Hepatic encephalopathy (HE) is a reversible neuropsychiatric and functional syndrome occurring in 50–70% of patients with advanced liver disease. The pathophysiology of HE is complex and it manifests with progressive deterioration of the superior neurological functions. HE occurs in the situation of insufficient hepatic clearance of toxins absorbed from the intestine, resulting in neurochemical abnormalities across the blood–brain barrier. The clinical manifestations of HE range from an altered mental status to deep coma 1.
The pathogenesis of HE is not entirely known but is thought to be related to circulating gut-derived toxins of nitrogenous origin and/or benzodiazepine-like compounds and changes in central neurotransmission, particularly of the dopaminergic and GABA-ergic systems 2.
Accumulation of ammonia induces glutamate neurotoxicity, leading to increased tone of the GABA-A receptor system in the brain, which results in HE. Factors either increasing the ammonia levels (e.g. protein load, constipation, sepsis, or gastrointestinal bleeding) or potentiating the functional activity of the GABA-ergic system (natural benzodiazepine-like compounds or exogenous benzodiazepines) may act as precipitating factors of HE 3.
The present standard of care in the management of HE is directed at decreasing the accumulation of ammonia in the hope of altering the induction of glutamate neurotoxicity and the consequent increased tone of the GABA-A receptor system in the brain 3. Several agents have been used to address this complication of end-stage liver disease. Lactulose has been the standard of care for the past three decades 4. Several antibiotics have been studied for use in HE, alone or in combination with lactulose. The antibiotic neomycin tends to be effective during acute exacerbations of the syndrome, whereas metronidazole has become quite favorable for preventing HE. However, all these agents are fraught with drug-related side effects and/or therapeutic compliance 5.
Rifaximin is a derivative of rifamycin that acts by inhibiting bacterial RNA synthesis. Rifaximin is virtually unabsorbed after oral administration and exhibits broad-spectrum antimicrobial activity against both aerobic and anaerobic gram-positive and gram-negative microorganisms within the gastrointestinal tract 6. Many studies reported that rifaximin decreases ammonia plasma levels and improves the symptoms related to HE in patients with liver cirrhosis. These studies reported rifaximin to be as effective as or more effective when compared with lactulose 7–11. In addition, rifaximin has a favorable profile in terms of tolerability and side effects 12. Most of the previous studies were performed on patients with chronic encephalopathy; however, few of them addressed the treatment of acute encephalopathy.
Aim of the study
The aim of this study was to determine the efficacy, tolerability, and safety of oral rifaximin in cirrhotic patients with mild-to-moderate acute HE.
Patients and methods
This was a prospective, randomized, controlled study carried out at the National Liver Institute (NLI), Menoufiya University, Egypt. The study protocol was approved by the Institutional Ethics Committee. Written informed consent was obtained from close relatives of all patients who participated in the study.
A total of 100 patients with liver cirrhosis and grade II–III acute HE were enrolled in the study. All patients had received third-generation cephalosporin (cefotaxim) (1 g every 12 h for 3 days) according to our Institutional guidelines. All patients underwent detailed physical and neurological assessment with particular focus on their drug history. Grading of HE was done according to the West Haven criteria (Table 1) 13.
Diagnosis of cirrhosis was based on clinical findings, imaging studies (abdominal ultrasound), and laboratory results. The severity of cirrhosis was graded according to the Child–Pugh classification. The cause of liver disease was chronic hepatitis C virus infection in all patients.
The criteria for exclusion from the study were: age below 18 years, presence of a major neuropsychiatric illness, presence of intestinal obstruction or inflammatory bowel disease, known hypersensitivity to rifamycin or disaccharides, and serum creatinine level more than twice normal. In addition; patients with hepatocellular carcinoma, spontaneous bacterial peritonitis or gastrointestinal bleeding, or concurrent medical diseases such as long-standing diabetes mellitus or hypertension were excluded from the study.
The patients were randomized into two groups. The first group included 50 patients who received the standard of care in the form of lactulose therapy (30 ml/total dissolved solids and titrated according to the frequency of bowel habits to achieve 2–3 loose motions/day). The second group included 50 patients who received rifaximin therapy (1200 mg/day in three divided doses) in addition to lactulose therapy.
Routine laboratory investigations including liver function tests (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, alkaline phosphatase, total bilirubin, and albumin) using the Beckman Coulter Clinical Auto analyzer Synchron Cx 9 ALX (Beckman Coulter Inc., Brea, California, USA) were performed for all patients, in addition to blood ammonia level measurements (initially at baseline and after 7 days).
The patients were followed up for 7 days. The primary efficacy endpoint was improvement in the HE grade between baseline and day 7. HE was considered to have improved if there was at least one point decrease in the grade of HE according to the West Haven criteria at day 7. The second endpoint of the study was the development of serious adverse events that required treatment discontinuation.
