From the Guidelines
Hyperammonemia is primarily caused by liver disease or liver failure, as well as kidney disease, certain medications, and genetic disorders such as urea cycle disorders. The liver plays a crucial role in removing ammonia from the blood, and its dysfunction can lead to elevated ammonia levels 1. Other causes of hyperammonemia include:
- Kidney disease, which can impair the excretion of ammonia 1
- Certain medications, such as valproic acid, which can inhibit the urea cycle 1
- Genetic disorders, such as urea cycle disorders, which can affect the body's ability to remove ammonia 1
- High-protein diets, gastrointestinal bleeding, and infections, which can increase ammonia production 1
- Conditions like Reye's syndrome, which can cause liver dysfunction and lead to hyperammonemia 1
It is essential to note that hyperammonemia can have severe neurological consequences, including cerebral edema and intracranial hypertension, especially in patients with acute liver failure 1. Therefore, it is crucial to consult a healthcare professional for proper evaluation and treatment if ammonia levels are elevated. The diagnosis and management of hyperammonemia require a comprehensive approach, taking into account the underlying cause and the patient's overall clinical condition 1.
From the FDA Drug Label
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured Hyperammonemia should also be considered in patients who present with hypothermia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons
The causes of hyperammonemia (elevated ammonia levels) include:
- Valproate therapy: Hyperammonemia has been reported in association with valproate therapy, even with normal liver function tests.
- Inborn errors of metabolism: Patients with inborn errors of metabolism may be at an increased risk for hyperammonemia.
- Reduced hepatic mitochondrial activity: Reduced hepatic mitochondrial activity may increase the risk of hyperammonemia.
- Concomitant use of topiramate and valproic acid: The interaction between topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons, leading to hyperammonemia.
- Urea cycle disorders: Hyperammonemia may be caused by underlying urea cycle disorders 2
From the Research
Causes of Hyperammonemia
- Liver dysfunction is a primary cause of hyperammonemia, as the liver plays a central role in the urea cycle, which is responsible for removing ammonia from the body 3, 4
- Inherited defects of the urea cycle and fatty acid oxidation can also lead to hyperammonemia, particularly in adults with no prior history of liver disease 4
- Other causes of hyperammonemia include:
- Excessive ammonia load, which can occur when the body's ability to detoxify ammonia is overwhelmed 4
- Portal blood from the intestines bypassing the liver, which can lead to a buildup of ammonia in the bloodstream 4
- Poor urea cycle function, which can be caused by a variety of factors, including genetic disorders and liver disease 4
- Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) can also lead to hyperammonemia, which is associated with worse neurological outcomes, including high-grade hepatic encephalopathy (HE), cerebral edema, and intracranial hypertension 5, 6, 7
- Renal failure can further exacerbate hyperammonemia in patients with ALF, as the kidneys play a crucial role in removing ammonia from the body 6
Risk Factors for Hyperammonemia
- Elevated arterial ammonia concentration is an independent risk factor for the development of severe hepatic encephalopathy (HE) and intracranial hypertension (ICH) 5
- Model for End-Stage Liver Disease (MELD) score is also independently predictive of HE, and its combination with ammonia increases specificity and accuracy 5
- Youth, requirement for vasopressors, and renal replacement therapy are additional independent risk factors for ICH 5
- Admission ammonia level (>120 µmol/L) is associated with higher mortality rate in patients with ALF and grade 3-4 HE 6