Clinical manifestations

Presentation and course

The clinical manifestations of hyperammonemia are dependent on the cause, the age of the individual, and the rapidity with which ammonia accumulates. Neonates with hyperammonemia can deteriorate within a few hours, initially exhibiting lethargy and poor feeding and progressing to encephalopathy with coma, temperature instability, loss of reflexes, and intracranial hemorrhage. Infants and children may exhibit failure to thrive, feeding problems, vomiting, chronic neurologic symptoms, intermittent encephalopathy with lethargy, ataxia, and seizures due to episodic hyperammonemia. In adolescents and adults, the symptoms of hyperammonemia may be mild ataxia or headaches, chronic neurologic or psychiatric symptoms, behavior problems, episodes of confusion, disorientation, lethargy, or psychosis, and symptoms are usually associated with catabolic stress or high protein intake. Often, adolescents and adults have had symptoms since childhood, but they were misdiagnosed. Metabolic disorders that cause hyperammonemia usually present during the neonatal period, with a second peak incidence as children (10 to 14 years of age), possibly due to the onset of puberty.

Prognosis and complications

Prognosis is dependent on the degree of hyperammonemia and the length of time an individual has hyperammonemia over his or her lifetime. As a result, early detection of hyperammonemia and treatment are essential.

Prognosis is improving with earlier detection and better treatment modalities of the hyperammonemia. Long-term prognosis remains dependent on the number and frequency of metabolic decompensations and on the underlying diagnosis (24; 01). Neurocognitive outcomes are primarily related to the peak and age of the hyperammonemic crises (17). The severity of hyperammonemia crises may be reduced in children with citrullinemia type 1 and argininosuccinic aciduria identified by newborn screening, but the number of episodes of hyperammonemia is not decreased (18). There may be subtle neurocognitive differences between urea cycle disorder subtypes (25; 26).

Clinical vignette

Case 1 (composite fictional patient). Baby boy 1 is a 60-hour-old infant born to a 22-year-old gravida 1, para 1 mother who had an uncomplicated pregnancy. The infant refused to feed and was lethargic. Due to these findings, the infant underwent analysis of his cerebrospinal fluid, urine, and blood for infection; bacterial, viral, and fungal cultures were all negative. A comprehensive metabolic panel, including serum transaminases, and a complete blood count were unremarkable for age. Plasma ammonia concentration was 1400 μmol/L (normal < 180 μmol/L). Family history was significant for a maternal uncle who died as a neonate with “sepsis” and a mother who avoided dietary protein. The infant was treated with hemodialysis within 4 hours of identifying the hyperammonemia. Plasma amino acid analysis obtained prior to hemodialysis showed a low citrulline (1 μmol/L) and arginine (12 μmol/L) concentration. Urinary organic acid analysis showed markedly elevated levels of orotic acid. Sequencing of the X-linked ornithine transcarbamoylase (OTC) gene showed a known causative mutation confirming OTC deficiency. The infant was maintained on a low-protein diet, including nitrogen scavengers and supplemental citrulline until he had a liver transplant at the age of 6 months.

Case 2 (composite fictional patient). Baby girl 2 is a 5-day-old infant born to a 36-year-old gravida 4, para 4 following an uncomplicated pregnancy. The infant had decreasing oral intake and increasing lethargy over 24 hours; therefore, she was brought to the emergency room with probable diagnosis of sepsis. The infant was found to have metabolic acidosis. Bacterial and viral cultures were collected from urine, blood, and cerebrospinal fluid. Comprehensive metabolic panel revealed serum bicarbonate of 7 mg/dL. Plasma amino acid analysis showed an elevated glycine concentration. Plasma ammonia was 800 μmol/L. While in the process of establishing access for hemodialysis because of the elevated ammonia, the primary care physician was informed that infant had an elevated propionylcarnitine on her newborn screen. A week after being drawn in the emergency room, this was confirmed on plasma acylcarnitine profile. Urine organic acid analysis obtained prior to hemodialysis indicated elevated methylcitrate and hydroxypropionate without elevated methylmalonic acid. These findings were consistent with her having propionic acidemia. The infant was treated with hemodialysis to decrease her ammonia and acidemia. She was maintained on dextrose-rich fluids and, following dialysis, was started on a diet appropriate for treating her propionic acidemia.

