Probiotics Prevent Hepatic Encephalopathy in Patients With Cirrhosis: A Randomized Controlled Trial

Clin Gastroenterol Hepatol. 2013 Nov 15. pii: S1542-3565(13)01743-6. doi: 10.1016/j.cgh.2013.11.006. [Epub ahead of print]

Lunia MK¹, Sharma BC², Sharma P¹, Sachdeva S¹, Srivastava S¹.

Abstract

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is associated with a poor prognosis in patients with advanced liver disease. Probiotics alter the intestinal microbiota with non-urease-producing organisms that reduce production of ammonia. We investigated the efficacy of probiotics for the primary prophylaxis of HE.

METHODS: We conducted a prospective trial at a tertiary care referral institute in New Delhi, India, from January 2012 through March 2013, of patients with cirrhosis without overt HE (age, 48.6 ± 11.1 y; 96 men and 64 women); 25 were Child-Turcotte-Pugh (CTP) class A, 51 were CTP class B, and 84 were CTP class C. Subjects were assigned randomly to groups given probiotics (1 × 10⁸ colony-forming units, 3 times daily; n = 86, 42 with minimal HE) or no test article (control, n = 74; 33 with minimal HE). All subjects underwent psychometric analyses, critical flicker fusion (CFF) threshold assessments, glucose hydrogen breath tests to identify small intestinal bacterial overgrowth (SIBO), and lactulose hydrogen breath tests to measure orocecal transit time (OCTT). The primary end point was the development of overt HE.

RESULTS: At baseline, subjects in each group had comparable CTP, model for end-stage liver disease scores, CFF assessments, psychometric hepatic encephalopathy scores, and OCTT. After a mean follow-up period of 38.6 ± 8.80 weeks for patients given probiotics and 40.3 ± 9.8 weeks for controls, 6 patients given probiotics and 7 controls died (P = .81). Three months of probiotic administration significantly reduced levels of arterial ammonia, SIBO, and OCTT; increased psychometric hepatic encephalopathy scores; and increased CFF thresholds, compared with baseline. Seven subjects in the probiotic group and 14 controls developed overt HE (P < .05; hazard ratio for controls vs probiotic group, 2.1; 95% confidence interval, 1.31-6.53). Psychometric hepatic encephalopathy scores, CTP scores, and SIBO correlated with the development of overt HE.

CONCLUSIONS: In a prospective, randomized controlled trial, probiotics were found to be effective in preventing HE in patients with cirrhosis. Trial registration no: CTRI/2012/07/002807.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS: ARR, CFF, CI, CTP, Child–Turcotte–Pugh, Clinical Trial, Cognitive Function, HE, MELD, MHE, Motor Function, NNT, OCTT, PHES, SIBO, Therapy, Treatment, absolute risk reduction, confidence interval, critical flicker frequency, hepatic encephalopathy, minimal hepatic encephalopathy, model for end stage liver disease, number needed to treat, orocecal transit time, psychometric hepatic encephalopathy score, small intestinal bacterial overgrowth

PMID: 24246768 [PubMed - as supplied by publisher]

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Evolving concepts: the negative effect of minimal hepatic encephalopathy and role for prophylaxis in patients with cirrhosis

Clin Ther. 2013 Sep;35(9):1458-73. doi: 10.1016/j.clinthera.2013.07.421. Epub 2013 Aug 22.

Prakash RK, Kanna S, Mullen KD.

MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio. Electronic address: ravi.prakash@case.edu.

Abstract

BACKGROUND: Hepatic encephalopathy (HE), which may be categorized as minimal or overt, is a serious and progressive neuropsychiatric condition that occurs in patients with liver disease or portosystemic shunting. Overt HE (OHE) presents as a wide spectrum of clinical signs and symptoms, ranging in severity from mild confusion to life-threatening coma. Minimal HE (MHE) is a more subtle form of the condition; it is characterized by deficits in cognitive function in patients with a normal clinical examination.

OBJECTIVE: The purpose was to review the effect of MHE on patients and caregivers, as well as its currently available diagnostic and treatment options.

METHODS: A MEDLINE search of published diagnostic assessments, clinical trials, and guidelines from 1985 to 2012 were reviewed and analyzed to assess the potential effect of MHE in the clinical practice setting.

RESULTS: Accumulating evidence suggests that MHE has a substantial negative effect on patient quality of life, particularly in activities that require attention, motor skills, and visuospatial ability. Because MHE lacks obvious clinical signs, specialized testing is required for diagnosis, although there is no consensus on the most appropriate assessment tools or treatment algorithms. Compounds derived from bacterial activities in the gut can cause neurochemical changes in the brain. These gut-derived toxins (eg, ammonia, benzodiazepine-like substances) are implicated in the pathophysiology of OHE. In patients with liver disease or portosystemic shunting, these toxins are inefficiently detoxified, accumulate in the blood, cross the blood-brain barrier, and result in abnormalities such as altered neurotransmission, astrocyte swelling, and impaired energy metabolism. Therefore, treatments have focused on toxin removal and the management of gut flora levels. Several studies have indicated that probiotics, nonabsorbable disaccharides, and nonsystemic antibiotics can all be effective in improving the symptoms of MHE. Furthermore, prophylaxis for MHE in patients with cirrhosis could serve to improve patient quality of life while preventing its transition to OHE.

