Although a number of other possible factors have been proposed to play a role in the pathogenesis of HE, such as, the production of central benzodiazepine agonists, endogenous opioids and false neurotransmitters, ammonia is still viewed as the key contributor.2
Thus the mainstay treatment for HE revolves about reducing the production and absorption of ammonia in the gut, and to improve its excretion by drug therapy or diet modification. Currently, lactulose and nonabsorbable antibiotics are most commonly used therapeutics to treat HE.1-3
Several placebo-controlled trials of lactulose have reported no proof of superiority versus a placebo. However, these negative results are believed to be due to the designs of trials, variables of efficacy, and to low numbers of enrolled patients.24-27
Lactulose is currently recommended as the first-line pharmacological treatment for HE by the practice guidelines proposed by the American College of Gastroenterology.28
However, the use of lactulose may be associated with nausea, flatulence, abdominal cramps, severe diarrhea, and dehydration.4,5,29
Protracted diarrhea may result in hypertonic dehydration with hypernatremia, which may aggravate the patient's mental state.30
Antibiotics are regarded as a therapeutic alternative to nonabsorbable disaccharides for HE treatment.28
Neomycin is a non-absorbable aminoglycoside that has also been prescribed for HE, but its ototoxicity and nephrotoxicity limit its use in HE.3
Metronidazole, which differs from neomycin in terms of its bacterial spectrum, also improves HE, however its potentially severe neurotoxicity in patients with cirrhosis limits its common use.31
Rifaximin is a semi-synthetic derivative of rifamycin, has broad-spectrum antimicrobial activity,6
and is characterized by its non-absorbability by the gut.32
Rifaximin remains in high concentrations in its active form in the gut and is excreted in feces without causing significant systemic side effects such as nephrotoxicity.6
Moreover, Rifaximin has been shown in previous studies to be effective at reducing HE parameters in cirrhotics.7-14
However, most reports on this subject have emanated from Europe. It has also been reported that combinatorial rifaximin and lactulose is superior to combined neomycin and lactulose for HE treatment.8
In addition, a recent randomized, controlled study conducted in Spain found that rifaximin and lactitol, a nonabsorbable disaccharide, have similar efficacies for the treatment of acute HE.14
The present study is the first, prospective randomized study to compare the efficacy of rifaximin with that of lactulose for the short-term treatment of HE in Asia. No data is available upon whether ethnic background affects the effectiveness of rifaximin for the treatment of HE. Our study confirms that rifaximin is as effective as lactulose for the treatment of HE in Korean patients. Administration at 1200 mg per day led to an objective and significant improvement in mental state, blood ammonia levels, and HE index. Moreover, no significant difference was found between rifaximin and lactulose in terms of their efficacies. These results suggest that ethnic differences do not significantly affect the efficacy of rifaximin as a HE treatment. In this study, the fact that hepatitis B virus is the predominant (75.9%) cause of HE should be considered. In Western countries, alcoholic abuse remains the most common etiology of liver cirrhosis with HE.18,19
Considering intestinal bacterial overgrowth due to alcohol,20
rifaximin might theoretically be a better choice in alcoholic HE than in viral hepatitisrelated HE. However, our results are similar to those of Western studies concerning the efficacy of rifaximin for the treatment of HE, which suggests that the cause of HE is of secondary importance when considering rifaximin as a therapeutic regimen for HE.
When we analyzed the clinical parameters of patients who showed an improvement with those who did not after rifaximin treatment, several factors were found to be significant by univariate analysis. However, limited patient numbers prevented multivariate analysis. We believe that further study of a larger number of patients would be necessary to identify those factors that determine responsiveness to rifaximin in HE treatment. Interestingly, mean baseline ammonia level and HE index were higher in the improvement group than in the no-improvement group after rifaximin treatment, which suggests that rifaximin can be a first-line choice for the treatment of moderate to severe grade HE.
The identification and correction of factors precipitating HE is of primary concern during the management of HE,29
because the correction of such factors usually results in improvement. Thus patients' precipitating factors should be carefully considered in any future trial. In our study, most patients had an identifiable precipitating factor, and the two treatment groups had reasonably similar precipitating factors profiles. Therefore, we believe that any potential bias caused by precipitating factors was minimal in the present study. Rifaximin was also fairly well tolerated; only one patient experienced abdominal pain attributed to the drug. Renal toxicity and other serious side effects were absent, and no ethnically distinct side effects were observed.
All HE therapeutic trials can be criticized from the perspective of evidence-based medicine.33
Criticisms include the definitions of study endpoints, the treatment of control groups, the proper quantification of therapeutic effects. Sanaka et al. prudently described the difficulties of designing good HE treatment tirals.34
The mental status evaluation system using the portal systemic encephalopathy (PSE) index developed by Conn et al.21
is currently widely used. However, the Food and Drug Administration (FDA) strongly objected to the use of this system and favoured the adoption of a detailed mental status evaluation system for HE.34
Although the present study has a limitation due to its being an open-label study, and may not overcome some of the challenges previously mentioned, it shows that rifaximin is as safe and as effective as lactulose in Korean patients with HE. Rifaximin offers a useful therapeutic option in Asian patients with HE who are unable to tolerate treatment with disaccharides or who have an impaired renal function. Further clinical trials using a new mental state evaluation system, which satisfies the FDA's requirements is required to confirm the efficacy of rifaximin for the treatment of HE.