Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010;362:1071-1081. (Reprinted with permission.)
Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P = 0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy.
Hepatic encephalopathy (HE) is a frequent complication of both acute and chronic liver disease. In the United States, 600,000 patients have been estimated to have cirrhosis; 30% to 45% of these patients develop overt hepatic encephalopathy (OHE),1 and 60% develop minimal hepatic encephalopathy (MHE).2 Annually, 25,000 deaths are caused by cirrhosis in the United States; this makes it the third most common cause of death after heart disease and cancer among persons 45 to 65 years of age.3 After the first episode of HE, the 1-year survival rate is 42%, and the 3-year survival rate is only 23% without liver transplantation.4
HE can be classified as MHE or OHE. MHE is a discrete clinical entity characterized by a normal clinical examination, although cognitive deficits can be elicited by neuropsychological testing. MHE may cause subtle but definite impairments in motor skills, attention, visual perception, and fine motor activities and thus lead to reduced function and quality of life.2 According to etiology, HE can be classified into three groups.5 Type A is associated with acute liver failure, type C is associated with cirrhosis, and type B is defined as HE due to portosystemic shunting in the absence of intrinsic liver disease. Type C, which is the most common type encountered, can be self-limited and caused by a precipitating factor or can be persistent and chronic.
Our understanding of the pathophysiology of HE remains incomplete. However, it is clear that an increased ammonia level is frequently implicated and that astrocytes are the primary cells involved. Acute liver failure may be associated with astrocyte swelling, which may be profound and result in brain edema, increased intracranial pressure, and brain herniation leading to death in 30% of patients. In contrast, the characteristic feature in patients with cirrhosis and HE is the presence of Alzheimer type II astrocytosis.6 The Alzheimer type II astrocyte is considered a manifestation of cerebral edema in chronic liver failure and is characterized by cytoplasmic enlargement, an enlarged swollen nucleus with a basophilic nucleolus, and chromatin clumping.6
The exact mechanism by which ammonia causes astrocyte swelling is unclear; however, astrocytes are the only cells in the brain that can detoxify ammonia. These cells contain glutamate transporters, which facilitate the intracellular movement of glutamate. Down-regulation of glutamate transporter 1 has been observed in rodents with hyperammonemia; this leads to abnormal glutamatergic neurotransmission and may be responsible for some of the neurological manifestations of HE.7 Cultured astrocytes exposed to ammonia develop a mitochondrial permeability transition, which can lead to astrocyte swelling.8
Within astrocytes, glutamate combines with ammonia to form glutamine. Glutamine in turn may cause osmotic stress resulting in further astrocyte edema. Glutamine also accumulates in the mitochondria of astrocytes, and this may lead to the production of reactive nitrogen and oxygen species and mitochondrial dysfunction.9 Ammonia also induces up-regulation of astrocytic/microglial mitochondrial benzodiazepine receptor expression, which results in increased synthesis of neurosteroids; these bind to gamma-aminobutyric acid A (GABA-A) receptors and cause increased GABA-generic tone and neuroinhibition.10
New technological advances using positron emission tomography scanning and radioactive ammonia studies have demonstrated increased ammonia uptake and metabolism in the brains of patients with cirrhosis. There is also an increase in the permeability–surface area product, which is a measure of the blood-brain barrier permeability.
