Causes of Elevated Ammonia
Elevated ammonia results from either primary urea cycle enzyme deficiencies, secondary metabolic disorders (organic acidemias), liver disease, acute kidney injury, or medication effects—most commonly valproic acid. 1
Primary Causes: Urea Cycle Disorders
The most fundamental cause of hyperammonemia involves congenital deficiencies of the six enzymes in the urea cycle 1:
- N-acetylglutamate synthase (NAGS) deficiency 1
- Carbamoyl phosphate synthase I (CPS) deficiency 1
- Ornithine transcarbamylase (OTC) deficiency—the most common UCD with an incidence of 1 in 56,500 births 1
- Argininosuccinate synthetase (ASS) deficiency 1
- Argininosuccinate lyase (ASL) deficiency 1
- Arginase 1 deficiency 1
These disorders typically present in the neonatal period with severe hyperammonemia, but partial enzyme deficiencies can manifest later in childhood, adolescence, or adulthood when triggered by metabolic stressors 1. Adult presentations are often nonspecific, including headache, avoidance of high-protein food, psychiatric symptoms triggered by heavy exercise or childbirth, autism, attention deficit, lethargy, and epilepsy 2.
Secondary Causes: Metabolic and Acquired Disorders
Organic Acidemias
- Methylmalonic acidemia, isovaleric acidemia, and multiple carboxylase deficiency occur in approximately 1 in 21,000 births and lead to hyperammonemia 1
- These disorders compromise the urea cycle indirectly 3
Medication-Induced
- Valproic acid (Depakene) inhibits the urea cycle and is a well-documented cause of drug-induced hyperammonemia 1, 4
Organ Dysfunction
- Acute liver failure prevents normal ammonia metabolism through the urea cycle 5, 6
- Acute kidney injury impairs ammonia excretion, leading to further accumulation 1, 7
- Patients with acute liver failure who develop concomitant renal failure experience compounded ammonia elevation due to decreased kidney excretion 7
Physiological Mechanisms of Ammonia Production
Ammonia is continuously produced through multiple pathways 1:
- Amino acid catabolism in tissues 1
- Glutamine dehydrogenase activity in liver, kidney, pancreas, and brain 1
- Deamination of AMP during exercise 1
- Bacterial splitting of urea in the intestines 1
Normal ammonia processing involves the urea cycle in hepatocytes converting ammonia to urea for urinary excretion, and conversion to glutamine that is partially excreted by kidneys 1. When these pathways fail, ammonia accumulates systemically 6.
Clinical Thresholds and Significance
Normal blood ammonia concentrations are ≤35 μmol/L (≤60 μg/dL) 1, 4. Hyperammonemia is defined as:
- >100 μmol/L (170 μg/dL) in neonates 1, 4
- ≥50 μmol/L (85 μg/dL) in term infants, children, and adults 1, 4
Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes 1, 4, and in acute liver failure patients, levels >200 μmol/L result in intracranial hypertension in 55% of cases 5. Admission ammonia levels >120 µmol/L are associated with higher mortality in acute liver failure patients with grade 3-4 hepatic encephalopathy 7.
When to Suspect Hyperammonemia
Suspect elevated ammonia in patients presenting with 1, 4:
- Unexplained neurological symptoms including confusion, lethargy, tremors, dysarthria 4
- Respiratory alkalosis (a key early finding) 1
- Ataxia, seizures, or coma 1, 4
- Neonatal presentations: lethargy, poor feeding, vomiting, hypotonia, rapid progression to coma 1
- Late-onset presentations: failure to thrive, irritability, intellectual disabilities, episodic encephalopathy triggered by illness or protein intake 1
Critical Pitfall
Do not assume hyperammonemia only occurs in patients with obvious liver disease. Urea cycle disorders can present for the first time in adulthood with nonspecific symptoms, and valproic acid can cause hyperammonemia even in patients with normal liver function 1, 2. Always measure ammonia levels in patients with unexplained encephalopathy, regardless of age or apparent liver health 1.