What causes increased ammonia levels?

Causes of Increased Ammonia Levels

Hyperammonemia is primarily caused by urea cycle disorders, liver disease, certain medications (particularly valproic acid), and renal dysfunction. 1

Primary Causes

• Congenital Urea Cycle Disorders (UCDs): Deficiency in any of the six enzymes in the urea cycle leads to ammonia accumulation, with Ornithine transcarbamylase (OTC) deficiency being the most common (1 in 56,500 births) 1
• Liver Disease: Reduced functioning hepatocyte mass in hepatic failure limits urea cycle capacity, compromising the liver's ability to detoxify ammonia 2
• Valproic Acid Therapy: Can inhibit the urea cycle and lead to hyperammonemia even at therapeutic doses and with normal liver function 1, 3, 4
• Acute Kidney Injury: Impairs ammonia excretion, contributing to elevated levels 1

Secondary Causes

• Organic Acidemias: Conditions such as methylmalonic acidemia, isovaleric acidemia, and multiple carboxylase deficiency (occurring in approximately 1 in 21,000 births) can lead to hyperammonemia 1
• Hypokalemia: In patients with hepatic failure, hypokalemia further impairs the remaining functional urea cycle capacity 2
• Concomitant Medications: Topiramate use with valproic acid has been associated with hyperammonemia with or without encephalopathy 3
• Bacterial Splitting of Urea: Intestinal bacteria can contribute to ammonia production 1

Physiological Mechanisms of Ammonia Production

• Amino Acid Catabolism: Normal breakdown of amino acids produces ammonia 1
• Glutamine Dehydrogenase Activity: Occurs in liver, kidney, pancreas, and brain 1
• AMP Deamination: Occurs during exercise 1
• Intestinal Bacteria: Split urea into ammonia in the intestines 1

Clinical Significance and Diagnostic Levels

• Normal Blood Ammonia: ≤35 μmol/L (≤60 μg/dL) 1, 5
• Hyperammonemia Definition:

  • 100 μmol/L (170 μg/dL) in neonates 1, 5

  • ≥50 μmol/L (85 μg/dL) in term infants, children, and adults 1, 5
• Critical Level: >200 μmol/L (341 μg/dL) is associated with poor neurological outcomes 1, 5, 6

Valproic Acid-Induced Hyperammonemia

• FDA Warning: Hyperammonemia has been reported with valproate therapy even with normal liver function tests 3
• Monitoring Recommendation: In patients on valproic acid who develop unexplained lethargy, vomiting, or changes in mental status, ammonia levels should be measured 3
• Multiple Mechanisms: Different decay kinetics of venous ammonia in the presence of high and low concentrations of valproic acid indicates more than one concurrent etiological mechanism 7
• Drug Interactions: Concomitant use of topiramate and valproate increases risk of hyperammonemia 3

Neurological Manifestations of Hyperammonemia

• Pathophysiology: Ammonia crosses the blood-brain barrier and is metabolized to glutamine by astrocytes, leading to cerebral edema and inflammatory cytokine release 5
• Common Symptoms: Tremors, dysarthria, confusion, lethargy, dizziness, hypotonia, headache, ataxia, seizures, and in severe cases, coma 5
• Encephalopathy Risk: Ammonia levels >100 μmol/L predict development of severe hepatic encephalopathy with 70% accuracy 6

Clinical Pearls and Pitfalls

• Suspect hyperammonemia in patients with unexplained neurological symptoms, respiratory alkalosis, ataxia, seizures, or coma 1
• Monitor ammonia levels in patients on valproic acid therapy who develop any change in mental status 3
• Consider multiple etiologies when hyperammonemia persists despite addressing the primary cause 7
• Youth, requirement for vasopressors, and renal replacement therapy are additional independent risk factors for intracranial hypertension in hyperammonemic patients 6