Despite convincing data favoring hyperammonemia in the pathogenesis of HE, there is a poor correlation between the plasma ammonia level and the severity of HE. This has led to the theory that other substances such as manganese, GABA, beta-phenylethanolamines, proinflammatory cytokines, short-chain and medium-chain fatty acids, and mercaptans may act synergistically with ammonia in the development of HE.11 Another contributing factor may be systemic inflammatory response syndrome. Ammonia has been shown to induce neutrophil dysfunction, which may result in systemic inflammatory response syndrome and the release of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor alpha.6 These cytokines cross the blood-brain barrier and activate transcription factors within the astrocytes; this results in further synthesis of intracerebral cytokines and astrocyte swelling.12
Lactulose is a nonabsorbable synthetic disaccharide and has been the mainstay of HE treatment for decades. It reaches the colon unaltered, in which it has cathartic activity, and it is also catabolized by the colonic bacterial flora to produce lactic acid and acetic acid.13 The resulting acidic colonic environment inhibits the growth of ammoniagenic coliform bacteria. The acidic pH also favors the conversion of ammonia into nonabsorbable ammonium, which is then excreted; this reduces the plasma ammonia concentration. However, lactulose is poorly tolerated, its gastrointestinal side effects result in reduced patient compliance, and breakthrough HE occurs frequently. A number of antibiotics, such as metronidazole, neomycin, vancomycin, paromomycin, quinolones, and rifaximin, have also been used in the treatment of HE. Rifaximin is a synthetic derivative of rifampin. The parent drug is altered so that it is minimally absorbed from the gut but retains its broad spectrum activity against aerobic and anaerobic gram-positive and gram-negative organisms. Rifaximin is safe in patients with liver failure, is well tolerated, and does not have the ototoxicity and nephrotoxicity associated with neomycin and paromomycin or the peripheral neuropathy associated with metronidazole. Microbial resistance has not been reported to date.14
In a study by Mas et al.,15 103 patients with acute HE were randomized to receive either rifaximin or lactulose for 5 to 10 days. This study showed no significant difference in improvement in the two groups (81.6% versus 80.4%), although the patients in the rifaximin group had a better portosystemic encephalopathy index because of an improvement in the electroencephalogram abnormalities and ammonia levels. A double-blind study by Bucci and Palmieri,16 comparing rifaximin and lactulose in 58 patients with moderate to severe HE, also showed improvement in the electroencephalogram findings and ammonia levels in the rifaximin group. Rifaximin was better tolerated and had a faster onset of action.
In a meta-analysis of randomized controlled trials comparing rifaximin and lactulose, Jiang et al.17 found only five trials, involving a total of 264 patients, that met the inclusion criteria. There was no significant difference between the two groups with respect to improvements in both acute and chronic HE (relative risk = 1.08, 95% confidence interval = 0.85-1.38, P = 0.53). However, in a meta-analysis of 14 randomized controlled trials (n = 650) and 3 cohort studies (n = 161), Lawrence and Klee18 found that rifaximin was more effective than nonabsorbable disaccharides and as effective as other antibiotics. It was also better tolerated and associated with less frequent and shorter hospitalization in comparison with lactulose. Leevy and Phillips19 evaluated 145 patients with HE who initially received lactulose for 6 months and then rifaximin for 6 months. The incidence of hospitalization was lower (0.5 versus 1.6, P < 0.001) and the duration of hospitalization was shorter (2.5 versus 7.3, P < 0.001) during therapy with rifaximin.
The study by Bass et al.20 is the first randomized, double-blind, placebo-controlled study that has evaluated rifaximin for the prevention of HE. This multicenter trial included 299 patients with chronic liver disease and a history of HE. Patients received either 550 mg of rifaximin or placebo twice daily for 6 months. Approximately 90% of the patients in both groups also received lactulose. The primary endpoint was the development of HE. Recurrence of HE was reported in 22.1% of the patients (31 of 140) receiving rifaximin and 45.9% of the patients (73 of 159) receiving the placebo (P < 0.001, 95% confidence interval = 0.28-0.64). The incidence of recurrent HE was reduced by 58% in the rifaximin group versus the placebo group with a number needed to treat of 4. The secondary endpoint of the study was time to first hospitalization due to HE, which was also reduced by 50% in rifaximin-treated patients with a number needed to treat of 9 (13.6% of the rifaximin group versus 22.6% of the placebo group, P = 0.01, 95% confidence interval = 0.29-0.87). No major adverse events were noted in the rifaximin group. The mortality rate was the same in the two groups.
This study concluded that rifaximin is more effective than placebo for the prevention of HE. In March 2010, rifaximin was approved by the Food and Drug Administration for the prevention of HE on the basis of this clinical trial.
The main question that remains unanswered after this important study is whether rifaximin can suffice as monotherapy because more than 90% of the patients were also on lactulose. Also, the efficacy of rifaximin in more severe cases of HE is unclear. The majority of the patients had a Model for End-Stage Liver Disease score ≤ 19. The long-term effects of rifaximin on the gut flora are also not known. Two patients in the rifaximin group developed a Clostridium difficile infection that was not related to the antibiotic per se according to the authors.
In summary, rifaximin is a promising advance in the treatment and prevention of HE; additional trials are needed to fully establish the efficacy of this agent used alone or in combination for HE associated with cirrhosis. We hope that studies such as the Rifaximin in Chronic Hepatic Encephalopathy trial, which is currently underway, will answer some of these questions.