Management of Overt Hepatic Encephalopathy

Guy W Neff, MD, MBA

In the United States, approximately 8 million people are at risk for chronic liver disease.¹¹ Of those, there are more than 600,000 cases of cirrhosis with up to 46% developing HE.^12,13 The more advanced a patient's liver disease, the more likely the patient will experience HE.⁴ Prognosis is poor, with a 58% mortality rate at 1 year and a 77% mortality rate at 3 years.^3,4

Despite national trends toward reducing inpatient care, the frequency of hospitalization for overt HE has doubled in the last decade (Figure 1). Between one-third to one-half of all hospitalizations of patients with cirrhosis are at least partially due to HE, and the average length of stay is 6 days.⁴ Total costs associated with such hospitalization are approximately $930 million, with a mean cost per hospital stay exceeding $35,000.¹⁴

Figure 1. Discharges of patients with HE are increasing.¹⁴ HE = hepatic encephalopathy; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification. *Data are calculated using ICD-9-CM codes 291.2 (alcoholic dementia, not elsewhere classified), 348.30 (encephalopathy, not otherwise specified), and 572.2 (hepatic coma). The data include all listed discharge diagnoses.

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Overt HE diagnosis is generally based on assessment of both mental status (using the West Haven criteria) and neuromotor function.¹⁵ A patient presenting with cirrhosis and portosystemic shunting that is accompanied by typical HE symptoms is usually sufficient to make a diagnosis. Otherwise, HE tends to be a diagnosis of exclusion, with similar neuropsychiatric symptoms accompanying a number of metabolic disorders, infections, intracranial processes, or ingested poison. Laboratory testing is required to rule out treatable causes (e.g., hypoxia, azotemia, hypoglycemia, and psychoactive drugs), and assessment of arterial or venous ammonia levels can help confirm a diagnosis and correlate with disease severity. A physical exam is important and additional evaluation (e.g., electroencephalogram, lumbar puncture, and/or cranial imaging) may be required to exclude other potential causes.⁵ There are several systems used to classify HE. The one used most frequently in the United States is the West Haven criteria for altered mental status (also called the Conn score), which is based on a patient's level of consciousness, intellectual function, and behavior (Table).¹⁰

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Overt hepatic encephalopathy treatment focuses on several important goals, including maintenance or restoration of function, avoidance of hospitalizations that negatively impact quality of life, and prevention of recurrence.¹ During an overt episode, it is critical to treat any precipitating factors (e.g., infection, gastrointestinal bleeding, electrolyte imbalance) and improve mental status. Once a patient is stable, the focus changes to preventing another overt event and improving activities of daily living. In either scenario, the patient should be evaluated for liver transplantation.⁵

Lactulose, a nonabsorbable disaccharide, had been the mainstay of overt HE therapy.¹⁶ Its laxative effect (a goal of 2 to 3 soft stools per day) is used to lower colonic pH and ultimately decrease plasma ammonia concentration.⁶ More specifically, lactulose is thought to acidify the gut lumen, which promotes the conversion of ammonia to ammonium, an ion that cannot be absorbed by the colon.⁵ For patients with grade 1 or 2 HE, lactulose is typically administered orally, from 2 to 4 times per day, whereas patients with grade 3 or 4 HE typically receive lactulose by nasogastric tube or enema.

Although lactulose is widely used, much of the research on which the treatment is based did not include standard HE definitions and grading scales, adequate sample sizes, and/or control groups.¹⁷ Furthermore, many of the papers that have been published often do not reflect favorably on its efficacy. For example, a meta-analysis of randomized trials concluded that there is not enough evidence to support or refute the use of lactulose for HE.¹⁸ A more recent study found that 74% of patients with overt HE had residual cognitive impairment, despite lactulose therapy (Figure 2).² Finally, of the 91% of patients in remission from recurrent HE who were taking lactulose in the placebo arm of a randomized, double-blind, placebo-controlled trial, 46% experienced breakthrough HE at 6 months.¹

Figure 2. Cognitive deficits may persist despite lactulose treatment.² HE = hepatic encephalopathy.

In addition to concerns about its efficacy, lactulose administration is typically accompanied by adverse events that can decrease a patient's quality of life, including abdominal bloating, distention, and cramping; flatulence; and severe and unpredictable diarrhea.^6,16,19 The latter can result in dehydration, hypokalemia, and hypernatremia and can also trigger another HE episode. Finally, lactulose has a sweet taste, which may not be palatable for some patients. All of these factors can lead to poor compliance, which may result in breakthrough episodes of HE. Indeed, a retrospective analysis of 137 patients with cirrhosis who began lactulose therapy after 1 HE episode found that 38% of the patients who experienced HE recurrence did not take lactulose as prescribed.²⁰ In total, 75% of the patients who were prescribed lactulose developed recurrent HE within an average of nine months following their index episode.

Conventional oral antibiotics (e.g., neomycin and metronidazole) have also been used to treat patients with HE. These drugs reduce enteric, ammonia-producing bacteria, but their potential for adverse events, including nephrotoxicity, ototoxicity, and peripheral neuropathy, may limit their utility.^21,22 Additionally, some are specifically contraindicated for patients with liver disease.^21,23

Unlike conventional oral antibiotics, rifaximin is a minimally absorbed, nonaminoglycoside, oral antimicrobial agent that binds to and inhibits the beta subunit of bacterial DNA–dependent RNA polymerase, decreasing bacterial RNA synthesis.²⁴ While most therapies focus on treating HE episodes as they occur, rifaximin is administered to patients in remission, to reduce the risk of subsequent HE episodes. In a randomized, double-blind, placebo-controlled trial, rifaximin reduced the risk of HE-related hospitalizations by 50% compared with placebo over a 6-month period (Figure 3). During the same time period, rifaximin also reduced the risk of HE recurrence by 58% compared with placebo (Figure 4).¹ At 6 months, 78% of patients in the rifaximin arm and 54% of patients in the placebo arm did not experience a breakthrough episode of HE.

Figure 3. Treatment effect of rifaximin: reduction in hospitalizations.^1,24 Hepatic encephalopathy–related hospitalization was defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred. Lactulose was used concomitantly by 91% of patients in both arms. HR = hazard ratio.

Figure 4. Treatment effect of rifaximin: reduction in risk of overt HE recurrence.^1,24 Hepatic encephalopathy breakthrough defined as increase in Conn score to ≥2 or if baseline Conn = 0, an increase of 1 each in Conn score and asterixis grade. Lactulose was used concomitantly by 91% of patients in both arms. HR = hazard ratio.

Rifaximin offers a safety and tolerability profile comparable to placebo when it is used as directed, which may make it conducive to chronic use. Dosage adjustment is not required for patients with liver or kidney disease, no significant drug-drug interactions have been reported,* and rifaximin has not been shown to cause clinically relevant resistance when used as directed. ^24-26

*The effect of rifaximin on CYP3A4 in patients with impaired liver function who have elevated systemic exposure is not known.

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Hepatic encephalopathy is a common, chronic neuropsychiatric syndrome associated with liver disease or portosystemic shunting and resulting in significant morbidity and mortality. Overt HE recurrence may cause lasting cognitive deficits, so prevention of future episodes is an important treatment goal. Successful HE management also involves early diagnosis and prompt treatment of precipitating factors. Rifaximin, used concomitantly with lactulose, is a highly tolerable treatment that has been clinically proven to reduce the risk of recurrence of overt HE and to reduce HE-related hospitalizations.

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Next month, The GI Digest will focus on bowel preparations for colonoscopy.