Biological basis

Etiology and pathogenesis

The etiology of hyperammonemia includes:

	• Urea cycle abnormalities (inability to metabolize nitrogen to water-soluble forms) (05)
	• Inhibition of urea cycle enzyme activity by toxins, lack of energy, or lack of required components (transporters at the cellular level or liver vascular bypass at the organ level)
	• Overwhelming ammonia production (eg, seizure, crush injury, or cell lysis)

Hyperammonemia affects the brain directly by altering its ability to use N-methyl-D-aspartate (NMDA) and glutamate as signals, resulting in central respiratory alkalosis.

Table 1. Disorders That Cause Hyperammonemia

Disorder	Pathogenesis and pathophysiology	Biochemical findings	Gene and other notes
Urea cycle
N-acetylglutamate synthase (NAGS) deficiency	Inability to synthesize N-acetylglutamate from glutamate	PAA: decreased to normal citrulline and arginine UOA: normal orotic acid	NAGS Treat with carbamylglutamate
Carbamyl phosphate synthase I (CPSI) deficiency	Inability of CPSI to combine ammonia to bicarbonate	PAA: decreased to normal citrulline and arginine UOA: normal orotic acid	CPSI Requires N-acetylglutamine for function
Ornithine transcarbamylase (OTC) deficiency	Inability of OTC to combine carbamyl phosphate to ornithine, producing citrulline	PAA: decreased to normal citrulline and arginine UOA: elevated orotic acid	X-linked OTC
Argininosuccinate synthase (ASS) deficiency	Inability of ASS to combine citrulline to aspartate	PAA: markedly increased citrulline and decreased arginine UOA: increased orotic acid	ASS
Argininosuccinate lyase (ASL) deficiency	Inability to metabolize the cleavage of argininosuccinate to fumarate and arginine	PAA: increased arginosuccinate acid; normal to moderately increased citrulline and decreased arginine UAA: markedly increased arginosuccinic acid	ASL
Arginase deficiency	Inability to split arginine into urea and ornithine	PAA: increased arginine UOA: normal to increased orotic acid	ARG
Citrin deficiency	Transporter of aspartate	PAA: increased citrulline	SLC25A13 Galactose-free diet, high-protein diet
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH)	Inability to transport ornithine between cytoplasm and mitochondrion	PAA: increased ornithine and normal arginine and citrulline UAA: increased ornithine and homocitrulline	Clotting disorder of factor VII and X
Lysinuric protein intolerance	Transporter of dibasic amino acids	Increased plasma LDH and ferritin UAA: increased arginine, lysine, and ornithine PAA: normal to decreased arginine, lysine, ornithine; normal to increased citrulline	Finland
Hypoprolinemia	Delta1-pyrroline-5-carboxylate (P5C) synthase is required to produce ornithine from glutamate	PAA: decreased proline, ornithine, arginine, and citrulline
Hyperinsulinism-hyperammonemia syndrome	Congenital hyperinsulinemia	Hypoglycemia Elevated serum insulin	GLDH
