Vitamin D supplementation for chronic liver diseases in adults

Goran Bjelakovic; Dimitrinka Nikolova; Marko Bjelakovic; Christian Gluud

doi:10.1002/14651858.CD011564.pub2

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Figure 1

Study flow diagram

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Figure 2

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

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Figure 3

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

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Figure 4

Funnel plot of comparison: 1 Vitamin D versus placebo or no intervention, outcome: 1.1 All‐cause mortality.

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Figure 5

Trial Sequential Analysis on all‐cause mortality up to 1.4‐year follow‐up in 15 vitamin D trials, based on mortality rate in the control group of 10%, a relative risk reduction of 28% in the 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 (blue line) did not cross the trial sequential monitoring boundary for benefit or harm (red inward sloping lines) and did not enter the trial sequential monitoring area for futility (inner‐wedge with red outward sloping lines).

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Figure 6

Trial Sequential Analysis on rapid virological response in the two vitamin D trials was performed based on a mortality rate in the control group of 5%, a relative risk reduction (RRR) of 30% in the 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 11958 participants. The cumulative Z‐curve crossed the conventional monitoring boundary for benefit. The trial sequential monitoring boundary is ignored due to little information use (1.56%).

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Figure 7

Trial Sequential Analysis on early virological response in the two vitamin D trials was performed based on a mortality rate in the control group of 5%, a relative risk reduction (RRR) of 30% in the 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 11958 participants. The cumulative Z‐curve crossed the conventional monitoring boundary for benefit. The trial sequential monitoring boundary is ignored due to little information use (1.17%).

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Figure 8

Trial Sequential Analysis on sustained virological response in the five vitamin D trials was performed based on a mortality rate in the control group of 5%, a relative risk reduction (RRR) of 30% in the 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 69798 participants. The trial sequential monitoring boundary is ignored due to little information use (0.45%).

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Figure 9

Trial Sequential Analysis on acute cellular rejection in the one vitamin D trial was performed based on a mortality rate in the control group of 5%, a relative risk reduction (RRR) of 30% in the 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 11958 participants. The cumulative Z‐curve did not cross the conventional monitoring boundary. The trial sequential monitoring boundary is ignored due to little information use (0.84%).

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Analysis 1.1

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

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Analysis 1.2

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 2 All‐cause mortality ('best‐worst' case and 'worst‐best' case scenarios).

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Analysis 1.3

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 3 Liver‐related mortality.

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Analysis 1.4

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 4 Serious adverse events.

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Analysis 1.5

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 5 Non‐serious adverse events.

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Analysis 1.6

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 6 Failure of rapid virological response.

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Analysis 1.7

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 7 Failure of early virological response.

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Analysis 1.8

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 8 Failure of sustained virological response.

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Analysis 1.9

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 9 Acute cellular rejection in liver transplant recipients.

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Analysis 1.10

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 10 Vitamin D status (ng/mL).

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Analysis 1.11

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 11 Biochemical indices.

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Summary of findings for the main comparison. Vitamin D compared to placebo or no intervention for chronic liver diseases in adults

