‐

‐

‐

Orally

Daily

24

24

‐

Behera 2018

2000

‐

‐

‐

‐

Orally

Daily

48

48

PEG‐IFN, RBV

Boonyagard 2016

‐

‐

‐

‐

‐

Orally

Daily

20

20

Dabbaghmanesh 2018

50,000

‐

‐

0.25

‐

Orally

Weekly and daily

12

12

Esmat 2015

2143

‐

‐

‐

‐

Orally

Weekly

48

72

PEG‐IFN, RBV

Foroughi 2016

7143

‐

‐

‐

‐

Orally

Weekly

10

10

‐

Geier 2018

2100

‐

‐

‐

‐

Orally

Daily

48

48

Hosseini 2018

600,000

‐

‐

‐

‐

Intramuscularly

Single dose

Single dose

4

Vitamin E 400 IU/day

Hussain 2019

50,000

‐

‐

‐

‐

Orally

Weekly

12

12

Jeong 2019

800

‐

‐

‐

‐

Orally

Daily

24, 48

48, 72

PEG‐IFN, RBV

Jha 2017

300,000; 800

‐

‐

‐

1000

Intramuscularly and orally

Single dose; daily

24

24

Komolmit 2017a

‐

60,000; 80,000; 100,000

‐

‐

‐

Orally

Weekly

6

6

Komolmit 2017b

‐

60,000; 80,000; 100,000

‐

‐

‐

Orally

Weekly

6

6

Lorvand Amiri 2016

1000

‐

‐

‐

500

Orally

Daily

10

12

‐

Mobarhan 1984

‐

17,857

2400

‐

‐

Orally

Daily

52

52

‐

Nimer 2012

2000

‐

‐

‐

‐

Orally

Daily

24

48

PEG‐IFN, RBV

Pilz 2016

2800

‐

‐

‐

‐

Orally

Daily

8

8

‐

Sakpal 2017

600,000

‐

‐

‐

‐

Intramuscularly

Single dose

Single dose

24

Sharifi 2014

3571

‐

‐

‐

‐

Orally

Twice a week

16

16

‐

Shiomi 1999a

‐

‐

‐

1

‐

Orally

Daily

52

52

‐

Shiomi 1999b

‐

‐

‐

1

‐

Orally

Daily

52

52

‐

Taghvaei 2018

50,000

‐

‐

‐

‐

Orally

Weekly

12

72

Lifestyle modification

Vosoghinia 2016

1600

‐

‐

‐

‐

Orally

Daily

12

12

PEG‐IFN, RBV

Xing 2013

‐

‐

‐

0.25

1000

Orally

Daily

4

4

‐

Yokoyama 2014

1000

‐

‐

‐

‐

Orally

Daily

16

24

PEG‐IFN, RBV

1,25(OH)2D: calcitriol
25(OH)D: calcidiol
IU: international unit
PEG‐IFN: pegylated‐interferon
RBV: ribavirin
SP: simeprevir

Figuras y tablas -
Table 3. Characteristics of included studies (III)
Ir a la tabla de la revisión
Comparison 1. Vitamin D versus placebo or no intervention

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 1.1 All‐cause mortality Show forest plot

27

1979

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.51, 1.45]

1.1.1 Non‐alcoholic fatty liver disease

11

803

Risk Ratio (M‐H, Random, 95% CI)

Not estimable

1.1.2 Chronic hepatitis C

10

836

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 3.13]

1.1.3 Liver cirrhosis

5

265

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.53, 1.55]

1.1.4 Liver transplant recipients

1

75

Risk Ratio (M‐H, Random, 95% CI)

Not estimable

1.2 1.1 All‐cause mortality according to vested interest Show forest plot

27

1979

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.51, 1.45]

1.2.1 Trials with vested interest

2

38

Risk Ratio (M‐H, Random, 95% CI)

2.69 [0.15, 48.64]

1.2.2 Trials without vested interest

25

1941

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.48, 1.41]

1.3 All‐cause mortality according to vitamin D status at entry Show forest plot

27

1979

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.51, 1.45]

1.3.1 Normal vitamin D status

8

549

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 3.13]

1.3.2 Low vitamin D status

19

1430

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.53, 1.55]

1.4 All‐cause mortality according to form of vitamin D Show forest plot

26

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.4.1 Vitamin D 3

20

1578

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.48, 1.41]

1.4.2 Vitamin D 2

3

150

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.15, 61.74]

1.4.3 1,25‐dihydroxyvitamin D

4

291

Risk Ratio (M‐H, Random, 95% CI)

Not estimable

1.4.4 25‐hydroxyvitamin D

1

12

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.15, 61.74]

1.5 All‐cause mortality (best‐worst‐case and worst‐best‐case scenarios) Show forest plot

24

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.5.1 Best‐worst‐case scenario

24

1737

Risk Ratio (M‐H, Random, 95% CI)

0.14 [0.06, 0.30]

1.5.2 Worst‐best‐case scenario

24

1737

Risk Ratio (M‐H, Random, 95% CI)

7.95 [3.55, 17.77]

1.6 Liver‐related mortality Show forest plot

1

18

Risk Ratio (M‐H, Random, 95% CI)

1.62 [0.08, 34.66]

1.7 Serious adverse events Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.7.1 Hypercalcaemia

1

76

Risk Ratio (M‐H, Random, 95% CI)

5.00 [0.25, 100.80]

1.7.2 Myocardial infarction

2

86

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.08, 6.81]

1.7.3 Thyroiditis

1

68

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 7.91]