Statistical analysis was performed using SPSS program (version 16.0; SPSS Inc., Chicago, Illinois, USA) for Windows. The data were expressed as mean±SD or proportions. Statistical analyses were performed using Student’s t-test, the paired t-test, Fisher’s exact test, and the χ2-test. A P value below 0.05 was considered statistically significant.
This study included 100 patients with cirrhosis and grade II–III acute HE. The patients were divided randomly into two groups as previously mentioned. The enrolled patients comprised 80 men and 20 women aged between 26 and 75 years (mean age 53.6±8.38 years). The demographic and clinical parameters and patient characteristics in the two groups showed no significant differences (Table 2). The identified precipitating factors included dehydration (n=13), protein overload (n=25), constipation (n=31), evidence of bacterial infection other than spontaneous bacterial peritonitis (n=19), and unknown causes (n=12). There was no significant difference between the two groups as regards the precipitating factors of HE (Table 3).
There was no significant difference between the two groups as regards the baseline grades of HE. The HE grade significantly improved in both rifaximin (86%) and lactulose (82%) groups, with no significant difference between the two groups (Table 3). There was no significant difference between the baseline blood ammonia levels in the two arms of therapy (Table 2). The mean levels of blood ammonia significantly decreased in both rifaximin and lactulose groups after therapy. Moreover, there was no significant difference between blood ammonia levels after therapy in the two groups (Table 4).
The overall patient compliance was excellent. One patient treated with rifaximin complained of abdominal pain and another patient treated with lactulose experienced moderate diarrhea; however, no patient was withdrawn from the trial because of undue adverse events (Table 5).
HE represents a challenging clinical complication of liver insufficiency and presents with a wide spectrum of neuropsychiatric symptoms that range from mild disturbances in cognitive function to coma 14,15. The pathogenesis of this complex syndrome is thought to be multifactorial, but a key role is played by circulating gut-derived toxins such as ammonia 15,16. With appropriate medical treatment, most clinical manifestations of HE are reversible when the precipitating factors are corrected for 16.
Traditionally, nonabsorbable disaccharides have been used as the first-line therapy for patients with HE 14 even if their effectiveness in comparison with placebo has not been proven 17. Although safe, the use of disaccharides often leads to frequent nausea, vomiting, and flatulence, which affects compliance 18. Poorly absorbed oral antibiotics such as neomycin, vancomycin, or paromomycin seem to be more effective than disaccharides 17, with fewer side effects, although ototoxicity 19, nephrotoxicity 20, neurotoxicity, and bacterial resistance have been reported 20,21. This significant risk of severe toxicity is the reason why most of these agents are seldom used in modern practice.
In contrast, rifaximin is an agent that appears to be effective in the treatment of HE without carrying the risk of severe side effects. It has the advantage of being well tolerated and has minimal risk of causing bacterial resistance 22. It was initially introduced in Italy in 1987 23 and was recently approved in the USA for the treatment 24 and prevention 25 of HE. The purported advantages of rifaximin over other oral agents make it a very attractive candidate for treatment of HE, although at a considerably greater expense 14.
Several randomized, placebo-controlled trials have been performed with rifaximin 6–12,26–35. These trials have studied the short-term management of acute episodes 9, long-term therapy, and prevention of recurrence 6,11,26–34. These studies reported rifaximin to be as effective as or more effective when compared with lactulose, the present standard of care for HE.
Our study showed that rifaximin is as effective as lactulose in patients with acute episodes of HE. Paik et al.9 showed that rifaximin is as effective as lactulose in the treatment of Korean patients with acute encephalopathy, with which our results are in agreement. Most of the previous studies were performed on patients with chronic encephalopathy. Few of them addressed treatment of acute encephalopathy. Bass and colleagues 6 demonstrated that administration of rifaximin with lactulose prevented hospitalizations and HE recurrences compared with administration of lactulose alone in patients who had two prior HE episodes, but this needs further evaluation in patients who have only had their first HE episode. There is also a huge cost difference between rifaximin and lactulose, and the evidence that rifaximin reduces overall costs and hospitalizations as shown by Bass et al. 6 is concluded from patients with chronic encephalopathy and not from patients with acute episodes as in our case.
The cost analysis between rifaximin and lactulose strongly favors the present standard of care, which was addressed in a study by Haung et al.35. Lactulose therapy costs about 15 Egyptian pounds, whereas rifaximin costs about 60 Egyptian pounds for a 7-day course of therapy.
In our study, we found that the adverse events of both lactulose and rifaximin are tolerable and never lead to discontinuation of the drug. The most frequent adverse events are diarrhea and abdominal cramps with lactulose and rifaximin, respectively.
