What are the causes of elevated blood ammonia?

Causes of Elevated Blood Ammonia

Elevated blood ammonia results from either impaired ammonia detoxification (hepatic dysfunction, urea cycle disorders, portosystemic shunting) or increased ammonia production (gastrointestinal bleeding, infection, high protein intake, renal ammonia release, medications). 1, 2

Primary Hepatic Causes

Chronic liver disease with portosystemic shunting is the most common cause of hyperammonemia in adults, where portosystemic collaterals bypass hepatic ammonia clearance—shunting can reach 41% in mild cirrhosis, 69% in moderate, and 85% in severe cases. 3 The combination of reduced hepatic metabolic capacity and increased shunting is sufficient to cause hyperammonemia even when ammonia production remains normal. 3

• Acute liver failure causes hyperammonemia through massive hepatocyte necrosis, allowing portal ammonia to pass directly into systemic circulation without detoxification. 4
• Congenital portosystemic shunts should be suspected in patients with unexplained hyperammonemia, cognitive deficits, or encephalopathy in the absence of cirrhosis—these rare vascular malformations can remain asymptomatic until the sixth or seventh decade. 5

Urea Cycle Disorders (Primary Metabolic Causes)

Congenital deficiency of any of the six urea cycle enzymes leads to ammonia accumulation despite normal liver enzyme tests. 1, 2

• Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder with an incidence of 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 can manifest later in childhood, adolescence, or adulthood when triggered by metabolic stressors such as illness or increased protein intake. 1

Secondary Causes: Increased Ammonia Production

Gastrointestinal bleeding is a major precipitating factor, increasing protein load from blood in the intestine that is metabolized by bacteria into ammonia. 2, 6

• Systemic infections and inflammation precipitate hyperammonemia even with normal liver enzymes through increased catabolism and altered ammonia metabolism. 2, 6
• High protein intake can overwhelm the body's capacity to metabolize ammonia in susceptible individuals. 2
• Constipation increases ammonia production by prolonging intestinal transit time, allowing increased bacterial ammonia generation in the colon. 2

Renal Contribution

The kidneys release ammonia from glutamine metabolism into systemic blood, and this renal ammonia release increases dramatically during gastrointestinal bleeding or hypokalemia, becoming a major source of elevated arterial ammonia. 4

• Acute kidney injury impairs ammonia excretion. 1
• Hypokalemia stimulates renal ammonia production and should be corrected aggressively. 6

Medication-Induced Hyperammonemia

Valproic acid (Depakene) inhibits the urea cycle and leads to hyperammonemia. 1

• Certain antibiotics (carbapenems) and chemotherapeutic agents can cause hyperammonemia. 2

Organic Acidemias

Organic acidemias such as methylmalonic acidemia, isovaleric acidemia, and multiple carboxylase deficiency occur in approximately 1 in 21,000 births and can lead to hyperammonemia. 1

Muscle Contribution

Muscles normally remove ammonia in a concentration-dependent manner and are the primary ammonia-lowering organ in most situations with elevated arterial ammonia. 4 However, during strenuous exercise, muscles produce large amounts of ammonia into systemic blood. 4

Critical Diagnostic Thresholds

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, 2 Normal blood ammonia concentrations are ≤35 μmol/L (≤60 μg/dL). 1

• Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes. 1

Common Pitfalls to Avoid

Do not assume all hyperammonemia is due to liver disease—normal liver enzymes with elevated ammonia should immediately trigger investigation for urea cycle disorders, congenital shunts, medications, or renal causes. 5, 2

• Proper sample collection is crucial: collect from fasting patients when possible, avoid venous stasis, use EDTA-containing tubes, place immediately on ice, and transport to laboratory within 60-90 minutes to avoid false-positive results. 5, 2
• Sample hemolysis, high lipemia, jaundice, high-protein diet, smoking, and exercise can all falsely elevate ammonia results. 5