What are the causes of hyperammonemia?

Causes of Elevated Ammonia

Hyperammonemia results from either primary urea cycle enzyme deficiencies, secondary metabolic disorders (organic acidemias, fatty acid oxidation defects), liver disease, acute kidney injury, or drug-induced inhibition of ammonia metabolism—with urea cycle disorders being the most common cause in neonates and liver disease accounting for approximately 90% of cases in adults. 1, 2

Primary Causes: Urea Cycle Disorders

Congenital enzyme deficiencies are the most important primary causes to recognize:

• Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, occurring in 1 in 56,500 births 1
• Other urea cycle enzyme deficiencies include N-acetylglutamate synthase (NAGS), carbamoyl phosphate synthase I (CPS), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and arginase 1 deficiency 1
• Partial enzyme deficiencies can present later in life (childhood, adolescence, or adulthood) when triggered by metabolic stressors such as illness, high protein intake, or physiological stress 1
• Neonatal presentations include lethargy, poor feeding, vomiting, hypotonia, seizures, and rapid progression to coma 1
• Late-onset presentations may manifest as failure to thrive, irritability, ataxia, intellectual disabilities, and episodic encephalopathy 1

Secondary Metabolic Causes

Organic acidemias and fatty acid oxidation defects are critical secondary causes:

• Organic acidemias (methylmalonic acidemia, isovaleric acidemia, propionic acidemia, multiple carboxylase deficiency) occur in approximately 1 in 21,000 births and can cause severe hyperammonemia 1, 3
• Defects in mitochondrial fatty acid oxidation compromise the urea cycle indirectly and cause hyperammonemia 3, 4
• Transport defects of dibasic amino acids can also lead to ammonia accumulation 4

Drug-Induced Hyperammonemia

Valproic acid (Depakene) is the most important drug cause:

• Valproic acid directly inhibits the urea cycle and can cause severe hyperammonemia 1
• This is a critical pitfall to recognize in patients on anticonvulsant therapy presenting with altered mental status 1

Liver Disease

Hepatic dysfunction is the most common cause in adults:

• Approximately 90% of hyperammonemic patients have underlying liver disease 2
• Liver damage impairs ureagenesis, the primary pathway for ammonia detoxification 5, 6
• Portal-systemic shunting allows intestinal ammonia to bypass hepatic metabolism 6, 2

Renal Causes

• Acute kidney injury impairs ammonia excretion, as the kidneys normally metabolize large amounts of glutamine and excrete ammonia as a urinary buffer 1, 2

Physiological Sources of Ammonia Production

Understanding ammonia production helps identify potential causes:

• Amino acid catabolism through transamination and deamination 1, 5
• Glutamine dehydrogenase activity in liver, kidney, pancreas, and brain 1
• AMP deamination during exercise 1
• Bacterial splitting of urea in the intestines—the gut produces substantial ammonia that is normally cleared by the liver via portal circulation 1, 5

Critical Diagnostic Thresholds

Recognize these levels to assess severity:

• Normal ammonia: ≤35 μmol/L (≤60 μg/dL) in adults 7, 8
• Hyperammonemia defined as: >100 μmol/L (170 μg/dL) in neonates or ≥50 μmol/L (85 μg/dL) in term infants, children, and adults 1, 7, 8
• Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes and require urgent intervention 1, 7, 8

Common Diagnostic Pitfalls

Avoid these critical errors:

• Improper sample collection causes falsely elevated results—must use free-flowing venous/arterial sample without tourniquet or fist clenching, collect in lithium heparin or EDTA tubes, transport on ice immediately, and process within 15 minutes 8
• Hemolysis falsely elevates ammonia 8
• Delayed processing leads to spuriously high levels 8
• In cirrhotic patients, ammonia may be elevated without hepatic encephalopathy, but a normal ammonia level casts doubt on the diagnosis of hepatic encephalopathy 8
• Suspect inherited metabolic disorders when ammonia >100 μmol/L occurs with family history of liver disease, neurological disorders, or unexplained severe neurological impairment 8

Clinical Recognition Triggers

Suspect hyperammonemia in patients presenting with:

• Unexplained neurological symptoms, respiratory alkalosis, ataxia, seizures, or coma 1
• Confusion, lethargy, tremors, dysarthria, or dizziness 7
• Severe compensated metabolic acidosis with large anion gap 9
• Progressive encephalopathy, particularly if triggered by protein intake or illness 1