1.7.4 Circular haemorrhoidal prolapse

1

20

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.14, 65.90]

1.7.5 Bronchopneumonia

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.02, 7.32]

1.8 Liver‐related morbidity Show forest plot

0

0

Risk Ratio (M‐H, Random, 95% CI)

Not estimable

1.9 Health‐related quality of life Show forest plot

0

0

Risk Ratio (M‐H, Random, 95% CI)

Not estimable

1.10 Non‐serious adverse events Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.10.1 Glossitis

1

65

Risk Ratio (M‐H, Random, 95% CI)

3.70 [0.16, 87.58]

1.10.2 Depression

1

20

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.14, 65.90]

1.10.3 Lower back pain

1

20

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.14, 65.90]

1.10.4 Abdominal bloating

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.02, 7.32]

1.10.5 Cold

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.02, 7.32]

1.10.6 Constipation

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.02, 7.32]

1.10.7 Sore throat

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.02, 7.32]

1.10.8 Sour taste in mouth

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.02, 7.32]

1.10.9 Contused lacerated wound

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.02, 7.32]

1.10.10 Multiple white matter lesions

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.02, 7.32]

1.10.11 Gastro‐oesophageal reflux

1

20

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.14, 65.90]

1.10.12 Abdominal menstrual cramps

1

20

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.14, 65.90]

1.10.13 Tubular colon adenoma

1

20

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.14, 65.90]

1.10.14 Gastric motility disturbance

1

20

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.14, 65.90]

1.10.15 Irritable bowel syndrome

1

20

Risk Ratio (M‐H, Random, 95% CI)

5.00 [0.27, 92.62]

1.10.16 Knee pain

1

20

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.14, 65.90]

1.10.17 Severe allergy

1

109

Risk Ratio (M‐H, Random, 95% CI)

5.09 [0.25, 103.64]

1.11 Failure of rapid virological response Show forest plot

3

247

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.60, 0.95]

1.12 Failure of early virological response Show forest plot

4

315

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.11, 1.00]

1.13 Failure of sustained virological response Show forest plot

7

630

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.42, 1.01]

1.14 Acute cellular rejection in liver transplant recipients Show forest plot

1

75

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 2.62]

1.15 Vitamin D status (ng/mL) Show forest plot

15

1078

Mean Difference (IV, Random, 95% CI)

18.49 [14.52, 22.47]

1.16 Bone mineral density (g/cm) Show forest plot

1

18

Mean Difference (IV, Random, 95% CI)

0.15 [0.04, 0.26]

1.17 Aspartate aminotransferase (IU/L) Show forest plot

12

774

Mean Difference (IV, Random, 95% CI)

‐1.75 [‐5.41, 1.91]

1.18 Alanine aminotransferase (IU/L Show forest plot

13

855

Mean Difference (IV, Random, 95% CI)

‐2.30 [‐7.60, 3.00]

1.19 Alkaline phosphatases (IU/L) Show forest plot

6

344

Mean Difference (IV, Random, 95% CI)

‐0.95 [‐15.10, 13.20]

1.20 Gamma‐glutamyl transpeptidase (IU/L) Show forest plot

4

227

Mean Difference (IV, Random, 95% CI)

‐2.69 [‐5.26, ‐0.11]

1.21 Bilirubin (mg/dL) Show forest plot

3

74

Mean Difference (IV, Random, 95% CI)

0.32 [0.00, 0.63]

1.22 Triglyceride (mg/dL) Show forest plot

5

460

Mean Difference (IV, Random, 95% CI)

11.27 [‐10.99, 33.53]

1.23 Cholesterol (mg/dL) Show forest plot

4

400

Mean Difference (IV, Random, 95% CI)

3.51 [‐2.83, 9.85]

1.24 LDL cholesterol (mg/dL) Show forest plot

4

400

Mean Difference (IV, Random, 95% CI)

‐0.97 [‐8.70, 6.76]

1.25 Albumin (g/L) Show forest plot

3

74

Mean Difference (IV, Random, 95% CI)

‐1.18 [‐2.96, 0.59]

1.26 HDL cholesterol (mg/dL) Show forest plot

4

400

Mean Difference (IV, Random, 95% CI)

1.14 [‐0.64, 2.92]

1.27 Calcium (mg/dL) Show forest plot

7

423

Mean Difference (IV, Random, 95% CI)

0.04 [‐0.12, 0.19]

1.28 Glucose (mg/dL) Show forest plot

6

469

Mean Difference (IV, Random, 95% CI)

1.44 [‐5.05, 7.94]

1.29 Phosphorus (mg/dL) Show forest plot

4

307

Mean Difference (IV, Random, 95% CI)

0.17 [‐0.16, 0.50]

1.30 Adiponectin (µg/mL) Show forest plot

4

276

Mean Difference (IV, Random, 95% CI)

1.02 [‐0.27, 2.30]

1.31 Insulin (mIU/mL) Show forest plot

6

428

Mean Difference (IV, Random, 95% CI)

0.03 [‐1.15, 1.21]

1.32 Parathyroid hormone (pg/mL) Show forest plot

2

118

Mean Difference (IV, Random, 95% CI)

‐15.18 [‐38.54, 8.18]

1.33 C‐reactive protein (mg/L) Show forest plot

4

254

Mean Difference (IV, Random, 95% CI)

‐0.50 [‐0.93, ‐0.07]
Figuras y tablas -
Comparison 1. Vitamin D versus placebo or no intervention
Ir a la tabla de la revisión