Dr. Chapman of George Washington University and Children’s National Rare Disease Institute has no relevant financial relationships to disclose.)
The authors of this clinical article discuss causes of hyperammonemia unrelated to liver failure. They provide information on differential diagnosis and testing to promptly identify these disorders. A basic outline of treatment is provided to help prevent long-term neurologic complications.
• Not all hyperammonemia is caused by acquired liver disease. Consider vascular liver bypass, medications, and metabolic diseases, including urea cycle disorders, organic acidemias, transporter defects, and energy-deficient states.
• Drugs that mimic metabolic disease or situations that increase protein catabolism to a degree that overwhelms urea cycle enzymes can cause hyperammonemia.
• Identify, diagnose, and treat hyperammonemia quickly (hours, not days) because the duration of hyperammonemia is positively correlated with long-term neurologic complications.
Historical note and terminology
Hyperammonemia is defined as plasma ammonia concentrations greater than 110 μmol/L (186 mg/dL) in healthy neonates. Sick neonates can have plasma ammonia concentrations as high as 180 μmol/L (305 mg/dL) without having an underlying metabolic cause. After the neonatal period, hyperammonemia is considered as concentrations greater than 80 μmol/L (135 mg/dL) (Zschocke and Hoffmann 2004).
In 1963, Russell and colleagues described a child with hyperammonemia unrelated to liver failure caused by a defect in the biosynthesis of urea (Russell et al 1962). By 1965, Wilmanns published a review of a new class of inborn errors called “urea cycle disorders,” which caused hyperammonemia that was not related to liver failure (Wilmanns 1965). Other inherited disorders of metabolism were identified that increased plasma ammonia concentrations, including defects in all the enzymes of the urea cycle and specific organic acidemias (eg, propionic acidemia and methylmalonic acidemia). Abnormal mitochondrial transport of precursors was also identified as a cause of hyperammonemia. In the early 1980s, some causes of Reye syndrome, in which hyperammonemia is a characteristic finding, were identified as being due to fatty acid oxidation defects, mitochondrial disease (often with concurrent liver failure), and carnitine transporter defects.
Metabolic diseases that cause hyperammonemia can be categorized into those that involve nitrogen metabolism and excretion (predominately urea cycle defects) and those with metabolites or toxins that inhibit urea cycle function or prevent adequate energy for its normal function (eg, organic acidemias, mitochondrial disorders, and fatty acid oxidation defects) (Batshaw 1984; Bachmann 2003; Braissant 2010). Other conditions that can cause hyperammonemia include those that prevent delivery of nitrogen to the liver (eg, portosystemic bypasses and patent ductus venosus), or those that cause increased ammonia production by stimulating protein catabolism (eg, crush injuries, tumor lysis syndrome, lung transplantation, and status epilepticus).
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