Other studies showed that the adverse events of both lactulose and rifaximin are comparable. The most common adverse events from lactulose are diarrhea, abdominal cramping, nausea, and flatulence. Although these side effects are prevalent, they rarely lead to discontinuation of the drugs. In addition, there is a gradual resolution of these adverse events as treatment progresses 27,29,30. The major clinical benefit of rifaximin is its low rate of adverse events and the corresponding high rate of compliance 34.
Seven randomized controlled trials showed that a significant reduction in serum ammonia levels was observed with both rifaximin and nonabsorbable disaccharides or neomycin or paromomycin. Participants who received rifaximin had lower serum ammonia levels in comparison with patients who received nonabsorbable disaccharides, although the difference did not reach statistical significance. Similar results were observed when comparing rifaximin with other oral antibiotics, and the differences were not statistically significant. When compared with controls, patients treated with rifaximin had an overall lower mean serum ammonia level, but this too was not statistically significant 9,25,27,33,36–38. In our study, the mean levels of blood ammonia significantly decreased in both rifaximin and lactulose groups, with no significant difference between the two arms of therapy. Moreover, there was no significant difference between blood ammonia levels after therapy in the two groups.
Indeed, lactulose is considered to be the standard of care in our institute for many years. In healthcare centers with limited resources, cost-benefit analysis is important to derive the best advantage from the available resources.
Rifaximin can be considered as a second-line therapy for HE in part due to the extreme cost difference between rifaximin and lactulose and also because lactulose therapy alone is effective for treatment of HE in most patients. Further studies are needed to address the role of rifaximin in prevention of recurrence of encephalopathy episodes in our patients and in patients with TIPS (tranjugular intrahepatic portosystemic shunt).
Conflicts of interest
There are no conflicts of interest.
1. Eltawil K, Laryea M, Peltekian K, Molinari M.Rifaximin
vs. conventional oral therapy for hepatic encephalopathy
: a meta-analysis.World J Gastroenterol2012;18:767–777.
2. Ahboucha S, Butterworth R.Pathophysiology of hepatic encephalopathy
: a new look at GABA from the molecular standpoint.Metab Brain Dis2004;19:331–343.
3. Zeneroli M, Avallone R, Corsi L, Venturini I, Baraldi C, Baraldi M.Management of hepatic encephalopathy
: role of rifaximin
4. Prasad S, Dhiman R, Duseja A, Chawla Y, Sharma A, Agarwal R.Lactulose
improves cognitive function and health-related quality of life in cirrhotic patients with minimal hepatic encephalopathy
5. Maclayton D, Eaton-Maxwell A.Rifaximin
for treatment of hepatic encephalopathy
6. Bass N, Mullen K, Sanyal A, Poordad F, Neff G, Leevy C.Rifaximin
treatment in hepatic encephalopathy
.N Engl J Med2010;362:1071–1081.
7. Williams R, James O, Warnes T, Morgan M.Evaluation of the efficacy and safety of rifaximin
in the treatment of hepatic encephalopathy
: a double blind, randomized, dose-finding multi-centre study.Eur J Gastroenterol Hepatol2000;12:203–208.
8. Venturini I, Ferrieri A, Farina F, Cosenza F, Avallone R, Corsi L, et al..Evaluation of rifaximin
, placebo and lactulose
in reducing the levels of benzodiazepine-like compounds in patients with liver cirrhosis
: a pilot study.Drugs Exp Clin Res2005;31:161–168.
9. Paik Y, Lee K, Han K, Song K, Kim M, Moon B, et al..Comparison of rifaximin
for the treatment of hepatic encephalopathy
: a prospective randomized study.Yonsei Med J2005;46:399–407.
10. Bajaj J, Heuman D, Wade J, Gibson D, Saeian K, Wegelin J, et al..Rifaximin
improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy
11. Leevy C, Phillips J.Hospitalizations during the use of rifaximin
for the treatment of hepatic encephalopathy
.Dig Dis Sci2007;52:737–741.
12. Williams R, Bass N.Rifaximin
, a nonabsorbed oral antibiotic, in the treatment of hepatic encephalopathy
: antimicrobial activity, efficacy, and safety.Rev Gastroenterol Disord2005;5Suppl 1S10–S18.
13. Poh Z, Chang P.A current review of the diagnostic and treatment strategies of hepatic encephalopathy
.Int J Hepatol2012;2012:1–10.
14. Phongsamran P, Kim J, Cupo Abbott J, Rosenblatt A.Pharmacotherapy for hepatic encephalopathy
15. Riordan S, Williams R.Treatment of hepatic encephalopathy
.N Engl J Med1997;337:473–479.
