What is the pathophysiology, diagnosis, and management of hepatic (liver) encephalopathy?

From the Guidelines

Hepatic encephalopathy should be managed with lactulose as the primary treatment, given at 20-30 g orally 3-4 times per day, with the goal of achieving 2-3 soft stools per day, as recommended by the most recent guidelines 1.

Overview of Hepatic Encephalopathy

Hepatic encephalopathy is a serious neuropsychiatric complication of liver disease where toxins, primarily ammonia, accumulate in the bloodstream and affect brain function due to the liver's inability to remove them. It occurs in patients with cirrhosis, acute liver failure, or portosystemic shunts. Symptoms range from mild confusion, personality changes, and sleep disturbances to severe manifestations including disorientation, asterixis (flapping tremor), and potentially coma.

Diagnosis

Diagnosis relies on clinical assessment, neurological examination, and blood tests for ammonia levels, while excluding other causes of altered mental status. Identifying and treating precipitating factors such as infections, gastrointestinal bleeding, electrolyte disturbances, or medication non-compliance are crucial in the management of hepatic encephalopathy, as outlined in the guidelines 1.

Treatment

The primary treatment is lactulose, a non-absorbable disaccharide. Rifaximin, a non-absorbable antibiotic, is often added at 400 mg three times/day or 550 mg twice/day to reduce ammonia-producing gut bacteria. Other treatment options include oral BCAA at 0.25 g/kg/day, intravenous LOLA at 30 g/day, and albumin at 1.5 g/kg/day until clinical improvement or for 10 days, maximum, as recommended by the guidelines 1.

Management of Precipitating Factors

Acute management includes identifying and treating precipitating factors such as:

• Gastrointestinal bleeding: treated with transfusion, endoscopy, or interventional radiology
• Infection: treated with antibiotics
• Constipation: treated with enema or laxatives
• Excessive protein intake: managed by limiting protein intake
• Dehydration: managed by stopping or reducing diuretics and fluid therapy
• Renal dysfunction: managed by stopping or reducing diuretics and fluid therapy
• Hyponatremia: managed by stopping or reducing diuretics and fluid restriction
• Hypokalemia: managed by stopping or reducing diuretics
• Benzodiazepine and opioids: managed by stopping the medication and using flumazenil or naloxone if necessary, as outlined in the guidelines 1.

Prevention of Recurrence

For prevention of recurrence, long-term lactulose and rifaximin are typically continued, and patients should avoid sedatives, opioids, and other medications that can worsen symptoms. Regular monitoring of liver function and mental status is essential, and patients with recurrent episodes may need evaluation for liver transplantation, as recommended by the most recent guidelines 1.

From the FDA Drug Label

For the prevention and treatment of portal-systemic encephalopathy, including the stages of hepatic pre-coma and coma. Controlled studies have shown that lactulose solution therapy reduces the blood ammonia levels by 25 to 50%; this is generally paralleled by the improvement in the patients’ mental state and by an improvement in EEG patterns.

• Hepatic Encephalopathy Treatment: Lactulose is used for the prevention and treatment of portal-systemic encephalopathy, including hepatic pre-coma and coma.
• Efficacy: The clinical response to lactulose therapy has been observed in about 75% of patients.
• Mechanism: Lactulose reduces blood ammonia levels by 25 to 50%, which is paralleled by an improvement in the patients’ mental state and EEG patterns.
• Duration of Treatment: Lactulose has been given for over 2 years in controlled studies for the treatment of chronic portal-systemic encephalopathy 2

From the Research

Definition and Classification of Hepatic Encephalopathy

• Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting 3
• It is a broad spectrum of neuropsychiatric manifestations usually affecting individuals with end-stage liver disease 4
• HE is classified according to the underlying disease, the severity of manifestations, its time course, and the existence of precipitating factors 5

Pathophysiology of Hepatic Encephalopathy

• The precise pathophysiology of HE is still under discussion, but the leading hypothesis focuses on the role of neurotoxins, impaired neurotransmission due to metabolic changes in liver failure, changes in brain energy metabolism, systemic inflammatory response, and alterations of the blood-brain barrier 5
• Elevated plasma and central nervous system ammonia levels are considered key factors in its pathogenesis 4

Clinical Symptoms and Diagnosis of Hepatic Encephalopathy

• The clinical symptoms of HE are widely variable, extending from subtle impairment in mental state to coma 3
• Minimal HE is diagnosed by abnormal psychometric tests, while clinically overt HE includes personality changes, alterations in consciousness, progressive disorientation in time and space, somnolence, stupor, and finally, coma 5
• Except for clinical studies, no specific tests are required for diagnosis 5

Treatment of Hepatic Encephalopathy

• The mainstay of treatment for many years has been nonabsorbable disaccharides, particularly lactulose 4
• Alternative treatments include zinc, antibiotics (neomycin, metronidazole, and rifaximin), ornithine aspartate, sodium benzoate, probiotics, and surgical intervention 4
• The combination of rifaximin and lactulose may be considered in the treatment of HE and in patients refractory to monotherapy, and should be considered for the prevention of HE, especially after the second episode of HE recurrence 6
• Lactulose and rifaximin have been shown to improve patient-reported outcomes, including health-related quality of life, social functioning, and sleep 7

Patient-Reported Outcomes in Hepatic Encephalopathy

• Patients with HE suffer from significant symptoms and impaired quality of life 7
• Lactulose and rifaximin have been shown to improve patient-reported outcomes, including health-related quality of life, social functioning, and sleep 7
• The results of studies examining the effects of lactulose and rifaximin on patient-reported outcomes may inform provider-patient communication and help manage patient expectations regarding the potential benefits of HE therapies 7