What causes elevated ammonia levels?

Causes of Elevated Ammonia Levels

Elevated ammonia levels result from either primary urea cycle enzyme deficiencies, secondary metabolic disorders (organic acidemias), liver disease impairing urea synthesis, acute kidney injury reducing ammonia excretion, or medication effects—most notably valproic acid. 1

Primary Causes: Urea Cycle Disorders (UCDs)

Congenital enzyme deficiencies are the fundamental primary cause of hyperammonemia:

• Ornithine transcarbamylase (OTC) deficiency is the most common UCD, occurring in 1 in 56,500 births 1
• Other enzyme deficiencies include N-acetylglutamate synthase (NAGS), carbamoyl phosphate synthase I (CPS), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and arginase 1 deficiency 1, 2
• Partial enzyme deficiencies may not manifest until childhood, adolescence, or adulthood when triggered by metabolic stressors like illness or increased protein intake 1

Secondary Causes

Metabolic Disorders

• Organic acidemias (methylmalonic acidemia, isovaleric acidemia, propionic acidemia, multiple carboxylase deficiency) occur in approximately 1 in 21,000 births and disrupt ammonia metabolism 1, 3

Medication-Induced

• Valproic acid (Depakene) directly inhibits the urea cycle and is a well-established cause of hyperammonemia 1, 3

Liver Disease

• Reduced urea synthesis capacity from acute liver failure (ALF) or cirrhosis prevents normal ammonia detoxification 4, 5
• Portacaval shunting in liver disease allows ammonia to bypass hepatic metabolism, contributing significantly to hyperammonemia 5
• Liver dysfunction is strongly associated with elevated systemic ammonia levels, though this is less common in metabolic dysfunction-associated steatotic liver disease 4

Renal Dysfunction

• Acute kidney injury impairs ammonia excretion, though kidneys can adapt by switching from net ammonia production to net excretion 1, 5
• Patients with ALF who develop acute kidney injury experience further ammonia elevation due to decreased renal clearance 6

Physiological Ammonia Production

Normal ammonia is generated through multiple pathways:

• Amino acid catabolism in various tissues 1
• Glutamine dehydrogenase activity in liver, kidney, pancreas, and brain 1
• AMP deamination during exercise 1
• Bacterial urea splitting in the intestines, particularly the large bowel where bacteria break down amino acids and urea 1, 5

Normal Metabolism and Thresholds

• Normal blood ammonia concentrations are ≤35 μmol/L (≤60 μg/dL) 1, 3
• Hyperammonemia is defined as >100 μmol/L (170 μg/dL) in neonates or ≥50 μmol/L (85 μg/dL) in term infants, children, and adults 1, 3
• Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes 1, 3

Critical Clinical Recognition

Suspect hyperammonemia in patients presenting with:

• Unexplained neurological symptoms including confusion, lethargy, tremors, ataxia, or seizures 1, 3
• Respiratory alkalosis—an important early distinguishing feature from other causes of encephalopathy 1
• Neonatal presentation: lethargy, poor feeding, vomiting, hypotonia within the first few days after feeding begins 1
• Late-onset presentation: failure to thrive, episodic encephalopathy, low protein tolerance, migraine-like headaches 1

Prognostic Significance

• Admission ammonia level >120 μmol/L is associated with higher mortality in acute liver failure patients (OR=7.188, p=0.026) 6
• Levels >200 μmol/L predict intracranial hypertension in 55% of ALF patients, though this threshold fails to identify most cases 7
• Duration of hyperammonemic coma is the most important prognostic factor, inversely correlating with neurological outcomes 1

Common Pitfall

Do not wait for advanced manifestations (seizures, coma, hypotonia) to measure ammonia—these represent late-stage disease, not early signs requiring immediate intervention 1