Identifying Hyperammonemia in the Emergency Department

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Overview

Clinical Assessment

Synopsis and Diagnostic FlowChart

Case Histories

Treatment Links

References

Overview of Hyperammonemia in Urea Cycle Disorders

Urea cycle disorders (UCD) result from defects in the metabolism of nitrogen produced by the breakdown of protein and other nitrogen-containing molecules.

Severe deficiency of any of the first four enzymes (CPSI, OTC, ASS, ASL) in the urea cycle or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life. Since no effective secondary clearance system for ammonia exists, disruption of this pathway results in the rapid development of symptoms.

Severity of the disease is influenced by the position of the defective enzyme in the pathway and the severity of the enzyme defect.  In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered by illness or stress at any time of life, resulting in elevations of plasma ammonia concentration.

The symptoms may be subtle and go unrecognized for years until a trigger results in catastrophic hyperammonemia.

Newborns

The catabolism normally present in the newborn period combines with the immaturity of the neonatal liver to accentuate defects in these enzymes. Infants with a urea cycle disorder often initially appear normal but within 12-72 hours rapidly develop symptoms:

Refusal to feed Vomiting

Irritability progressing to lethargy

and somnolence

Hypothermia

Seizures

Hyperventilation leading to

respiratory alkalosis

Neurologic posturing

Coma

Hypoventiation with respiratory arrest  

Because newborns are usually discharged from the hospital within one to two days after birth, the symptoms of a urea cycle disorder are often not seen until the child is at home and may not be recognized in a timely manner by the family and primary care physician. The typical initial symptoms of an infant with hyperammonemia can be non-specific.  Sepsis is often suspected; therefore, it is recommended that serum ammonia level be included in standard sepsis workup in order to facilitate early detection of hyperammonemia in these infants.

Children and Adults

In patients with partial enzyme deficiencies, the first recognized clinical episode may be delayed for months or years. Although the clinical abnormalities vary somewhat with the specific urea cycle disorder, a hyperammonemic episode may be marked by a spectrum of symptoms:

Loss of appetite Vomiting
Lethargy Behavioral abnormalities
Agitation Sleep disorder
Confusion Delusions, hallucinations, psychosis
Bizarre/unusual behavior Stroke-like symptoms

Treatment Guidelines

Contact metabolic geneticist promptly and alert nephrology for possible hemodialysis.

The mainstays of treatment for UCD:

  • Reduce catabolism through the introduction of calories supplied by carbohydrates and fat
  • Reduce plasma ammonia concentration
  • Rreduce the risk of neurologic damage
  • Pharmacologic management to allow alternative pathway excretion of excess nitrogen
  • Reducing the amount of nitrogen in the diet

Clinical Assessment24

  • Assess cardiac, respiratory, neurologic, and hydration status.

  • Identify potential precipitant(s) of metabolic decompensation such as infection (presence of fever) or any other physical stressor (e.g. injury, surgery).

Initial laboratory tests to order:

  • Plasma ammonia (1.5 ml blood in sodium-heparin tube sent STAT to lab on ice, run   immediately)

  • Plasma amino acid profile

  • Urine orotic acid

  • Liver function tests (AST,ALT, alakaline phospatase, bilirubin)

  • Arterial or venous blood gas

  • Serum electrolytes, bicarbonate, BUN, creatinine

  • Blood glucose

  • Blood, urine, and/or CSF cultures (as clinically indicated)

Diagnosis/testing

The diagnosis of a urea cycle disorder is based on evaluation of clinical, biochemical, and molecular data. A plasma ammonia concentration of 150 mmol/L or higher, associated with a normal anion gap and a normal serum glucose concentration, is a strong indication for the presence of a UCD. Plasma quantitative amino acid analysis can be used to diagnose a specific urea cycle disorder. Plasma concentration of arginine may be reduced in all urea cycle disorders, except arginase deficiency, in which it is elevated. Plasma concentration of citrulline helps discriminate between the proximal and distal urea cycle defects, as citrulline is the product of the proximal enzymes (OTC and CPSI) and a substrate for the distal enzymes (ASS, ASL, ARG). Urinary orotic acid is measured to distinguish CPSI deficiency and NAGS deficiency from OTC deficiency. A definitive diagnosis of CPSI deficiency, OTC deficiency, or NAGS deficiency depends on determination of enzyme activity from a liver biopsy specimen; however, the combination of family history, clinical presentation, amino acid and orotic acid testing, and molecular genetic testing are often sufficient for diagnostic confirmation, eliminating the risks of liver biopsy. Molecular genetic testing is clinically available for all urea cycle disorders.

Recommendations

1. Plasma ammonia measurement is a simple yet important screening in the ED for patients with unexplained stupor or delirium. Recognizing the symptoms of the disease is often delayed and/or mistaken.4

2. Although UCD is usually identified in early childhood, partial or mild forms may not be recognized until unmasked by an environmental trigger that can lead to catastrophic hyperammonemic crisis.14

3.  Altered consciousness should always lead to blood ammonia measurement.21

4.  Ornithine transcarbamylase deficiency should be suspected in adult patients who develop recurrent hyperammonemia and encephalopahty following bariatric surgery.5

5.  The diagnosis of OTC deficiency should be considered in nonhepatic adult patients wiht hyperammonemic coma, particularly if they have a history of protein avoidance and neurological symptoms.13