Carbonic anhydrase VA deficiency	Inability to provide bicarbonate to the urea cycle and carboxylases	Hypoglycemia PAA: increased glutamine, alanine, and low-to-normal citrulline UOA: carboxylase substrates	CA5A
Organic acidemias
Propionic acidemia (propionyl-CoA carboxylase deficiency)	Inability of propionyl-CoA carboxylase to metabolize propionyl-CoA to methylmalonyl-CoA. Propionic acid inhibits CPSI activity. Overall energy deficiency	ACP: elevated propionylcarnitine (C3) UOA: elevated 3-hydroxypropionic acid and methylcitrate	PCCA PCCB
Methylmalonic acidemia, cobalamin C/D deficiency	Inability of methylmalonyl mutase to metabolize methylmalonyl-CoA to succinyl-CoA (B12/cobalamin-requiring enzyme). Propionic acid inhibits CPSI activity. Question of overall energy	UOA and plasma organic acids: elevated methylmalonic acid ACP: elevated propionylcarnitine (C3) UOA: elevated 3-hydroxypropionic acid and methylcitrate PAA: elevated homocysteine for cobalamin C/D	Methylmalonyl mutase (MM) MMACHC C2orf25
Isovaleric acidemia	Inability of isovaleryl-CoA dehydrogenase to metabolize isovaleryl-CoA to 3-methylcrotonyl-CoA	UOA: increased isovaleryl-glycine and 3-hydroxyisovaleric acid ACP: increased isovaleryl carnitine (C5)	IVD
Maple syrup urine disease (MSUD)	Deficiency of branched-chain keto dehydrogenase	PAA: elevated leucine and presence of alloisoleucine
Other
Vascular bypass	Ammonia is not delivered to the liver
Cardiopulmonary bypass	Hepatic damage due to bypass
Orthotopic lung transplant	Hepatic glutamine synthase enzyme deficiency
Urease bacterial overgrowth	Overproduction of ammonia		eg, gastric bypass or urea plasma sepsis
Transient hyperammonemia of the newborn	Immaturity of liver enzymes	Elevated plasma ammonia	Infancy only, resolves with time and maturity
Drugs: 5’fluorouracil valproic acid cyclophosphamide	Increased renal ammonia, decreased glutamine synthetase activity, and inhibition of CPSI activity
5-pentanoic acid (Jamaican vomiting sickness)	Ackee fruit-hypoglycin A and B inhibition of urea cycle enzymes
Carbamazepine
Asparaginase
Methanol intoxication
Olanzapine
Oxaliplatin
Glufosinate-ammonium
Capecitabine
Energy deficiencies
Fatty acid oxidation defects	Secondary liver cell dysfunction due to energy deficiency	Specific metabolites consistent with specific disorder on UOA and ACP	Medium-chain acyl-CoA, long-chain acyl-CoA, and very long-chain hydroxyacyl-CoA deficiencies, carnitine palmitoyltransferase 1 and 2.
Mitochondrial defects	Energy deficiency and acidosis	Usually increased lactate, diagnosis-specific changes on muscle biopsy, and electron-chain transport abnormalities. Multiple organ dysfunctions.	Especially mitochondrial depletion syndromes
(PAA: plasma amino acids, UOA: urinary organic acids, UAA: urinary amino acids, ACP: acylcarnitine profile)

