At what level of hyperammonemia (elevated ammonia) does hepatic encephalopathy occur?

From the Guidelines

Hepatic encephalopathy typically occurs when blood ammonia levels exceed 150-200 μmol/L (255-340 μg/dL), though there is no absolute threshold as individual susceptibility varies. Ammonia levels between 55-150 μmol/L (94-255 μg/dL) may cause mild symptoms in some patients, especially those with underlying liver disease or portal hypertension. It's essential to understand that the correlation between ammonia levels and encephalopathy severity is imperfect, as some patients develop symptoms at lower levels while others remain asymptomatic at higher levels. Other factors that influence the development of hepatic encephalopathy include inflammation, electrolyte disturbances, medication effects, and blood-brain barrier integrity. Some studies suggest that ammonia levels above 100 mmol/L may be indicative of a poor prognosis 1. However, the most recent and highest quality study recommends using lactulose as secondary prophylaxis following a first episode of overt HE, and should be titrated to obtain 2-3 bowel movements per day 1. Key points to consider in managing patients at risk for hepatic encephalopathy include:

• Regular monitoring of ammonia levels and neurological status
• Lowering ammonia levels through medications like lactulose or rifaximin
• Protein restriction
• Addressing precipitating factors such as gastrointestinal bleeding, infection, or electrolyte abnormalities
• Considering liver transplantation in patients with recurrent or persistent HE 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. Brain imaging by CT scan or MRI should be performed in case of diagnostic doubts or non-response to treatment 1. No cerebral imaging proves a diagnosis of HE, and the development of grade 3–4 HE is associated with brain oedema and intracranial hypertension in 38% to 81% of patients 1. The historical criteria, such as those developed by King’s College Hospital, are used to select candidates for liver transplantation, and include factors such as pH, prothrombin time, creatinine level, and HE grade 1. Recent studies have confirmed the clinically acceptable specificity but more limited sensitivity of these systems, and alternative prognostic systems and markers have been proposed to replace or supplement existing criteria 1. The use of factor V levels, vasopressors need, routine laboratory measurements, and composite laboratory determinations such as the MELD score have been proposed as alternative prognostic systems 1. The close relationship between elevated arterial ammonia levels and the development of encephalopathy, with a greater risk of intracranial hypertension when ammonia levels are sustained between 150 and 200 mmol/L, highlights the importance of monitoring and managing ammonia levels in patients at risk for hepatic encephalopathy 1.

From the Research

Ammonia Levels and Hepatic Encephalopathy

• The exact ammonia level that causes hepatic encephalopathy is not specified in the provided studies 2, 3, 4, 5, 6.
• However, it is established that ammonia plays a crucial role in the pathogenesis of hepatic encephalopathy 3, 5, 6.
• Hyperammonemia is linked to the development of hepatic encephalopathy, and therapies directed at reducing ammonia levels are being developed 5.
• The ammonia hypothesis suggests that ammonia homeostasis is a multiorgan process involving the liver, brain, kidneys, and muscle, as well as the gastrointestinal tract 6.

Treatment of Hepatic Encephalopathy

• Non-absorbable disaccharides, such as lactulose, and antibiotics, such as rifaximin, are used to reduce gut ammoniagenesis and systemic inflammation 2, 3, 4, 6.
• Probiotics, nutritional support, and correction of hypokalemia, hypovolemia, and acidosis also assist in reducing ammonia production 6.
• Early and aggressive treatment of infection, avoidance of sedatives, and modification of portosystemic shunts are also helpful in reducing the neurocognitive effects of hyperammonemia 6.

Ammonia Scavengers

• Ammonia scavengers, such as AST-120, glycerol phenylbutyrate, sodium phenylacetate, and ornithine phenylacetate, have been used to improve hepatic encephalopathy symptoms 5.
• Bowel cleansing with polyethylene glycol 3350 appears to be a promising therapy, with a recent study demonstrating a more rapid improvement in overt hepatic encephalopathy than lactulose 5.