16. Abou-Assi S, Vlahcevic Z.Hepatic encephalopathy
. Metabolic consequence of cirrhosis often is reversible.Postgrad Med2001;109:52–54.
17. Als-Nielsen B, Gluud L, Gluud C.Non-absorbable disaccharides for hepatic encephalopathy
: systematic review of randomised trials.BMJ2004;328:1046–1051.
18. De Melo R, Charneski L, Hilas O.Rifaximin
for the treatment of hepatic encephalopathy
.Am J Health Syst Pharm2008;65:818–822.
19. Berk D, Chalmers T.Deafness complicating antibiotic therapy of hepatic encephalopathy
.Ann Intern Med1970;73:393–396.
20. Greenberg L, Momary H.Audiotoxicity and nephrotoxicity due to orally administered neomycin.JAMA1965;194:827–828.
21. Jiang Q, Jiang X, Zheng M, Jiang L, Chen Y, Wang L.Rifaximin
versus nonabsorbable disaccharides in the management of hepatic encephalopathy
: a meta-analysis.Eur J Gastroenterol Hepatol2008;20:1064–1070.
22. Brigidi P, Swennen E, Rizzello F, Bozzolasco M, Matteuzzi D.Effects of rifaximin
administration on the intestinal microbiota in patients with ulcerative colitis.J Chemother2002;14:290–295.
23. Koo HL, DuPont H.Rifaximin
: a unique gastrointestinal-selective antibiotic for enteric diseases.Curr Opin Gastroenterol2010;26:17–25.
24. Bajaj J, Riggio O.Drug therapy: rifaximin
25. Siddique A, Kowdley K.Gut instinct: rifaximin
for the prevention of hepatic encephalopathy
26. Di Piazza S, Gabriella Filippazzo M, Valenza L, Morello S, Pastore L, Conti A, et al..Rifaximin
versus neomycin in the treatment of portosystemic encephalopathy
.Ital J Gastroenterol1991;23:403–407.
27. Bucci L, Palmieri G.Double-blind, double-dummy comparison between treatment with rifaximin
in patients with medium to severe degree hepatic encephalopathy
.Curr Med Res Opin1993;13:109–118.
28. Sidhu S, Goyal O, Mishra B, Sood A, Chhina RS, Soni RK.Rifaximin
improves Psychometric Performance and Health Related Quality of Life in Patients with Minimal Hepatic Encephalopathy
(The RIME trial).Am J Gastroenterol2011;106:307–316.
29. Alcorn J.Review: rifaximin
is equally or more effective than other antibiotics and lactulose
for hepatic encephalopathy
.ACP J Club2008;149:11.
30. Lawrence K, Klee J.Rifaximin
for the treatment of hepatic encephalopathy
31. Sanyal A, Younossi Z, Bass N, Mullen K, Poordad F, Brown R, et al..Randomised clinical trial: rifaximin
improves health-related quality of life in cirrhotic patients with hepatic encephalopathy
- a double-blind placebo-controlled study.Aliment Pharmacol Ther2011;34:853–861.
32. Irimia R, Trifan A.Efficacy of rifaximin
for reducing the recurrence of overt hepatic encephalopathy
and hopitalizations in cirrhosis.Rev Med Chir Soc Med Nat Iasi2012;116:1021–1027.
33. Festi D, Mazzella G, Orsini M, Sottili S, Sangermano A, Li Bassi S, et al..Rifaximin
in the treatment of chronic hepatic encephalopathy
; results of a multicenter study of efficacy and safety.Curr Ther Res1993;54:598–609.
34. Puxeddu A, Quartini M, Massimetti A, Ferrieri A.Rifaximin
in the treatment of chronic hepatic encephalopathy
.Curr Med Res Opin1995;13:274–281.
35. Haung E, Esprailian E, Spiegel B.The cost-effectiveness and budget impact of competing therapies in hepatic encephalopathy
– a decision analysis.Aliment Pharmacol Ther2007;26:1147–1161.
36. Pedretti G, Calzetti C, Missale G, Fiaccadori F.Rifaximin
versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy
of cirrhotics. A double-blind, randomized trial.Ital J Gastroenterol1991;23:175–178.
37. Parini P, Cipolla A, Ronchi M, Salzetta A, Mazzella G, Roda E.Effect of rifaximin
and paromomycin in the treatment of porto-systemic encephalopathy
.Curr Ther Res1992;52:34–39.
38. Mas A, Rodés J, Sunyer L, Rodrigo L, Planas R, Vargas V, et al..Comparison of rifaximin
and lactitol in the treatment of acute hepatic encephalopathy
: results of a randomized, double-blind, double-dummy, controlled clinical trial.J Hepatol2003;38:51–58.