Secondary Prophylaxis of Hepatic Encephalopathy in Cirrhosis
Secondary Prophylaxis of Hepatic Encephalopathy in Cirrhosis
HE develops in 50–70% of patients with cirrhosis, and its occurrence is an indicator of a poor prognosis, with projected 1- and 3-year survival rates of 42% and 23%, respectively, without liver transplantation. HE is now considered a continuous spectrum of neurocognitive abnormalities, which range from no dysfunction (HE0) to MHE (detected with psychometric tests) and overt encephalopathy (grades 1–4). We and others have previously shown the high prevalence of cognitive abnormalities assessed by psychometry tests after clinical recovery of HE. The secondary prophylaxis of HE is an emerging concept; however, there is no definitive recommendation or consensus on secondary prophylaxis of HE and therefore the use of lactulose or rifaximin for the prevention of HE is not yet routine practice.
This study showed that the use of lactulose and probiotics as compared with no therapy is more effective in secondary prophylaxis of HE. Of 197 patients, 77 (39.1%) developed an episode of overt HE over a follow-up period of 12 months. In all, 18 (26.2%) in Gp-L, 22 (34.4%) in Gp-P, and 37 (56.9%) in Gp-N developed HE (P=0.001). In our previous study, 12 (19.6%) of 61 patients in the HE-L group and 30 (46.8%) of 64 in the HE-NL group (P=0.001) developed HE over a median follow-up of 14 months (range 1–20 months), and we have shown that lactulose is better than no treatment for the secondary prophylaxis of HE. The results of this study corroborate those of our previous study, which indicated that lactulose is more effective than no therapy for secondary prophylaxis of HE. Recently, Bass et al. also showed that, over a 6-month period, treatment with rifaximin and lactulose in the majority of such patients maintained remission from HE more effectively than did placebo. However, lactulose causes diarrhea and is not tolerable by some patients, and long-term rifaximin poses a risk of gastrointestinal infection with Clostridium difficile; evaluating long-term safety in cirrhotics requires more data.
Lactulose works in part by altering gut flora to decrease ammonia production and absorption. The evidence suggests that the lactulose effects occur because lactulose serves as a "prebiotic" ingredient, encouraging the growth of endogenous bacteria that resemble those found in many probiotics. Thus, the concept that therapeutic manipulation of the endogenous gut bacterial flora (gut flora therapy) by probiotics might hold for HE. Probiotics have been used to treat HE by decreasing urease-producing bacteria and promoting the growth of non-urease-producing bacteria. They may be particularly useful in scenarios of noncompliance or intolerance to lactulose. Loguercio and colleagues reported in a pilot study that Enterococcus faecium was as effective as lactulose in reducing ammonia levels and improving mental status among chronic HE patients. Similarly, in a randomized trial on the use of probiotic yogurt on psychometric performance of cirrhotic patients with MHE, the number of episodes of HE at follow-up was significantly lower than that observed in the no-treatment arm of the study. Probiotics have been used for the treatment of MHE and have been shown to improve the Child score in patients with cirrhosis. All published studies on the effect of probiotics on HE have demonstrated efficacy. These studies used high doses of non-urease-producing bacteria, either L. acidophilus or E. faecium SF68. The mechanisms of action of these probiotic strains in liver disease or HE are uncertain and require validation in future trials. We found that probiotics were as efficacious as lactulose and better than no therapy for the secondary prophylaxis of HE with minimum side effects. Hence, probiotics is a good alternative to secondary prophylaxis of HE.
Gut-derived nitrogenous substances are universally acknowledged to play a major role in HE. Specifically, ammonia is thought to be a critical factor in its pathogenesis. Increased levels of ammonia have been implicated in the pathogenesis of HE, and nonabsorbable disaccharides and minimally absorbed antibiotics have been effective in reducing the activity of colonic bacteria involved in the production of ammonia. The results of this study substantiate our previous findings that the baseline arterial ammonia and two or more than two abnormal psychometry tests independently predict future episodes of HE.
CFF appears to detect a broad spectrum of neurophysiological abnormalities ranging from visual signal processing (retinal gliopathy) to cognitive functions, and CFF <38 Hz is predictive of further bouts of overt HE. We also found that CFF used alone for the detection of patients with two or more abnormal psychometry test results had a sensitivity and specificity of 63.2% and 83.6%, respectively, and patients developing HE had significantly lower CFF at baseline than those who did not. We found it to be a simple bedside tool for identifying patients with abnormal psychometric tests, even after recovery from overt HE. However, in this study we did not find CFF to be a predictor of recurrence of HE upon multivariate analysis.
The limitation of this study is that it was not blinded; however, 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. We used a high concentration of probiotics and the results could be strain-specific, which could not be identified with treatment of another probiotics with a different strain and hence require validation with other probiotic combinations. Treatment with lactulose and probiotics caused few side effects, which could be managed well without stopping drug treatment. In conclusion, lactulose and probiotics were equally effective in secondary prophylaxis of HE.
