From the Guidelines
Hyperammonemia can be caused by various conditions, including liver dysfunction, genetic disorders, certain medications, gastrointestinal bleeding, infections, kidney failure, excessive protein intake, and rare conditions like Reye's syndrome and organic acidemias. According to the most recent study 1, ammonia levels are always elevated in cases of hepatic encephalopathy (HE) and correlate with the severity and prognosis of HE. The study also suggests that ammonia levels may be elevated without any HE symptoms and can remain stable and elevated during follow-up, even in patients no longer presenting with overt HE.
Causes of Hyperammonemia
- Liver diseases such as cirrhosis, hepatitis, and liver failure
- Genetic disorders like urea cycle defects
- Certain medications including valproic acid, carbamazepine, and some chemotherapy drugs
- Gastrointestinal bleeding
- Infections, particularly those affecting the urinary tract
- Kidney failure
- Excessive protein intake or extreme exercise
- Rare conditions like Reye's syndrome and organic acidemias
Diagnosis and Management
The diagnosis of hyperammonemia involves measuring blood ammonia levels, which can be elevated in patients with liver disease, genetic disorders, or other conditions 1. The management of hyperammonemia depends on identifying and addressing the underlying cause while supporting liver function and reducing ammonia production. In cases of severe hyperammonemia, inherited metabolic disorders should be suspected and further explored 1.
Clinical Features and Treatment
The clinical features of hyperammonemia vary depending on the age of the patient and the cause of the elevation in plasma ammonia levels 1. Early symptoms include lethargy, loss of appetite, and vomiting, which can progress to hyperventilation, hypotonia, ataxia, disorientation, seizures, and coma if left untreated. Treatment depends on the underlying cause and may involve supporting liver function, reducing ammonia production, and managing symptoms. In pediatric patients, the management of hyperammonemia is challenging due to non-specific clinical symptoms and age-specific etiologies 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 Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.
Causes of hyperammonemia include:
- Valproate therapy
- Concomitant administration of topiramate and valproic acid
- Inborn errors of metabolism
- Reduced hepatic mitochondrial activity 2
From the Research
Causes of Hyperammonemia
- Liver disease is closely linked to hyperammonemia, as the liver is responsible for converting ammonia to urea for excretion from the body 3, 4, 5, 6
- Impairment of the urea cycle, which can occur in the later stages of liver cirrhosis, can disrupt ammonia detoxification and cause hyperammonemia 5
- Certain medications, such as sodium valproate, can cause hyperammonemia, particularly in people with underlying liver disease or inherited metabolic disorders like urea cycle disorders 7
- Bacterial splitting of urea in the intestine can also contribute to the production of ammonia in the body 3
- Other factors, such as transamination and deamination activities involving amino acid, purine, pyrimidines, and biogenic amines, can also produce ammonia in the body 3
Associated Conditions
- Hyperammonemia is associated with widespread toxicities, including cerebral edema, hepatic encephalopathy, immune dysfunction, promoting fibrosis, and carcinogenesis 3, 4
- It is also a hallmark of hepatic encephalopathy and has been strongly associated with liver-related outcomes in patients with cirrhosis and liver failure 4, 6
- Elevated systemic ammonia levels can lead to hepatic fibrosis progression, sarcopenia, immune dysfunction, and cancer 4