Hyperammonemia
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A plasma ammonia above the age-specific upper limit in a symptomatic patient (roughly > 100 µmol/L in a neonate, > 80 µmol/L beyond infancy, with anything > 150 µmol/L treated as a metabolic emergency). The clinical picture is encephalopathy out of proportion to the rest of the labs: lethargy, poor feeding, vomiting, tachypnea, progressive obtundation, seizures, cerebral edema. Ammonia is directly neurotoxic; every hour the brain sits at > 200 µmol/L compounds long-term injury, and dialysis is on the table early.
The cardinal question in front of a hyperammonemic patient is whether acidosis is present.
- Hyperammonemia WITHOUT acidosis (often respiratory alkalosis from CNS hyperventilation) → urea cycle defect until proven otherwise.
- Hyperammonemia WITH high anion-gap acidosis and ketosis → organic acidemia (propionic acidemia, methylmalonic acidemia, isovaleric acidemia).
Once a UCD is suspected, the next two labs decide the gene: plasma citrulline (proximal vs distal block) and urine orotic acid (cytosolic vs mitochondrial enzyme).
Urea cycle defects (algorithm by citrulline and orotic acid)
| Plasma citrulline | Urine orotic acid | Disorder | Inheritance |
|---|---|---|---|
| Low | Low | NAGS deficiency | AR |
| Low | Low | CPS1 deficiency | AR |
| Low | High | OTC deficiency | X-linked |
| Very high | High | ASS1 (citrullinemia type 1) | AR |
| Moderately high (+ ASA in urine) | High | ASL deficiency (argininosuccinic aciduria) | AR |
| Normal-low (high arginine) | Variable | ARG1 (arginase) deficiency | AR |
| High ornithine + homocitrullinuria | High | HHH syndrome (SLC25A15) | AR |
The exam favorite is OTC deficiency: an X-linked, partially-penetrant cause that classically presents as a previously well boy or a manifesting female carrier with episodic hyperammonemia after a protein load, illness, or postpartum catabolism. Low citrulline plus high orotic acid is the splitting branch off CPS1/NAGS.
Organic acidemias (ammonia AND acidosis AND ketosis)
Propionic, methylmalonic, and isovaleric acidemias inhibit N-acetylglutamate synthase secondarily, so ammonia rises alongside the dominant high anion-gap acidosis. Urine organic acids and plasma acylcarnitine profile crack the case (C3 in PA/MMA, C5 in IVA).
Other causes worth a glance
- Liver failure of any etiology (galactosemia, tyrosinemia, neonatal hemochromatosis).
- Portosystemic shunt (Abernethy malformation) presenting in older children.
- Valproate-induced (often unmasks an underlying OTC carrier).
- Pyruvate carboxylase deficiency, lysinuric protein intolerance (rare).
- No acidosis, often respiratory alkalosis → urea cycle defect.
- High anion-gap acidosis with ketosis → organic acidemia.
- Low citrulline + high urine orotic acid → OTC (X-linked; manifesting female carriers exist).
- Massively elevated citrulline → ASS1 (citrullinemia type 1).
- Argininosuccinic acid detectable in urine → ASL.
- Previously well child on the third postpartum day with progressive lethargy → late-onset OTC (or another UCD) until disproven.
- Valproate-precipitated coma → think undiagnosed OTC carrier.
In a patient with ammonia > 150 µmol/L, treatment and diagnosis run in parallel. Don't wait on labs to escalate.
- Repeat ammonia free-flowing, on ice, run STAT. Tourniquet artifact and delayed processing falsely elevate.
- Venous blood gas, glucose, lactate, electrolytes (anion gap), ketones: classify the metabolic phenotype.
- Plasma amino acids (citrulline is the branch point), plasma acylcarnitine profile (PA/MMA/IVA signatures), urine organic acids, urine orotic acid.
- Liver function (rule out hepatic failure as the cause).
- Empiric treatment while results return: stop protein intake, start D10 IV at 1.5× maintenance to suppress catabolism, give IV nitrogen-scavengers (sodium benzoate + sodium phenylacetate, marketed as Ammonul), IV L-arginine (provides substrate for the urea cycle distal to CPS1).
- Hemodialysis (preferred over CRRT for speed) for ammonia > 500 µmol/L, rising despite scavengers, or coma. Peritoneal dialysis and exchange transfusion are slower and last-resort.
- Targeted gene sequencing once the biochemical phenotype is in hand; broad metabolic panel or exome if unclear.
- No acidosis + high ammonia = UCD. The single most useful initial sorting rule. Respiratory alkalosis (from central hyperventilation) is the tell.
- Citrulline is the gene-localizer. Low + high orotic = OTC. Very high citrulline = ASS1. Argininosuccinic acid = ASL.
- OTC is X-linked but female carriers can present, sometimes triggered by pregnancy, surgery, or valproate. Don't reject OTC in a girl.
- Ammonia > 500 = dialysis. Hours of hyperammonemic coma map onto IQ points lost. Call nephrology before the labs are back.
- Newborn screening catches most organic acidemias before the first crisis; a child in crisis is often pre-screen or false-negative. Re-check the screen.