What are the possible causes of hyperammonemia?

Causes of Hyperammonemia

Hyperammonemia results from either primary urea cycle enzyme deficiencies or secondary conditions that impair ammonia metabolism, with the most common causes being urea cycle disorders in neonates and liver disease in adults. 1

Primary Causes: Urea Cycle Disorders

Primary hyperammonemia occurs when the urea cycle itself is directly defective due to congenital enzyme deficiencies 1, 2:

• Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, occurring in approximately 1 in 56,500 births 1
• N-acetylglutamate synthase (NAGS) deficiency prevents the formation of the essential urea cycle activator 1, 3
• Carbamoyl phosphate synthase I (CPS1) deficiency blocks the first committed step of the urea cycle 1, 3
• Argininosuccinate synthetase (ASS) deficiency (citrullinemia) prevents citrulline conversion to argininosuccinate 1, 3
• Argininosuccinate lyase (ASL) deficiency (argininosuccinic aciduria) impairs arginine formation 1, 3
• Arginase 1 (ARG1) deficiency prevents the final conversion of arginine to urea 1, 3

These disorders typically present in the neonatal period with severe hyperammonemia, but partial enzyme deficiencies can manifest later in childhood, adolescence, or even adulthood when triggered by metabolic stressors 4, 5.

Secondary Causes: Metabolic and Acquired Conditions

Secondary hyperammonemia occurs when the urea cycle is inhibited by toxic metabolites, substrate deficiencies, or organ dysfunction 2:

Organic Acidemias

• Methylmalonic acidemia, propionic acidemia, isovaleric acidemia, and multiple carboxylase deficiency collectively occur in approximately 1 in 21,000 births and cause secondary urea cycle inhibition through accumulation of toxic organic acids 1, 6

Drug-Induced Hyperammonemia

• Valproic acid (Depakene) directly inhibits the urea cycle and can cause hyperammonemia even with normal liver function 1, 7
• The FDA label specifically warns that hyperammonemia has been reported with valproate therapy and may be present despite normal liver function tests 7
• Concomitant use of valproic acid with topiramate increases the risk of hyperammonemic encephalopathy 7

Organ Dysfunction

• Acute kidney injury impairs ammonia excretion, leading to accumulation 1
• Liver disease accounts for approximately 90% of hyperammonemic patients, as the liver is the primary site of ureagenesis 8

Transport Defects

• Citrin deficiency and other transport defects of dibasic amino acids can impair substrate delivery to the urea cycle 6, 8

Fatty Acid Oxidation Defects

• Beta-oxidation defects can cause secondary hyperammonemia by depleting energy substrates needed for urea cycle function 6

Clinical Recognition

Suspect hyperammonemia in any patient with unexplained neurological symptoms, particularly when accompanied by respiratory alkalosis 1:

• Early-onset (neonatal) presentations include lethargy, poor feeding, vomiting, hypotonia, seizures, and rapid progression to coma if untreated 4
• Late-onset presentations may include failure to thrive, irritability, ataxia, intellectual disabilities, and episodic encephalopathy triggered by illness or protein intake 4, 5
• Atypical presentations can occur, such as acute liver injury with disproportionately elevated ammonia relative to aminotransferases, particularly in adults with previously undiagnosed partial enzyme deficiencies 9

Diagnostic Thresholds

• Normal blood ammonia is ≤35 μmol/L (≤60 μg/dL) in adults 1, 10
• Hyperammonemia is defined as >100 μmol/L (170 μg/dL) in neonates or ≥50 μmol/L (85 μg/dL) in older children and adults 1, 10
• Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes and require urgent intervention 1, 10

Critical Pitfall

The duration and severity of hyperammonemia are the primary determinants of neurological outcome, making rapid recognition and treatment essential to prevent irreversible brain damage 5, 2. Delayed diagnosis, particularly in adults with partial enzyme deficiencies presenting atypically, can lead to catastrophic outcomes that are preventable with prompt metabolic evaluation and therapy 9.