From the Guidelines
Refractory elevated ammonia levels are most commonly caused by severe liver dysfunction, inborn errors of metabolism, medication effects, excessive protein intake or catabolism, gastrointestinal bleeding, infections or sepsis, and renal failure. The causes of refractory elevated ammonia can be multifactorial, including:
- Severe liver dysfunction, such as advanced cirrhosis, acute liver failure, or portosystemic shunts, which impairs the liver's ability to convert ammonia to urea efficiently 1
- Certain inborn errors of metabolism, like urea cycle disorders or organic acidemias, that disrupt normal ammonia processing 1
- Medication effects from drugs like valproic acid, carbamazepine, or certain chemotherapeutics that can interfere with ammonia metabolism 1
- Excessive protein intake or catabolism that overwhelms the body's clearance capacity 1
- Gastrointestinal bleeding that increases protein breakdown in the gut 1
- Infections or sepsis that increase protein catabolism 1
- Renal failure that impairs ammonia excretion 1 Management typically involves treating the underlying cause while implementing ammonia-lowering therapies, such as lactulose or rifaximin, or in severe cases, continuous renal replacement therapy 1. Prompt identification and treatment of the underlying cause are essential for preventing neurological complications, as ammonia is neurotoxic at high levels, causing cerebral edema and potentially hepatic encephalopathy 1.
From the Research
Causes of Refractory Elevated Ammonia
Refractory elevated ammonia can be caused by various factors, including:
- Hepatic encephalopathy (HE), a serious neuropsychiatric complication seen in patients with liver failure 2
- Valproic acid exposure, which can result in hyperammonemic encephalopathy even in the absence of hepatotoxicity or inborn errors of metabolism 3, 4
- Inadequate treatment of hyperammonemia, which can lead to persistent elevated ammonia levels
- Presence of other underlying medical conditions, such as cirrhosis, that can contribute to elevated ammonia levels
Medication-Related Causes
Certain medications, such as valproic acid, can increase the risk of developing refractory elevated ammonia:
- Valproic acid-induced hyperammonemic encephalopathy can occur in patients with normal liver function and normal doses of the medication 4
- The use of valproic acid requires careful monitoring of ammonia levels, especially in patients with a history of encephalopathy or liver disease
Treatment-Related Challenges
The treatment of refractory elevated ammonia can be challenging due to:
- Limited understanding of the pathogenesis of hepatic encephalopathy and the role of ammonia in its development 2
- Lack of effective treatments that can specifically target ammonia and reduce its levels in the blood
- Need for further research to evaluate the potential benefits and harms of novel ammonia-lowering agents, such as glycerol phenylbutyrate and polyethylene glycol 5, 6