Several other inborn errors of metabolism, such as tyrosinemia I and galactosemia, can cause generalized liver dysfunction or failure resulting in hyperammonemia.

Epidemiology

Urea cycle defects incidence is about one urea cycle disorder patient for every 35,000 births (23). Partial urea cycle defects may be more common.

Prevention

Risk factors are dependent, in part, on cause. In general, catabolic states associated with illness, poor nutrition, fever, and dehydration, and nitrogen loads (usually by dietary indiscretion) can result in hyperammonemia. Valproic acid has been implicated in worsening status due to its putative inhibition of CPSI activity. Administration of systemic corticosteroids can also precipitate hyperammonemia. Delivery of an infant or involution of the uterus in the postpartum period may also precipitate hyperammonemia in an individual with a urea cycle disorder.

Differential diagnosis

Table 2. Differential Diagnosis of Hyperammonemia Not Caused By Liver Failure

Urea cycle disorders
	• N-acetylglutamate synthetase deficiency • Carbamoyl phosphate synthetase deficiency • Ornithine transcarbamylase deficiency (most common urea cycle defect) • Citrullinemia type I (argininosuccinate synthetase deficiency) • Argininosuccinic aciduria (argininosuccinate lyase deficiency) • Argininemia (arginase deficiency), mild hyperammonemia, progressive spasticity • Delta-1-pyrroline-5-carboxylate synthetase deficiency (preprandial hyperammonemia is greater than postprandial) • Hyperinsulinism-hyperammonemia-syndrome (glutamate dehydrogenase C-terminal mutation leading to increased oxidation)
Transporters
	• Homocitrullinuria-hyperornithinemia-hyperammonemia syndrome (ornithine transporter I defect) • Lysinuric protein intolerance (y+ L-amino acid transporter 1 defect, SLC7A7 gene defect), often associated with alveolar proteinosis, hemophagocytosis • Citrin deficiency (SLC25A13) • Carnitine palmitoyltransferase deficiency I, and II, usually with hypoglycemia • Carnitine/acylcarnitine translocase deficiency
Organic acidurias
	• Propionic acidemias (propionyl-CoA carboxylase deficiency) • Methylmalonic acidurias, including defects of cobalamin metabolism • 3-hydroxy-3-methylglutaric aciduria (3-hydroxy-3-methylglutaryl-CoA lyase deficiency) • Beta-ketothiolase deficiency (2-methylacetoacetic aciduria) • Pyroglutamic aciduria • Maple syrup urine disease • Isovaleric acidemia
Mitochondrial disorders
	• Pyruvate carboxylase deficiency • Pyruvate dehydrogenase deficiency • TMEM70 • Fumarate hydratase deficiency • Mitochondrial depletion syndromes • Respiratory chain defects (mainly complex 1 and 2 and multiple acyl-CoA dehydrogenase deficiency) • Carbonic anhydrase VA deficiency
Fatty acid beta-oxidation defects
	• Medium-chain acyl-CoA dehydrogenase deficiency (hypoglycemia, Reye-like syndrome) • Very long-chain acyl-CoA dehydrogenase deficiency • Long-chain hydroxyacyl-CoA dehydrogenase/-ketoacyl-CoA thiolase/enoyl-CoA hydratase deficiency • Primary carnitine deficiency
Other
	• TANGO2 mutations • Medications: valproic acid, pivalate-ester-containing antibiotics, 5’fluorouracil, cyclophosphamide, asparaginase, sunitinib • Multiple myeloma • Infections with urease-positive bacteria (blind loop syndrome, neurogenic bladder) • Nutritional arginine or carnitine deficiency (total parenteral nutrition) • Lead intoxication • 5-pentanoic acidemia (Jamaican vomiting sickness) • Orthotopic lung transplant • Seizures (only locally and acutely) • Transient hyperammonemia of the newborn • Infections, particularly herpes simplex • Refeeding syndrome
Vascular
	• Patent ductus venosus Arantii • Vascular malformations with portosystemic bypass • Cardiopulmonary bypass

Diagnostic workup

Once hyperammonemia is identified, a comprehensive metabolic profile, urinalysis, and arterial blood gas should be obtained. Results of these studies should be rapidly available and can suggest further studies to obtain a more definitive diagnosis. If there is coagulopathy or elevated serum transaminase activities, hepatic failure is likely the cause. In the absence of generalized hepatic dysfunction, a specific inborn error of metabolism or anatomic anomaly causing hyperammonemia is likely. The next studies are typically urinary organic acid analysis, plasma acylcarnitine profile, and plasma amino acid analysis (14; 13). Even in an ideal situation, results of these studies still take hours before they are available.

It is important to determine if there is acidosis or alkalosis. In the typical presentation of urea cycle disorders, there is often a respiratory alkalosis. Acidosis may be present if coma has progressed to respiratory depression; this is a late finding. Plasma amino acid analysis can help identify the specific urea cycle disorder. Plasma citrulline concentration will be decreased in the proximal urea cycle, which includes N-acetylglutamate synthase deficiency, carbamyl phosphate synthetase deficiency, and ornithine transcarbamylase deficiency. Plasma citrulline will be markedly elevated in citrullinemia (argininosuccinic acid synthase deficiency) and will be moderately elevated in argininosuccinate lyase deficiency or arginase deficiency. Argininosuccinic acid is present in argininosuccinate lyase deficiency, and arginine is markedly elevated in arginase deficiency. Orotic acid may be elevated in individuals with ornithine transcarbamylase deficiency or more distal defects in the urea cycle.

