Rifaximin for the Treatment of Hepatic Encephalopathy

Kenneth R. Lawrence, Pharm.D.; Jacqueline A. Klee, Pharm.D.

Disclosures

Pharmacotherapy. 2008;28(8):1019-1032. 

In This Article

Abstract and Introduction

Abstract

Objective: To review the effectiveness and safety of rifaximin for the treatment of hepatic encephalopathy.
Methods: A literature search was conducted of MEDLINE (1966-September 2007), the Cochrane Database of Systematic Reviews (1995-2007), and the Cochrane Hepato-Biliary Group Reviews (2003-2007). English-language articles identified from the data sources were evaluated. All available studies were reviewed, including placebo-controlled, treatment comparison, and open label.
Results: Rifaximin was effective in improving behavioral, laboratory, mental status, and intellectual abnormalities associated with hepatic encephalopathy. Some studies demonstrated superior and more rapid improvement in signs or symptoms of encephalopathy during treatment with rifaximin compared with nonabsorbable disaccharides (lactulose, lactitol). Patients treated with rifaximin also required less hospitalization, had shorter duration of hospitalization, and lower hospital charges compared with lactulose-treated patients. Adverse effects of rifaximin were mostly minor gastrointestinal complaints; however, rifaximin was better tolerated than other pharmacologic treatments.
Conclusion: Rifaximin was at least equally effective as and in some studies superior to nonabsorbable disaccharides and antimicrobials in relieving signs or symptoms observed in patients with mild-to-moderately severe hepatic encephalopathy. Future clinical trials should focus on using standardized methods of evaluating mental status and limiting enrollment to patients with mild-to-moderate, episodic, persistent, or minimal hepatic encephalopathy. Well-designed studies are needed to fully delineate the efficacy of rifaximin and other pharmacologic treatments for patients with hepatic encephalopathy.

Introduction

Hepatic encephalopathy describes a wide range of neuropsychiatric disturbances associated with acute and chronic liver failure. Alterations in sleep, behavior, personality, cognition, and motor abilities characterize this condition.[1] These central nervous system abnormalities are usually attributed to the accumulation of toxins, such as ammonia and manganese, normally removed by the liver.[1] Blood ammonia levels are increased in patients with hepatic cirrhosis as a result of both deteriorating liver function and portal-systemic shunting. Long-term exposure to increased levels of ammonia has been shown to lead to morphologic changes in astrocytes or Alzheimer's type II astrocytosis.[2] Astrocytes occupy one third of the volume of the cerebral cortex and are involved in blood-brain barrier function and neurotransmission.[3] Recent data suggest that accumulation of manganese also may lead to changes in astrocytes.[2]

Accumulation of ammonia and manganese may also be responsible for alterations in γ-aminobutyric acid neurotransmission that have been observed in patients with hepatic encephalopathy. Both substances are implicated in increasing the expression of "peripheral-type" benzodiazepine receptor sites in the brain.[1,2] Also, endogenous, or natural, benzodiazepine levels are increased in patients with liver disease and may contribute to alterations in mental status.[1,4]

Historically, clinical definitions of hepatic encephalopathy were ambiguous and lacked standardization. Consequently, in 1998, the Working Party at the 11th World Congress of Gastroenterology proposed standardized nomenclature to differentiate types of hepatic encephalopathy.[5] Their final report described three types of hepatic encephalopathy ( Table 1 ). Type A is associated with acute liver failure and may progress rapidly, resulting in coma or death if not treated. Type B is very rare and occurs in patients with portal-systemic bypass who do not have intrinsic hepatocellular disease. The most common hepatic encephalopathy, type C, is associated with cirrhosis and portal hypertension. Type C hepatic encephalopathy is further divided into three categories: episodic (including spontaneous, precipitated, or recurrent), persistent (including mild, severe, or treatment dependent), and minimal.[5] Treatment of type C hepatic encephalopathy focuses on identifying precipitating factors and reducing elevated levels of ammonia by using pharmacologic treatment.

Several grading systems have been proposed to evaluate the mental status of patients with hepatic encephalopathy. The most frequently used grading system was developed in the 1950s and modified in the 1970s by investigators from the West Haven Veterans Administration Medical Center (West Haven, CT) and is referred to as the West Haven grading system ( Table 2 ).[6] This grading scale is based on changes in behavior, consciousness, and intellectual function. This scale, along with the Glasgow Coma Scale, is recommended by the American College of Gastroenterology for classifying the severity of hepatic encephalopathy.[5,7]

Criteria for describing the overall severity of hepatic encephalopathy were also developed by the same investigators.[8] The portal-systemic encephalopathy (PSE) score and index are composed of five elements: mental status, presence and intensity of asterixis, time taken to complete tests of intellectual function (e.g., number connection test or trail-making test), venous or arterial ammonia level, and electroencephalogram (EEG) abnormalities ( Table 3 ).[8] The grade for each of the five components is weighted in proportion to importance. Mental status is given a factor of 3, and the other four variables are each assigned a factor of 1, for a maximum PSE score is 28. The PSE index is calculated as the ratio of the patient's PSE sum to the maximum PSE score of 28. Some studies multiply the PSE ratio x 100.

The treatment of hepatic encephalopathy includes identifying and correcting precipitating factors (e.g., gastrointestinal hemorrhage, infections, renal or electrolyte imbalances, excessive dietary protein, and constipation), limiting maximum dietary protein content to 1.2 g/kg/day (range 1-1.5 g/kg/day), and decreasing blood ammonia levels. Blood ammonia levels can be reduced by use of lactulose and other nonabsorbable disaccharides that act as cathartics to enhance fecal excretion of ammonia.[3,7] Antibiotics such as neomycin and metronidazole work primarily by reducing the concentration of ureaseproducing bacterial flora, which are responsible for increasing production of ammonia.[3,7] Both of these pharmacologic treatments are effective in treating hepatic encephalopathy. However, future episodes or persistent symptoms of hepatic encephalopathy may occur. Most important, the 1-year survival rate after the first episode of hepatic encephalo-pathy is 42%.[9]

Despite their apparent effectiveness, neither nonabsorbable disaccharides nor antibiotics have been rigorously studied in patients with hepatic encephalopathy in placebo-controlled or well-designed clinical trials. In addition, these agents are associated with adverse events that affect drug therapy adherence or are considered serious.[10,11] For these reasons, other pharmacologic treatments for hepatic encephalopathy that demonstrate efficacy and safety in well-designed, placebo-controlled trials are needed.

Rifaximin is an antibacterial agent with activity against organisms that have been implicated in producing ammonia. It was designated an orphan drug for the treatment of hepatic encephalopathy by the United States Food and Drug Administration (FDA) in February 1998.[12] Rifaximin is a derivative of rifamycin, which inhibits RNA synthesis and has in vitro activity against many aerobic and anaerobic grampositive and gram-negative bacteria.[13] After oral administration, rifaximin has a bioavailability of less than 0.5%. Most of the orally administered dose is eliminated unchanged in the feces. Dosage adjustments are not required for patients with liver or kidney dysfunction, and significant drug-drug interactions have not been reported.[13] Rifaximin was approved by the FDA for the treatment of traveler's diarrhea in May 2004. The drug is approved for the treatment of hyperammonemia in some European countries.[14]

As hepatic encephalopathy still results in a high mortality rate and current pharmacotherapy is associated with poor adherence due to adverse events, to gain a better understanding of rifaximin's place in therapy, we reviewed all available published studies of the effectiveness and safety of rifaximin for the treatment of hepatic encephalopathy.

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