Hyperammonemia in the Emergency Department

Identification of Hyperammonemia in Urea Cycle Disorder and other inborn errors of metabolism

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Causes of Decreased Ammonia Elimination
Inborn error of metabolism

  • Urea cycle disorders
  • Lysinuric protein intolerance
  • Organic acidurias
  • Fatty acid oxidation defects

Liver failure (ASA and OTC can present with elevated liver enzymes)
Acetaminophen, steroid, or valproic acid ingestion

Unexplained vomiting, headache, lethargy
Confusion, ataxia, slurred speech
Agitation, unusual irritability, unusual behavior
Unexplained psychosis, delusions or hallucinations, postpartum psychosis (adults)
Stroke-like symptoms

Respiratory alkalosis
Irritability progressing to lethargy, somnolence, coma
Decerebrate posturing

Presenting Symptoms in 260 UCD Patients at First Presentation of Hyperammonemia (Longitudinal Study of Urea Cycle Disorders, Urea Cycle Disorders Consortium)
• Neurologic symptoms (100%)
• Decreased level of consciousness (63%)
• Abnormal motor function or tone (30%)
• Seizures (10%)
• Vomiting (19%)
• Infection (30%)
• Subjective: Decreased appetite, fussy
• Physiologic: Respiratory alkalosis followed by apnea

Protein aversion
Loss of appetite
Sleep disorders
Psychiatric or behavioral disorders
Trichorrhexis nodosa (due to dysregulated arginine)

Sudden onset of symptoms following high protein diet or supplements
Catabolic state

Triggers - Causes of Increased Ammonia Production (*commonly seen in UCD)
*Virus or Infection
Urease producing bacteria (Proteus, Klebsiella)
Protein load and increased catabolism
*High protein diet or supplements
*Severe exercise
Trauma or burns, massive hemolysis (large bone fracture or trauma)
*Steroid administration
*Starvation, excessive dieting
*Gastric bypass surgery
GI hemorrhage
Increased renal ammonia production
Increased splanchnic ammonia production
*Increased peripheral catabolism due to deficiency of essential amino acids
TPN (*adults)
Cancer (multiple myeloma)

Drug or supplement ingestion
Corticosteroids (most commonly prednisone)
Valproic acid
MDMA ecstasy
Systemic antifungals

Medical History (may include any)
Behavioral disorder (ADD, ADHD, other), psychiatric disorder (bipolar, depression, schizophrenia)
Poor feeding or protein avoidance
Cyclic vomiting
Recent drug changes (antibiotics, valproate, corticosteroids)
Recent vaccination (triggers catabolism; effects may also be linked to preexisting mitochondrial defects in children with IEM)
Recent surgeries (anesthesia in peds and adults, TURP in adults)
GI bleeding
Urinary tract infection

Social History
Previous death in family
Infant (SIDS, sudden coma, unexplained encephalopathy, etc.)
Childhood (chicken pox vaccine, DPT, unexplained encephalopathy or coma)
Adult (sudden encephalopathy, stroke-like symptoms, psychiatric)
Recent travel (hepatitis A, vaccination, viral infection)
Illicit drug use
Learning disability or developmental delay
Unexplained lethargy or sleep disturbances
Unusual behavior (agitation, irritability, personality change)
Maternal history of migraine headache

Diagnostic Evaluation
Serum Ammonia level (vacutainer on ice, run STAT)
CBC w/differential
Blood cultures
Urine and plasma amino acids
Blood gas

Lactose is not recommended for the treatment of hyperammonemia in inborn errors of metabolism.
Valproic acid

Contact medical genetics/metabolic genetics immediately
Transfer to ICU
IV support with D10

Additional considerations (urea cycle disorders)
In addition to plasma ammonia, laboratory data useful in the diagnosis of UCDs include pH, CO2, the anion gap, blood lactate, plasma acylcarnitine profile, plasma and urine amino acids, and urine organic acid analyses including the specific determination of orotic acid. Patients with true urea cycle defects will typically have normal glucose and electrolyte levels. The pH and CO2 can vary with the degree of cerebral edema and hyper- or hypo-ventilation. In neonates it should be remembered that the basal ammonia level is elevated over that of adults, which typically is less than 35 μmol/L (less than 110 μmol/L in neonates). An elevated plasma ammonia level of 150 μmol/L (>260 μg/dl) or higher in neonates and >100 μmol/l (175 μg/dl) in older children and adults, associated with a normal anion gap and a normal blood glucose level, is a strong indication for the presence of a urea cycle defect. Quantitative plasma amino acid analysis can be used to evaluate these patients and arrive at a tentative diagnosis. Summer ML, Le Mons CL, ed. Physician’s Guide to Urea Cycle Disorders (download pdf). Online at nordphysicianguides.org/urea-cycle-disorders