In the other inborn errors associated with hyperammonemia, metabolic acidosis is typically present. Urinary organic acid analysis or the acylcarnitine profile can be diagnostic. Children with organic acidemias and fatty acid oxidation defects will have specific pathognomonic elevated metabolites in the urine and on the acylcarnitine profile. Those with organic acidemias, including propionic acidemia, methylmalonic acidemia, and isovaleric acidemia, will likely have ketosis, even in the newborn period, whereas those with fatty acid defects will not have ketosis (21; 10).

Individuals with anatomic anomalies resulting in hyperammonemia (patent ductus venosus, portosystemic shunts) may have surprisingly normal plasma amino acids, urinary organic acids, and plasma acylcarnitine profile. Hyperammonemia with normal results on these tests should suggest imaging studies for anatomic lesions.

Management

Treatment should be tailored to the underlying cause of the hyperammonemia. If the cause is a treatable disorder, appropriate therapy should be initiated. If medications are the cause, they should be discontinued; another medication that is known not to cause hyperammonemia should be used. For hyperammonemia associated with vascular bypass, surgical correction and therapies that decrease production of ammonia in the bowel, lactulose and neomycin, and a bowel regimen should be considered. In addition, some therapies used for inborn errors may be appropriate. In fatty acid oxidation defects, treatment includes providing appropriate calories and avoiding causative dietary fatty acids and fasting (12).

Disorders of the urea cycle and severe hyperammonemia require emergent interventions. Acute management includes reducing ammonia production by stopping dietary protein for about 24 hours and reversing catabolism. Consult a metabolic specialist for optimal management. The mainstays of acute management include the following.

Studies of valproic acid-induced hyperammonemia have demonstrated some benefit to using levocarnitine in addition to stopping the valproic acid (07; 11).

Direct removal of ammonia. The best way to reduce plasma ammonia concentration quickly is by dialysis. The faster the flow rate, the faster the clearance. The method employed depends on the affected individual's circumstances and available resources. In general, the best choice for an individual patient depends on whatever method the local treating team is most comfortable with and can be implemented most quickly. Fastest is use of pump-driven dialysis in which an extra corporeal membrane oxygenation (ECMO) pump is used to drive a hemodialysis machine. Other methods are hemofiltration (both arteriovenous and venovenous) and hemodialysis. These are more likely to be available than ECMO-driven dialysis. Note: Peritoneal dialysis is relatively ineffective for acute hyperammonemia and is generally not recommended if these other options are available.

Pharmacological interventions to facilitate alternative pathway excretion of excessive nitrogen. Nitrogen scavenger therapy (available as an intravenous therapy for acute situations and oral therapy for long-term maintenance) and appropriate replacement of deficient intermediates depending on the diagnosis, including arginine (intravenous administration) or citrulline (oral), can be used (09; 08). Intravenous scavengers can be used in organic acidemias in acute situations at the same doses (pharmacological agents are listed in Table 3). Oral dosing for scavengers is listed in Table 4.

Treatment with carglumic acid. Carglumic acid is a stable analog of N-acetylglutamate and is the standard of care treatment for the rarest of the urea cycle disorders, N-acetylglutamate synthetase deficiency. In propionic and methylmalonic acidemia, hyperammonemia may be caused by secondary inhibition of N-acetylglutamate synthetase. Hyperammonemia in propionic and methylmalonic acidemia has been shown to be responsive to carglumic acid.

