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Reuters Health Information (2012-07-06): Probiotics good second option for preventing recurrence of hepatic encephalopathy


Probiotics good second option for preventing recurrence of hepatic encephalopathy

Last Updated: 2012-07-06 10:28:18 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Probiotics were as effective as lactulose for secondary prevention of hepatic encephalopathy (HE) in a randomized controlled trial in India.

The researchers -- Dr. Praveen Sharma and colleagues from the Department of Gastroenterology, G.B. Pant Hospital in New Delhi -- still recommend lactulose as the first-line treatment. They say probiotics are a good alternative for patients who have trouble tolerating lactulose.

HE develops in 50% to 70% of patients with cirrhosis and predicts a poor outcome unless patients can undergo liver transplantation, they pointed out June 19 online in the American Journal of Gastroenterology.

"HE is now considered a continuous spectrum of neurocognitive abnormalities, which range from no dysfunction (HE0) to minimal HE (MHE) (detected with psychometric tests) and overt encephalopathy (grades 1-4)," they say.

Studies have shown a high prevalence of cognitive abnormalities assessed by psychometry tests after HE resolves. Preventing recurrence of HE is an "emerging concept," the authors add.

Lactulose is known to be effective for secondary prophylaxis of HE, but it has side effects, particularly diarrhea, that some patients can't tolerate. Rifaximin is also an option, but it poses a risk of gastrointestinal infection with Clostridium difficile when taken long term, the investigators say.

Probiotics have been shown to improve MHE, but no study has investigated secondary prophylaxis of overt HE using probiotics, until now.

Dr. Sharma and colleagues evaluated 235 cirrhotic patients who had recovered from HE and were randomly assigned to no therapy (n=78); lactulose 30 mL three times daily (n=80); or three capsules daily of the commercially available high-potency probiotic mixture VSL#3 (n=77). Each probiotic capsule contains 112.5 billion viable lyophilized bacteria - specifically, four strains of Lactobacillus, three strains of Bifidobacterium and one strain of Streptococcus salivarius subsp. thermophilus (i.e., S. thermophiles).

The primary end point was the development of overt HE according to West Haven criteria or a follow-up of 12 months.

Thirty-eight of the 235 patients (16.2%) were lost to follow-up (12 in the lactulose group, 13 in the probiotics group, and 13 in the control group).

Seventy-seven (39.1%) of the remaining patients developed an episode of HE: 18 (26.5%) of 68 using lactulose, 22 (34.4%) of 64 using probiotics, and 37 (56.9%) of 68 controls.

There was a significant difference between lactulose and no treatment (p=0.001) and between probiotics and no treatment (p=0.02) but no difference between lactulose and probiotics (p=0.349), according to the investigators.

There were no between-group differences in rates of readmission for causes other than HE (p=0.134) or deaths (p=0.56).

The prevalence of abnormal psychometry test results was high. Overall, 71.5% had abnormal results on the number connection test A (NCT-A), 69.2% on the NCT-B, 76.9% on the digit symbol test (DST) and 85.2% on the block design test (BDT).

Forty-eight subjects took the figure connection test (FCT) due to illiteracy and 35 (72.7%) had an abnormal result. Half of the study subjects had abnormal results on the critical flicker frequency (CFF) test.

"These cognitive functions have been shown to be affected by an episode of overt HE and to predict future episodes without any prophylaxis of HE," the authors point out.

Dr. Sharma and colleagues also found a high prevalence of two or more abnormal psychometry tests (71%). They note that MHE defined by more than two psychometric tests has been shown to predict a first episode of overt HE.

Ammonia is been regarded as the key precipitating factor in HE and lower ammonia levels have been shown to improve HE. In the current study, there was a significant decrease in ammonia levels (from baseline to three months) with lactulose (p=0.03) and probiotics (p=0.04) but not in the control group (p=0.597).

In multivariate analysis, "recurrence of overt HE was significantly associated with two or more abnormal psychometric tests and arterial ammonia after the recovery of an episode of HE," the authors report.

They mention that they found the CFF test "to be a simple bedside tool for identifying patients with abnormal psychometric tests, even after recovery from overt HE." However, in this study they didn't find CFF to be a predictor of recurrence of HE upon multivariate analysis.

Commenting on the results in an email to Reuters Health, Dr. Sharma noted that for secondary prophylaxis of HE, "lactulose should be used and in patients who are intolerant to lactulose, probiotics (VSL#3) could be an alternative as it is as effective as lactulose."

"A topic for future research," Dr. Sharma said, is testing "the combination therapy of lactulose plus rifaximin or probiotics with rifaximin for secondary prophylaxis to see whether the combination is better than either one alone."

The researchers acknowledge that the precise mechanisms of action of probiotics in liver disease or HE are uncertain.

They also acknowledge that their study wasn't blinded; however, they say, "because treatment with lactulose induces changes in bowel habits, it is difficult to remain blind to treatment and it would have been wiser to evaluate the changes in bacterial flora of the gut before and after therapy."

They also note that they used a high concentration of probiotics and the results could be strain-specific.

Dr. Jasmohan Bajaj of Virginia Commonwealth University and McGuire VA Medical Center in Richmond, who reviewed the study for Reuters Health, said, "Given the socioeconomic and medical implications of HE, the prevention of further episodes is a worthy goal from a patient, hospital and caregiver perspective. While this group has already demonstrated that lactulose alone can prevent recurrence and a large multicenter study showed that rifaximin (in patients mostly on lactulose) can also prevent HE recurrence, the use of probiotics in this study deserves mention."

Dr. Bajaj noted that the study team used a probiotic preparation with multiple strains.

An issue with probiotic studies in HE, Dr. Bajaj said, is that these specific preparations are usually not available beyond a restricted market and "the batch-to-batch variability needs to be studied. This study however, increases the scope of use of probiotics and potentially changing the gut microbiota in HE but further blinded trials are also needed."

In 2008, Dr. Bajaj and colleagues reported in the American Journal of Gastroenterology that supplementation with a probiotic yogurt may help reverse minimal HE in cirrhotic patients. (See Reuters Health story August 11, 2008).

The current study received no specific financial support and the authors have no competing interests.


Am J Gastroenterol 2012.

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