CONCLUSIONS: Although MHE detection and treatment is not currently the standard of care, several therapies have been reported to improve cognitive function and quality of life. Interest is increasing in the proactive diagnosis and management of MHE in the clinical practice setting. However, research is required to determine the conditions under which the putative benefits of prophylactic MHE therapy outweigh the costs.

© 2013 Published by Elsevier HS Journals, Inc.

KEYWORDS: cirrhosis, hepatic encephalopathy, lactulose, minimal, overt, probiotics, rifaximin

PMID: 23972578 [PubMed - in process]

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Hepatitis C and Dietary Supplements: What the Science Says

May 2013

Milk Thistle

Milk thistle (scientific name Silybum marianum) is a plant from the aster family. Silymarin is an active component of milk thistle believed to be responsible for the herb’s health-related properties. Milk thistle has been used in Europe for treating liver disease and jaundice since the 16th century. In the United States, silymarin is the most popular dietary supplement taken by people with liver disease.

Strength of Evidence

• Much research supports the conclusion that there little evidence of benefit for milk thistle as a treatment for hepatitis C.

Research Results

• A 2012 controlled clinical trial, cofunded by NCCAM and NIDDK, showed that two higher-than-usual doses of silymarin were no better than placebo in reducing the high blood levels of an enzyme that indicates liver damage. In the study, 154 people who had not responded to standard antiviral treatment for chronic hepatitis C were randomly assigned to receive 420 mg of silymarin, 700 mg of silymarin, or placebo three times per day for 24 weeks. At the end of the treatment period, blood levels of the enzyme were similar in all three groups.
• Results of the HALT-C study suggested that silymarin use by hepatitis C patients was associated with fewer and milder symptoms of liver disease and somewhat better quality of life, but there was no change in virus activity or liver inflammation. The researchers emphasized that this was a retrospective study (one that examined the medical and lifestyle histories of the participants). Its finding of improved quality of life in patients taking silymarin was not confirmed in the more rigorous 2012 study described above.
• A 2009 Cochrane systematic review assessed the beneficial and harmful effects of milk thistle in patients with alcoholic liver disease and/or hepatitis B or C liver diseases and found that there is not enough high-quality evidence to support the use of this intervention.

Safety

• Available evidence from clinical trials in people with liver diseases suggests that milk thistle is generally well-tolerated.
• Side effects can include a laxative effect, nausea, diarrhea, abdominal bloating and pain, and occasional allergic reactions.
• In NIH-funded studies of silymarin in people with hepatitis C that were completed in 2010 and 2012, the frequency of side effects was similar in people taking silymarin and those taking placebos. However, these studies were not large enough to prove that silymarin is safe for people with chronic hepatitis C.

Other Supplements

Other supplements have been studied for hepatitis C, but overall, no benefits have been clearly demonstrated.

Probiotics

Probiotics are live microorganisms that are intended to have a health benefit when consumed.

Strength of Evidence

• Only a few studies have examined the effects of probiotics on hepatitis C.

Research Results

• Research hasn’t produced any clear evidence that probiotics are helpful in people with hepatitis C.

Safety

• Most people can use probiotics without experiencing any side effects—or with only mild gastrointestinal side effects such as intestinal gas —but there have been some case reports of serious adverse effects in people with underlying serious health conditions.

Zinc

Strength of Evidence

• Preliminary studies, most of which were conducted outside the United States, have examined the use of zinc for hepatitis C.

Research Results

• Zinc supplements might help to correct zinc deficiencies associated with hepatitis C or reduce some symptoms, but the evidence for these possible benefits is limited.
• A few preliminary studies have looked at the effects of combining supplements such as lactoferrin, SAMe, or zinc with conventional drug therapy for hepatitis C. The evidence is not sufficient to draw clear conclusions about benefit or safety.

Safety

• Zinc is generally considered to be safe when used appropriately, but it can be toxic if taken in excessive amounts.

Glycyrrhizin

Glycyrrhizin (or glycyrrhizic acid) is a compound found in licorice root.

Strength of Evidence

• Glycyrrhizin has been tested in only a few clinical trials in patients with hepatitis C.

Research Results

• There is currently not enough evidence to determine if glycyrrhizin is helpful for hepatitis C.

Safety

• In large amounts, glycyrrhizin or licorice can be dangerous in people with a history of hypertension (high blood pressure), kidney failure, or cardiovascular diseases.

Colloidal Silver

Colloidal silver consists of tiny silver particles suspended in liquid. Colloidal silver products are often promoted for treating various diseases, including hepatitis C.

Strength of Evidence

• Scientific evidence does not support the use of colloidal silver to treat any disease, and serious, irreversible side effects can result from its use.

Research Results

• There is currently no research to support its use for hepatitis C.

Safety

• Colloidal silver is known to cause serious side effects, including a permanent bluish discoloration of the skin called argyria.

NCCAM Clinical Digest is a service of the National Center for Complementary and Alternative Medicine, NIH, DHHS. NCCAM Clinical Digest, a monthly e-newsletter, offers evidence-based information on CAM, including scientific literature searches, summaries of NCCAM-funded research, fact sheets for patients, and more.

The National Center for Complementary and Alternative Medicine is dedicated to exploring complementary and alternative healing practices in the context of rigorous science, training CAM researchers, and disseminating authoritative information to the public and professionals. For additional information, call NCCAM’s Clearinghouse toll-free at 1-888-644-6226, or visit the NCCAM Web site at nccam.nih.gov. NCCAM is 1 of 27 institutes and centers at the National Institutes of Health, the Federal focal point for medical research in the United States.

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