Discussion
HE develops in 50–70% of patients with cirrhosis, and its occurrence is an indicator of a poor prognosis, with projected 1- and 3-year survival rates of 42% and 23%, respectively, without liver transplantation. HE is now considered a continuous spectrum of neurocognitive abnormalities, which range from no dysfunction (HE0) to MHE (detected with psychometric tests) and overt encephalopathy (grades 1–4). We and others have previously shown the high prevalence of cognitive abnormalities assessed by psychometry tests after clinical recovery of HE. The secondary prophylaxis of HE is an emerging concept; however, there is no definitive recommendation or consensus on secondary prophylaxis of HE and therefore the use of lactulose or rifaximin for the prevention of HE is not yet routine practice.
This study showed that the use of lactulose and probiotics as compared with no therapy is more effective in secondary prophylaxis of HE. Of 197 patients, 77 (39.1%) developed an episode of overt HE over a follow-up period of 12 months. In all, 18 (26.2%) in Gp-L, 22 (34.4%) in Gp-P, and 37 (56.9%) in Gp-N developed HE (P=0.001). In our previous study, 12 (19.6%) of 61 patients in the HE-L group and 30 (46.8%) of 64 in the HE-NL group (P=0.001) developed HE over a median follow-up of 14 months (range 1–20 months), and we have shown that lactulose is better than no treatment for the secondary prophylaxis of HE. The results of this study corroborate those of our previous study, which indicated that lactulose is more effective than no therapy for secondary prophylaxis of HE. Recently, Bass et al. also showed that, over a 6-month period, treatment with rifaximin and lactulose in the majority of such patients maintained remission from HE more effectively than did placebo. However, lactulose causes diarrhea and is not tolerable by some patients, and long-term rifaximin poses a risk of gastrointestinal infection with Clostridium difficile; evaluating long-term safety in cirrhotics requires more data.
Lactulose works in part by altering gut flora to decrease ammonia production and absorption. The evidence suggests that the lactulose effects occur because lactulose serves as a "prebiotic" ingredient, encouraging the growth of endogenous bacteria that resemble those found in many probiotics. Thus, the concept that therapeutic manipulation of the endogenous gut bacterial flora (gut flora therapy) by probiotics might hold for HE. Probiotics have been used to treat HE by decreasing urease-producing bacteria and promoting the growth of non-urease-producing bacteria. They may be particularly useful in scenarios of noncompliance or intolerance to lactulose. Loguercio and colleagues reported in a pilot study that Enterococcus faecium was as effective as lactulose in reducing ammonia levels and improving mental status among chronic HE patients. Similarly, in a randomized trial on the use of probiotic yogurt on psychometric performance of cirrhotic patients with MHE, the number of episodes of HE at follow-up was significantly lower than that observed in the no-treatment arm of the study. Probiotics have been used for the treatment of MHE and have been shown to improve the Child score in patients with cirrhosis. All published studies on the effect of probiotics on HE have demonstrated efficacy. These studies used high doses of non-urease-producing bacteria, either L. acidophilus or E. faecium SF68. The mechanisms of action of these probiotic strains in liver disease or HE are uncertain and require validation in future trials. We found that probiotics were as efficacious as lactulose and better than no therapy for the secondary prophylaxis of HE with minimum side effects. Hence, probiotics is a good alternative to secondary prophylaxis of HE.
Gut-derived nitrogenous substances are universally acknowledged to play a major role in HE. Specifically, ammonia is thought to be a critical factor in its pathogenesis. Increased levels of ammonia have been implicated in the pathogenesis of HE, and nonabsorbable disaccharides and minimally absorbed antibiotics have been effective in reducing the activity of colonic bacteria involved in the production of ammonia. The results of this study substantiate our previous findings that the baseline arterial ammonia and two or more than two abnormal psychometry tests independently predict future episodes of HE.
CFF appears to detect a broad spectrum of neurophysiological abnormalities ranging from visual signal processing (retinal gliopathy) to cognitive functions, and CFF <38 Hz is predictive of further bouts of overt HE. We also found that CFF used alone for the detection of patients with two or more abnormal psychometry test results had a sensitivity and specificity of 63.2% and 83.6%, respectively, and patients developing HE had significantly lower CFF at baseline than those who did not. We found it to be a simple bedside tool for identifying patients with abnormal psychometric tests, even after recovery from overt HE. However, in this study we did not find CFF to be a predictor of recurrence of HE upon multivariate analysis.
The limitation of this study is that it was not blinded; however, 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. We used a high concentration of probiotics and the results could be strain-specific, which could not be identified with treatment of another probiotics with a different strain and hence require validation with other probiotic combinations. Treatment with lactulose and probiotics caused few side effects, which could be managed well without stopping drug treatment. In conclusion, lactulose and probiotics were equally effective in secondary prophylaxis of HE.