Vitamin D compared to placebo or no intervention for chronic liver diseases in adults
Patient or population: adults with chronic liver diseases. Setting: inpatients and outpatients from Austria, China, Egypt, Iran, Israel, Italy, Japan, USA. Intervention: vitamin D Comparison: placebo or no intervention
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (trials)	Quality of the evidence (GRADE)	Comments
	Risk with placebo or no intervention	Risk with vitamin D
All‐cause mortality at the end of follow‐up Follow‐up: 0.1 to 1.4, mean 0.6 years	Study population		OR 0.70 (0.09 to 5.38)	1034 (15 RCTs)	⊕⊝⊝⊝ Very low^1,2,3	Trial Sequential Analyses‐adjusted CI was 0.00 to 2534.
	4 per 1.000	3 per 1.000 (0 to 21)
Liver‐related mortality Follow‐up: mean 1 year	Study population		RR 1.62 (0.08 to 34.66)	18 (1 RCT)	⊕⊝⊝⊝ Very low^1,3	Due to few data, we did not conduct Trial Sequential Analysis which would only have revealed larger imprecision.
	0 per 1.000	0 per 1.000 (0 to 0)
Serious adverse events ‐ hypercalcaemia Follow‐up: mean 1 year	Study population		RR 5.00 (0.25 to 100.80)	76 (1 RCT)	⊕⊝⊝⊝ Very low^1,3	Due to few data, we did not conduct Trial Sequential Analysis which would only have revealed larger imprecision.
	0 per 1.000	0 per 1.000 (0 to 0)
Serious adverse events ‐ myocardial infarction Follow‐up: 0.2 to 1, mean 0.6 years	Study population		RR 0.75 (0.08 to 6.81)	86 (2 RCTs)	⊕⊝⊝⊝ Very low^1,3	Due to few data, we did not conduct Trial Sequential Analysis which would only have revealed larger imprecision.
	25 per 1.000	19 per 1.000 (2 to 170)
Serious adverse events ‐ thyroiditis Follow‐up: mean 0.2 years	Study population		RR 0.33 (0.01 to 7.91)	68 (1 RCT)	⊕⊝⊝⊝ Very low^1,3	Due to few data, we did not conduct Trial Sequential Analysis which would only have revealed larger imprecision.
	29 per 1.000	10 per 1.000 (0 to 233)
Failure of sustained virological response Follow‐up: 0.3 to 1.4, mean 0.9 years	Study population		RR 0.59 (0.28 to 1.21)	422 (5 RCTs)	⊕⊝⊝⊝ Very low ^1,2,3,6	The trial sequential monitoring boundary is ignored due to little information use (0.6%).
	465 per 1.000	275 per 1.000 (130 to 563)
Acute cellular rejection in liver transplant recipients Follow‐up: mean 0.08 years	Study population		RR 0.33 (0.04 to 2.62)	75 (1 RCT)	⊕⊝⊝⊝ Very low ^1,3,7	The trial sequential monitoring boundary is ignored due to little information use (0.84%).
	120 per 1.000	40 per 1.000 (5 to 314)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; RCT: randomised clinical trial; OR: Odds ratio.
GRADE Working Group grades of evidence High quality: this research provides a very good indication of the likely effect; the likelihood that the effect will be substantially different is low. Moderate quality: this research provides a good indication of the likely effect; the likelihood that the effect will be substantially different is moderate. Low quality: this research provides some indication of the likely effect; however, the likelihood that it will be substantially different is high. Very low quality: this research does not provide a reliable indication of the likely effect; the likelihood that the effect will be substantially different is very high.
¹ Downgraded one level due to risk of bias: all trials were at high risk of bias. ² Downgraded one level due to inconsistency of evidence: intertrial heterogeneity was significant. ³ Downgraded one level due to imprecision of evidence: Trial Sequential Analysis of vitamin D trials shows that we had insufficient information. ⁴ Downgraded one level due to indirectness of evidence: rapid virological response is a surrogate outcome. ⁵ Downgraded one level due to indirectness of evidence: early virological response is a surrogate outcome. ⁶ Downgraded one level due to indirectness of evidence: sustained virological response is a surrogate outcome. ⁷ Downgraded one level due to indirectness of evidence: acute cellular rejection is a surrogate outcome.

Summary of findings for the main comparison. Vitamin D compared to placebo or no intervention for chronic liver diseases in adults

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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	2	High	NI	72	44	47
Atsukawa 2016	No	Parallel	2	High	NI	115	50	64
Barchetta 2016	Yes	Parallel	2	High	PL	65	35	59
Esmat 2015	No	Parallel	2	High	NI	101	25	40
Foroughi 2016	Yes	Parallel	2	High	PL	60	52	48
Lorvand Amiri 2016	Yes	Parallel	3	High	PL	120	38	41
Mobarhan 1984	No	Parallel	3	High	NI	18	0	61
Nimer 2012	No	Parallel	2	High	NI	50	58	47
Pilz 2016	Yes	Parallel	2	High	PL	36	25	61
Sharifi 2014	No	Parallel	2	High	PL	60	51	60
Shiomi 1999a	No	Parallel	2	High	NI	76	66	61
Shiomi 1999b	No	Parallel	2	High	NI	34	100	56
Vosoghinia 2016	Yes	Parallel	2	High	NI	68	13	42
Xing 2013	No	Parallel	3	High	PL	75	17	48
Yokoyama 2014	No	Parallel	2	High	NI	84	49	59
n: number of participants; NI: no intervention; PL: placebo.

Table 1. Characteristics of included trials (I)

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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
Esmat 2015	Chronic hepatitis C genotype 4	Sustained virological response	No information	Egypt
Foroughi 2016	NAFLD	Liver steatosis, liver function	No	Iran
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
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
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
NAFLD: non‐alcoholic fatty liver disease.