Table 3. Intravenous Therapeutics for Hyperammonemia

Neonates to young children:
		Loading dose (90 min)	Maintenance dose
Components of infusion solution	Ammonul (sodium phenylacetate and sodium benzoate injection)	2.5 mL/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) Recommended to be diluted in at least 25 mL/kg 10% dextrose solution	2.5 mL/kg/24 hr (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) Recommended to be diluted in at least 25 mL/kg 10% dextrose solution
	Arginine HCl injection, 10%	2.0 mL/kg (NAGS, CPSI, OTC deficiencies) or 6.0 mL/kg (unknown, ASS, and ASL deficiencies)	2.0 mL/kg/24 hr (NAGS, CPSI, OTC deficiencies) or 6.0 mL/kg/hr (unknown, ASS, and ASL deficiencies
Older children and adults:
		Loading dose (90 min)	Maintenance dose
Components of infusion solution	Ammonul (sodium phenylacetate and sodium benzoate injection)	55 mL/m2 (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate) Recommended to be diluted in at least 25 mL/kg 10% dextrose solution	55 mL/m2/24 hr (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate) Recommended to be diluted in at least 25 mL/kg 10% dextrose solution
	Arginine HCl injection, 10%	2.0 mL/kg (NAGS, CPSI, OTC deficiencies) or 6.0 mL/kg (unknown, ASS, and ASL deficiencies)	2.0 mL/kg (NAGS, CPSI, OTC deficiencies) or 6.0 mL/kg/hr (unknown, ASS, and ASL deficiencies)

Table 4. Oral Dosing for Scavengers

Medication	Dosage
Sodium phenylbutyrate	< 20 kg: 450-600 mg/kg/day > 20 kg: 9.9-13 g/m2/day Doses > 20 g have not been studied
Glycerol phenylbutyrate > 2 years	(Sodium phenylbutyrate naïve) 4.5-11.2 mL/m2/day= 5-12.4 g/m2/day Do not exceed doses > 17.5 mL/day
Sodium benzoate	< 20 kg: 250 mg/kg/day > 20 kg: 5.5 g/m2/day

Nutritional management. In acute hyperammonemia due to inherited metabolic disorders, catabolism of protein, either exogenous or endogenous, is typically the cause. Catabolism is treated with calories from glucose, fats, and essential amino acids. If the underlying diagnosis is due to defects in fatty acid oxidation, calories should be given as glucose and amino acids. Multiple other strategies to reverse catabolism must be employed to convert to an anabolic state. Low-dose, continuous infusion of insulin with maintenance of adequate glucose delivered by continuous delivery of carbohydrate-containing fluids has been used effectively. This must be performed cautiously because these individuals are exquisitely sensitive to insulin. Ensuring adequate stores of essential amino acids with frequent monitoring of plasma concentrations is critical. Complete restriction of protein should not exceed 12 to 24 hours because depletion of essential amino acids results in increased endogenous protein catabolism and nitrogen release.

The only exception to low protein, high carbohydrates is citrin deficiency, which requires high protein and low carbohydrate delivery in the acute and chronic setting to prevent hyperammonemia (20).

For chronic long-term treatment of urea cycle abnormalities once an individual is stable, appropriate protein restriction is the mainstay of therapy. Because these individuals have personal requirements that change with age, they should be followed by a metabolic geneticist and a dietician well versed in the nutritional requirements of such disorders. Excessively low-protein diets can be as harmful as high-protein loads in this population because they induce endogenous protein catabolism and subsequent hyperammonemia (22). For those with fatty acid oxidation defects, constant calorie delivery is essential. For those with urea cycle defects, oral scavenger therapy is useful for eliminating excess nitrogen.

Liver transplant. Liver transplantation has successfully been used to normalize blood ammonia concentrations in urea cycle defects and improves protein tolerance in organic acidemias (06; 16).

Special considerations

Pregnancy

Successful pregnancies have occurred in individuals with urea cycle defects, organic acidemias, and mitochondrial defects. Delivery and the immediate postpartum period are particularly catabolic states, and, therefore, close monitoring and treatment are necessary. Pregnant individuals with these disorders or those wishing to become pregnant should be evaluated and followed closely by a metabolic specialist and maternal fetal specialist (15).

Anesthesia

Anesthesia risk is related to the underlying diagnosis. Avoidance of catabolism in all inborn errors and other triggers, including medications, for elevated ammonia is necessary.