What are the causes of elevated blood ammonia (hyperammonemia)?

Causes of Elevated Blood Ammonia (Hyperammonemia)

Elevated ammonia levels result from either impaired ammonia detoxification (primarily urea cycle disorders and liver disease) or increased ammonia production (intestinal bacteria, protein catabolism, certain medications, and kidney dysfunction). 1

Primary Causes: Urea Cycle Disorders

Congenital enzyme deficiencies in the urea cycle are the most common cause of severe hyperammonemia in neonates and should be suspected in any patient with unexplained neurological symptoms and respiratory alkalosis. 1

• 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 childhood, adolescence, or adulthood, triggered by metabolic stressors such as illness, increased protein intake, or pregnancy 1

Secondary Causes: Metabolic and Acquired Conditions

Organic Acidemias

• Methylmalonic acidemia, isovaleric acidemia, propionic acidemia, and multiple carboxylase deficiency occur in approximately 1 in 21,000 births 1
• These disorders indirectly impair urea cycle function through accumulation of toxic metabolites 2

Liver Disease

• Liver disease is the most common cause of hyperammonemia in adults due to impaired hepatic ammonia clearance from loss of metabolic capacity combined with portosystemic shunting 1, 3
• Altered protein metabolism, particularly of branched-chain amino acids that support extrahepatic ammonia detoxification, accelerates protein breakdown and increases ammonia production 1
• Cirrhosis, acute liver failure, and acute-on-chronic liver failure all result in hyperammonemia 3

Medication-Induced

• Valproic acid (Depakene) inhibits the urea cycle and is a well-recognized cause of hyperammonemia 1, 4
• 5-fluorouracil (5-FU) chemotherapy can cause hyperammonemia 4

Renal Dysfunction

• Acute kidney injury impairs ammonia excretion, as the kidneys normally excrete glutamine and contribute to ammonia metabolism 1
• Correction of hypokalemia, hypovolemia, and acidosis assists in reducing ammonia production in the kidney 5

Hematologic Malignancies

• Certain blood cancers can cause hyperammonemia through increased protein turnover and cell lysis 4

Physiological Sources of Ammonia Production

Understanding normal ammonia metabolism helps identify pathological states:

• Amino acid catabolism is the primary source of ammonia in the body 1
• Intestinal bacterial splitting of urea in the colon produces significant ammonia, which is absorbed into the portal circulation 1, 3
• Glutamine dehydrogenase activity in liver, kidney, pancreas, and brain generates ammonia 1
• Deamination of AMP during exercise produces ammonia 1
• The small intestine is the key source through diet, luminal bacterial activity, and deamination of glutamine in enterocytes 6

Clinical Thresholds and Significance

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

Critical Diagnostic Clues

The presence of respiratory alkalosis with unexplained neurological symptoms is an important early clue that distinguishes hyperammonemia from other causes of encephalopathy. 1, 7

• Suspect hyperammonemia in patients with unexplained stupor, delirium, ataxia, seizures, or coma 1, 4
• In neonates, lethargy, poor feeding, and vomiting within the first few days after feeding begins are the earliest signs 1
• In older patients, failure to thrive, irritability, episodic vomiting, migraine-like headaches, and low protein tolerance may be subtle indicators 1
• Psychiatric manifestations including learning disabilities, delusion, and psychosis can occur before overt neurological deterioration 1

Common Pitfalls

• Do not assume normal liver function excludes hyperammonemia—urea cycle disorders, organic acidemias, and medication effects can cause severe hyperammonemia with completely normal liver enzymes 4
• Do not wait for advanced signs like seizures or coma to measure ammonia—these represent late manifestations, and early recognition is crucial to prevent irreversible brain damage 1
• Blood samples for ammonia must be collected and processed according to specific guidelines (immediate icing, rapid transport) to ensure accurate results, as the test is notoriously unreliable if not performed meticulously 1, 6