Is elevated ammonium (ammonia) a requirement for the diagnosis of hepatic encephalopathy?

From the Guidelines

Elevated ammonium levels are not a prerequisite for the diagnosis of hepatic encephalopathy (HE), as normal ammonia levels can be present in patients with clinically evident HE. According to the most recent guidelines, specifically the 2022 EASL clinical practice guidelines on the management of hepatic encephalopathy 1, the diagnosis of HE should be based on clinical findings, and ammonia levels may help support the diagnosis or monitor treatment response, but they correlate poorly with HE severity. The guidelines also state that in patients with suspected HE, alternative or additional causes of neuropsychiatric impairment should be identified to improve prognostic accuracy and the results of treatment 1.

Key points to consider in the diagnosis and management of HE include:

• The West Haven criteria should be used for HE grading when at least temporal disorientation is present 1
• The Glasgow coma scale should be added in patients with grades III-IV West Haven criteria 1
• Patients with HE should not be classified based on the aetiology of their underlying liver disease 1
• In patients with delirium/encephalopathy and liver disease, plasma ammonia measurement should be performed, as a normal value brings the diagnosis of HE into question 1
• Treatment focuses on addressing the underlying liver condition, reducing ammonia production, correcting precipitating factors, and providing supportive care, with lactulose and rifaximin being recommended as secondary prophylaxis following a first episode of overt HE 1.

The pathophysiology of HE involves multiple neurotoxins that disrupt brain function when the liver fails to clear them, with ammonia being just one component of this complex process. As stated in the 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases, increased blood ammonia alone does not add any diagnostic, staging, or prognostic value for HE in patients with chronic liver disease 1. Therefore, the diagnosis of HE should be based on a comprehensive clinical evaluation, rather than relying solely on ammonia levels.

From the FDA Drug Label

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. Lactulose causes a decrease in blood ammonia concentration and reduces the degree of portal-systemic encephalopathy.

Hepatic Encephalopathy can occur with or without elevated ammonium levels. The FDA drug label does not explicitly state that elevated ammonium is a requirement for hepatic encephalopathy, but it does indicate that lactulose therapy reduces blood ammonia levels and improves the mental state of patients with portal-systemic encephalopathy 2 2.

• The clinical response to lactulose therapy has been observed in about 75% of patients.
• Lactulose therapy reduces the degree of portal-systemic encephalopathy by decreasing blood ammonia concentration.

From the Research

Hepatic Encephalopathy and Ammonium Levels

• Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency and/or portal-systemic shunting, and it is related to gut-derived substances 3.
• The pathophysiology of HE is not fully understood, but ammonia production is believed to be an important contributing factor 4.
• Elevated ammonium levels are often associated with HE, but it is not clear if elevated ammonium is a necessary condition for HE to occur.

Treatment of Hepatic Encephalopathy

• Lactulose and rifaximin are commonly used to treat HE, and they have been shown to be effective in reducing ammonia levels and improving symptoms 5, 6, 7.
• Rifaximin has been found to be a good alternative to lactulose in the treatment of HE, with rapid action and few side effects 7.
• The combination of rifaximin and lactulose has been shown to be more effective than lactulose alone in reducing hospitalization rates and improving treatment outcomes 5, 6.

Diagnosis and Management of Hepatic Encephalopathy

• Proper diagnosis and classification of HE are important for improving management and treatment outcomes 3.
• The diagnosis of HE is based on clinical criteria, including mental status, behavior, and asterixis, as well as laboratory tests such as serum ammonia concentration 4, 7.
• The management of HE includes prophylaxis of overt HE, primary prophylaxis after upper gastrointestinal bleeding, and treatment of mild forms of HE 3.