Probiotics Are Helpful in Hepatic Encephalopathy: A Meta-analysis of Randomized Trials

Sammy Saab; Duminda Suraweera; Jennifer Au; Elena G. Saab; Tori S. Alper; Myron J. Tong

Disclosures

Liver International. 2016;36(7):986-993. 

In This Article

Results

Fourteen studies were included in the meta-analysis and are summarized in Table 1. Four studies compared the use of probiotics with lactulose[22–25] and seven studies compared the use of probiotics with placebo.[26–32] In three studies, there were multiple comparisons using probiotics, lactulose and placebo.[33–35] Most of the studies were conducted in India[23,25,27,29,30,32–34] (Table 2). The remaining studies were conducted in China, Italy, USA, Israel, Egypt and Iran.[22,24,26,28,31,35] The most common probiotic used in the studies wasVSL#3.[25,29,32,35] VSL#3 contains four strains of lactobacilli, three strains of Bifidobacteria and 1 strain Streptococcus thermophilus. The rest of the studies used unique probiotic combinations, usually with lactobacillus[22,24,26,28,31,35] (Table 2).

The duration of treatment varied from 1 to 12 months. In most studies, patients were treated for 3 months or less.[22–27,30–33,35] Treatment duration was 6 months in two studies[28,29] and 12 months in one study.[34]

Mortality

Information on mortality comparing probiotic vs placebo/no treatment or lactulose was available in 10 studies.[22,24,25,29–35] Overall there was no difference in survival. For instance, OR was 1.07 (95% CI: 0.47–2.44, P = 0.88) in the analysis of six studies comparing the use of probiotics with lactulose.[22,24,25,33–35] There was no significant heterogeneity in the analysis (P = 0.27, I 2 = 17%). Similarly, in the seven studies comparing the use probiotics with no treatment/placebo, the OR was 0.699 (95% CI: 0.42–1.14, P = 0.15).[29–35] Again there was no significant heterogeneity in the analysis (P = 0.97, I 2 = 0%).

Minimal Hepatic Encephalopathy

Improvement in MHE was generally assessed through a combination of instruments and psychometric tests in nine studies.[23,25–28,30,31,33,35] The authors of several studies utilized alternative tests if patients were illiterate.[30,33] Although there was no difference between patients treated with probiotics vs lactulose (OR: 0.81, 95% CI: 0.52–1.27, P = 0.35),[23,25,27,35] there was a significantly greater likelihood of MHE improvement with probiotics vs no treatment/placebo (OR: 3.91, 95% CI: 2.25–6.80, P < 0.00001; Fig. 2).[23,25–28,30,31,33,35] In the seven studies comparing the use of the probiotics to no treatment, 38% (66/174) of the patients who received probiotics had improvement of MHE in contrast to 16% (28/178) in the placebo arm. There was no significant heterogeneity in the analysis (P = 0.20, I 2 = 33%).

Figure 2.

Forest plot on improvement on minimal hepatic encephalopathy comparing probiotics and no treatment/placebo. CI, confidence interval; M-H, Mantel-Haenszel.

Hospitalizations

Five studies compared hospitalization rates between patients who were treated with probiotics vs no treatment/placebo or lactulose.[24,28,29,33,34] Reasons for admission were generally liver related, but not necessarily because of hepatic encephalopathy. The odds of hospitalization were significant when comparing probiotics and no treatment/placebo (OR: 0.53, 95% CI: 0.33 to 0.86, P = 0.01; Fig. 3).[28,29,33,34] The hospitalization rate was 22% (41/188) in the probiotic group, and 33% (62/187) in the placebo group. There was no significant heterogeneity in the analysis (P = 0.69, I2 = 0%). In contrast, there was no difference in hospitalization between the probiotic and lactulose groups (OR: 1.02, 95% CI: 0.52–1.99, P = 0.96).[24,33,34]

Figure 3.

Forest plot on hospitalization comparing probiotics and no treatment/placebo. CI, confidence interval; M-H, Mantel-Haenszel.

Progression to Overt Hepatic Encephalopathy

Ten studies assessed the progression to OHE in patients with minimal encephalopathy.[22,24,25,28,29,31–35] The definition of OHE differed among the studies. Most studies based the diagnosis from objective criteria such as PHES scoring or the West Haven criteria.[24,25,29,32,34] One study did not specifically mention the criteria utilized to diagnose OHE.[33] The difference in the likelihood of progression to OHE in patients with MHE or worsening OHE in patients with existing diagnosis was statistically significant in the analyses comparing probiotics and no treatment/placebo (OR: 0.40, 95% CI: 0.26–0.60, P < 0.0001; Fig. 4);[28,29,31–35] 17% (55/317) and 32% (95/294) of the patients treated with probiotics and placebo or no treatment, respectively, developed OHE. There was no significant heterogeneity in the analysis (P = 0.82, I 2 = 0%). However, the likelihood of progression to or worsening OHE was similar when comparing the probiotic and lactulose groups (OR: 1.24, 95% CI: 0.73–2.10, P = 0.42);[22,24,25,33–35] 17% (38/224) of the patient treated with probiotics and 15% (38/225) treated with lactulose progressed to OHE.

Figure 4.

Forest plot on improvement on progression or worsening hepatic encephalopathy comparing probiotics and no treatment/placebo. CI, confidence interval. M-H, Mantel-Haenszel.

Further subgroup analysis of the use of probiotics as primary prophylaxis in preventing patients from developing OHE was also assessed. The odds of developing OHE were significantly decreased when patients were treated with probiotics as compared to no treatment/placebo (OR: 0.31, 95% CI: 0.15–0.67, P = 0.003; Fig. 5).[31–33,35] There was no significant heterogeneity in the analysis (P = 0.68, I2 = 0%). However no significant difference was seen when comparing the use of probiotics to lactulose (OR: 1.16, 95% CI: 0.54–2.52, P = 0.70).[24,25,33,35]

Figure 5.

Forest plot on effectiveness of probiotics as primary prophylaxis in preventing hepatic encephalopathy comparing probiotics and no treatment/placebo. CI, confidence interval; M-H, Mantel-Haenszel.

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