TREATMENT INFORMATION

New England Consortium of Metabolic Programs Treatment Guidelines

Rare Diseases Clinical Research Network Urea Cycle Disorders Consortium

References

  1. Hainline B, Clay A.  Hyperammonemia in the ICU. Chest 2007;132;1368-1378
  2. Lien J,  Nyhan WL, Barshop BA. Fatal Initial Adult-Onset Presentation of Urea Cycle Defect. Arch Neurol. 2007; 64(12):1777-1779
  3. Aronson PL, Mistry RD. Ornithine transcarbamylase deficiency presenting as hepatitis. Ped Emerg Care. 2011 Jun;27(6):527-9
  4. Weng TI, Shih FF, Chen WJ, Unusual causes of hyperammonemia in the ED. Am J Emerg Med. 2004 Mar;22(2):105-7
  5. Hu, WT, Kantarci, OH, Merritt II, JL, McGrann , Dyck PJB, Lucchinetti CF, Tippmann-Peikert, M. Ornithine Transcarbamylase Deficiency Presenting as Encephalopathy During Adulthood Following Bariatric Surgery. Arch Neurol. 2007;64:126-128
  6. Fenves.  Fatal Hyperammonemic Encephalopathy After Gastric Bypass Surgery. Am J Med. 2008 Jan;121(1):e1-e2
  7. Enns, GM, O’Brien, WE, Kobyashi K, Shinzawa H, Pellegrino J. Postpartum “Psychosis” in Mild Argininosuccinate Synthetase Deficiency. Obstetrics and Gynecology, Vol. 105, No. 5, Part 2, May 2005
  8. Rimbaux S, Hommet C, Perrier D, Cottier JP, Legras A, Labarthe F, Lemarcis L, Autrer A, Maillot F. Adult onset ornithine transcarbamylase deficiency: an unusual cause of semantic disorders.  J. Neurol. Neurosurg. Psychiatry 2004;75;1073-1075
  9. Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith M,  Summar M. Urea Cycle Disorders: Clinical Presentation Outside the Newborn Period. Crit Care Clin 21 (2005) S9–S17
  10. Priester T, Khoo, TK, Fernandez-Perez E, Regner K, Tracy J, Mitchell S, Summar M, Babovic-Vuksanovic D. Hyperammonemia from a urea cycle disorder presenting in adulthood. Open Critical Care Medicine Journal. 2009;2;9-12
  11. Enns G, Packman S. Diagnosing inborn errors of metabolism in the newborn: clinical features. NeoReviews.  2001;2;183-190
  12. Barrueto F, Hack J. Hyperammonemia and coma without hepatic dysfunction induced by valproate therapy.  Academic Emergency Medicine. October 2001, Vol. 8, Issue 10, 999-1001
  13. Gaspari R, Arcangeli A, Mensi S, Schembri-Wismayer D, Tartaglione T, Antuzzi D, Conti G, Proletti R. Late-onset presentation of ornithine transcarbamylase deficiency in a young woman with hyperammonemic coma. Annals of Emergency Medicine. Jan 2003; Vol. 41, Issue 1;104-109
  14. Houston B, Reiss K, Merlo C. Healthy, but comatose. Am J Med. 2011 Apr;124(4):303-5.
  15. Summar M, Barr, F, Dawling S, Smith W, Lee B, Singh R, Rhead W, Sniderman-King L, Christman B. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin 21 (2005) S1–S8
  16. Schmidt J, Kroeber K,  Irouschek A, Birkholz T, Schroth M, Albrecht S. Anesthetic management of patients with ornithine transcarbamylase deficiency.  Pediatric Anesthesia 2006 16: 333–337
  17. Scaglia F, Zheng Q, O’Brien W, Henry J, Rosenberger J, Reeds P, Lee B.  An Integrated Approach to the Diagnosis and Prospective Management of Partial Ornithine Transcarbamylase Deficiency. Pediatrics 2002;109;150-152
  18. Enns, GM. Neurologic Damage and Neurocognitive Dysfunction in Urea Cycle Disorders. Semin Pediatr Neurol 15:132–139
  19. Gropman A, Rigas A.  Neurometabolic disorders: urea cycle disorders, outcomes, development and treatment.  Pediatric Health (2008)2(6)
  20. Krivitzky L, Babikian T, Lee H,  Hattiangadi Thomas N, Burk-Paull K, Batshaw ML. Intellectual, Adaptive, and Behavioral Functioning in Children with Urea Cycle Disorders.  Pediatr Res. 2009 July ; 66(1): 96–101 
  21. Seashore, MR. What’s new in the urea cycle: new research and treatments. Grand Rounds Presentation. Yale University School of Medicine, Department of Genetics. June 2010
  22. Testai FD, Gorelick PB, Inherited Metabolic Disorders and Stroke Part 2 Homocystinuria, Organic Acidurias, and Urea Cycle Disorders. Arch Neurol/Vol 67 (No. 2), Feb 2010 148-153
  23. NIH Rare Diseases Clinical Research Network Urea Cycle Disorders Consortium http://rarediseasesnetwork.epi.usf.edu/ucdc/physicians/index.htm
  24. New England Consortium of Metabolic Programs http://newenglandconsortium.org/for-professionals/acute-illness-protocols/urea-cycle-disorders/ornithine-transcarbamylase-deficiency-otc/

 

 

 

 

Symptoms of HA in IEM

Newborns

Refusal to feed

Vomiting

Irritability

Lethargy/symnolence

Respiratory alkalosis

Hypoventilation/respiratory
   arrest

Hypothermia

Seizures

Neurologic posturing

Coma

Suspected sepsis

Children/Adults

Loss of appetite
Vomiting
Lethargy

Disorientation

Confusion
Agitation

Combativeness

Stroke-like symptoms
Behavioral abnormalities
Sleep disorder
Delusions, hallucinations, psychosis

Triggers for HA in UCD

High protein load or
supplements

Catabolic state

Steroid administration

Virus or infection

Excessive exercise

Gastric bypass surgery

Synposis and Diagnostic FlowChart


Case Histories