Table 2. Characteristics of included trials (II)

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Table 3. Characteristics of included studies (III)

Study ID	Vitamin				Calcium (mg)	Regimen*	Treatment (weeks)	Follow‐up (weeks)	Cointervention
Study ID	D₃ (IU)	D₂ (IU)	25(OH)D (IU)	1,25(OH)₂D (µg)	Calcium (mg)	Regimen*	Treatment (weeks)	Follow‐up (weeks)	Cointervention
Abu‐Mouch 2011	2000	‐	‐	‐	‐	Daily	48	72	PEG‐INF, RBV
Atsukawa 2016	2000	‐	‐	‐	‐	Daily	16	16	PEG‐INF, RBV, SP
Barchetta 2016	2000	‐	‐	‐	‐	Daily	24	24	‐
Esmat 2015	2143	‐	‐	‐	‐	Weekly	48	72	PEG‐INF, RBV
Foroughi 2016	7143	‐	‐	‐	‐	Weekly	10	10	‐
Lorvand Amiri 2016	1000	‐	‐	‐	500	Daily	10	12	‐
Mobarhan 1984	‐	17,857	2400	‐	‐	Daily	52	52	‐
Nimer 2012	2000	‐	‐	‐	‐	Daily	24	48	PEG‐INF, RBV
Pilz 2016	2800	‐	‐	‐	‐	Daily	8	8	‐
Sharifi 2014	3571	‐	‐	‐	‐	Twice a week	16	16	‐
Shiomi 1999a	‐	‐	‐	1	‐	Daily	52	52	‐
Shiomi 1999b	‐	‐	‐	1	‐	Daily	52	52	‐
Vosoghinia 2016	1600	‐	‐	‐	‐	Daily	12	12	PEG‐INF, RBV
Xing 2013	‐	‐	‐	0.25	1000	Daily	4	4	‐
Yokoyama 2014	1000	‐	‐	‐	‐	Daily	16	24	PEG‐INF, RBV
* Vitamin D was administered orally in all trials. 1,25(OH)₂D: calcitriol; 25(OH)D: calcidiol; PEG‐INF: pegylated‐interferon; RBV: ribavirin; SP: simeprevir.

Table 3. Characteristics of included studies (III)

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Comparison 1. Vitamin D versus placebo or no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality Show forest plot	15	1034	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.70 [0.09, 5.38]

2 All‐cause mortality ('best‐worst' case and 'worst‐best' case scenarios) Show forest plot	15		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

2.1 'Best‐worst' case scenario	15	1034	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.11 [0.05, 0.24]
2.2 'Worst‐best' case scenario	15	1034	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.80 [3.67, 16.57]
3 Liver‐related mortality Show forest plot	1	18	Risk Ratio (M‐H, Random, 95% CI)	1.62 [0.08, 34.66]

4 Serious adverse events Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Hypercalcaemia	1	76	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.25, 100.80]
4.2 Myocardial infarction	2	86	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.08, 6.81]
4.3 Thyroiditis	1	68	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.91]
5 Non‐serious adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Glossitis	1	65	Risk Ratio (M‐H, Random, 95% CI)	3.70 [0.16, 87.58]
6 Failure of rapid virological response Show forest plot	2	187	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.52, 0.94]

7 Failure of early virological response Show forest plot	2	140	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.03, 0.33]

8 Failure of sustained virological response Show forest plot	5	422	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.28, 1.21]

9 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]

10 Vitamin D status (ng/mL) Show forest plot	6	424	Mean Difference (IV, Random, 95% CI)	17.24 [12.46, 22.02]

11 Biochemical indices Show forest plot	6		Mean Difference (IV, Random, 95% CI)	Subtotals only

11.1 Aspartate aminotransferase (IU/L)	6	313	Mean Difference (IV, Random, 95% CI)	‐1.40 [‐2.88, 0.08]
11.2 Alanine aminotransferase (IU/L)	6	313	Mean Difference (IV, Random, 95% CI)	‐0.52 [‐5.10, 4.06]
11.3 Alkaline phosphatases (IU/L)	2	96	Mean Difference (IV, Random, 95% CI)	7.39 [‐39.89, 54.67]
11.4 Gamma‐glutamyl transpeptidase (IU/L)	2	101	Mean Difference (IV, Random, 95% CI)	3.64 [0.33, 6.96]
11.5 Albumin (g/L)	2	48	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.40, 0.20]
11.6 Bilirubin (mg/dL)	2	48	Mean Difference (IV, Random, 95% CI)	0.38 [0.21, 0.55]
11.7 Triglyceride (mg/dL)	2	115	Mean Difference (IV, Random, 95% CI)	23.69 [‐13.90, 61.27]
11.8 Cholesterol (mg/dL)	1	55	Mean Difference (IV, Random, 95% CI)	2.75 [‐4.75, 10.25]
11.9 Calcium (mg/dL)	2	72	Mean Difference (IV, Random, 95% CI)	2.01 [‐0.53, 4.56]

Comparison 1. Vitamin D versus placebo or no intervention

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