From the Guidelines
Encephalopathy and liver failure are closely linked conditions where liver dysfunction leads to brain impairment, and the primary goal of treatment is to address the underlying liver disease while managing encephalopathy symptoms, with lactulose and rifaximin being the primary medications, as recommended by the most recent guidelines 1.
Treatment Approach
When the liver fails, it cannot properly filter toxins like ammonia from the blood, allowing these substances to cross the blood-brain barrier and disrupt normal brain function.
- Lactulose (typically 25-30 mL orally 2-4 times daily) is the primary medication, working by trapping ammonia in the gut and promoting its excretion.
- Rifaximin (550 mg twice daily) is often added as it reduces ammonia-producing gut bacteria.
- Patients require close monitoring of mental status, with dosage adjustments based on response.
Management Considerations
- Protein restriction is no longer routinely recommended, but small, frequent meals with vegetable protein may be better tolerated.
- Identifying and treating precipitating factors like infection, gastrointestinal bleeding, or electrolyte disturbances is crucial.
- In severe cases, patients may need intensive care support.
Long-term Management
- Long-term management includes treating the underlying liver disease, considering liver transplantation evaluation for eligible patients, and preventing recurrent episodes through medication adherence and avoiding hepatotoxic substances, as emphasized by recent studies 1.
- The development of grade 3–4 hepatic encephalopathy is associated with brain edema and intracranial hypertension in 38% to 81% of patients, highlighting the importance of early recognition and management 1.
- Hyperammonemia is associated with cerebral edema and intracranial hypertension in acute liver failure patients, and treatments such as lactulose and rifaximin have not demonstrated benefit in this population 1.
From the FDA Drug Label
The efficacy of XIFAXAN 550 mg taken orally two times a day was evaluated in a randomized, placebo-controlled, double-blind, multi-center 6-month trial of adult subjects from the U.S., Canada, and Russia who were defined as being in remission (Conn score of 0 or 1) from hepatic encephalopathy (HE). Breakthrough overt HE episodes were experienced by 31 of 140 subjects (22%) in the XIFAXAN group and by 73 of 159 subjects (46%) in the placebo group during the 6-month treatment period.
Encephalopathy and Liver Failure: Rifaximin (XIFAXAN) has been shown to reduce the risk of hepatic encephalopathy (HE) breakthrough by 58% during a 6-month treatment period in patients with a history of HE associated with chronic liver disease. The treatment also reduced the risk of HE-related hospitalizations by 50% during the same period 2.
- Key Findings:
- Reduced risk of HE breakthrough
- Reduced risk of HE-related hospitalizations
- Patient Population: Adults with a history of HE associated with chronic liver disease, defined as being in remission (Conn score of 0 or 1) from HE.
From the Research
Encephalopathy and Liver Failure
- Hepatic encephalopathy is a common and devastating complication of chronic liver disease, associated with severe morbidity and mortality 3, 4.
- The management of hepatic encephalopathy varies depending on the acuity of liver failure, but five basic steps are critical: stabilization, addressing modifiable precipitating factors, lowering blood ammonia, managing elevated intracranial pressure, and managing complications of liver failure 3.
- Liver transplantation is the definitive treatment for patients with acute liver failure and hepatic encephalopathy 3.
- In patients with chronic hepatic encephalopathy, lactulose and rifaximin remain a mainstay of therapy, and it is essential to identify reversible causes of hepatic encephalopathy such as increased ammonia production and/or decreased clearance 3, 5.
Treatment Options
- Meta-analyses report beneficial effects of lactulose, branched-chain amino acids, rifaximin, and to some degree L-ornithine L-aspartate on the manifestations of hepatic encephalopathy in patients with cirrhosis 4, 5.
- A network meta-analysis found that rifaximin and lactulose are the most effective treatments for minimal hepatic encephalopathy, and L-ornithine L-aspartate and lactulose are the most effective in preventing overt hepatic encephalopathy 6.
- Probiotics and the combination of probiotics and lactulose may also be effective in reversing minimal hepatic encephalopathy and preventing overt hepatic encephalopathy 6.
Intensive Care Management
- Hepatic encephalopathy is a leading cause for hospital readmission, intensive care treatment, and mortality in patients with chronic liver disease 7.
- The complex and multifaceted pathogenesis of hepatic encephalopathy is not yet fully understood, but hypotheses focus on ammonia and systemic inflammation, which are the main targets for currently available therapies in clinical practice 7.
- Further research is needed to unravel the full spectrum of pathomechanisms and develop novel, highly targeted therapies for hepatic encephalopathy 7.