eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Hyperammonemia: Differential Diagnoses & Workup

Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Contributor Information and Disclosures

Updated: Jun 3, 2009

Differential Diagnoses

Arginase Deficiency
Methylmalonic Acidemia
Argininosuccinate Lyase Deficiency
N-Acetylglutamate Synthetase Deficiency
Carbamoyl Phosphate Synthetase Deficiency
Ornithine Transcarbamylase Deficiency
Citrullinemia
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)
Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Hyperinsulinemia

Other Problems to Be Considered

Organic acid disorders (eg, isovaleric acidemia)
Lysinuric protein intolerance
Transient hyperammonemia of the newborn
Hepatic insufficiency/dysfunction
Mitochondrial diseases and pyruvate carboxylase deficiency
Valproate ingestion
L-asparaginase ingestion
Reye syndrome

Workup

Laboratory Studies

  • Plasma ammonia level
    • Obtain this measurement when clinical signs and symptoms are suggestive of hyperammonemia.
    • No other laboratory test can substitute for this measurement, nor does any other test indicate need for it.
    • Only clinical suspicion indicates need.
  • Liver function studies (ie, serum transaminases, prothrombin time [PT]/activated partial thromboplastin time [aPTT]), alkaline phosphatase levels, bilirubin levels): Severe liver disease can cause hyperammonemia; therefore, evaluating the function of the liver is always appropriate as a first approximation to etiology.
  • Plasma amino acid level quantitation
    • Certain primary genetic causes can be suspected based on specific increases in amino acid levels, such as increased citrulline or argininosuccinic acid levels.
    • By contrast, severe liver disease tends to cause a generalized increase in plasma amino acid levels.
  • Urinary organic acid profile
    • Disorders that involve metabolic intermediates of amino acid catabolism can cause mild-to-moderate inhibition of the urea cycle, resulting in hyperammonemia as a secondary phenomenon.
    • This test can help to identify level increases in such intermediates as propionic acid, methylmalonic acid, isovaleric acid, or other organic acids and aid in diagnosis.
  • Urine amino acid levels: These are helpful in confirming argininosuccinic aciduria; lysinuric protein intolerance; or hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome.
  • Blood lactate levels: This is useful in ruling out mitochondrial diseases.
  • Blood gas levels
    • Patients with urea cycle disorders may have alkalosis due to stimulation of the respiratory drive by ammonia.
    • Patients with urea cycle disorders are rarely acidotic. Severe refractory acidosis suggests organic acid disorder or mitochondrial disorder.
  • BUN level: This is often very low (<3 mg of urea/100 mL) in persons with urea cycle disorders.
  • N -carbamoyl-L-glutamic acid: In infants with confirmed hyperammonemia, oral loading with N -carbamoyl-L-glutamic acid has been advocated as both diagnostic and therapeutic for patients with N -acetylglutamate (NAG) synthetase deficiency.

Imaging Studies

  • Some authors advocate baseline MRI studies in patients with confirmed genetic causes of hyperammonemia; this is because some suggestive data indicate an elevated risk for stroke in these patients.

More on Hyperammonemia

Overview: Hyperammonemia
Differential Diagnoses & Workup: Hyperammonemia
Treatment & Medication: Hyperammonemia
Follow-up: Hyperammonemia
Multimedia: Hyperammonemia
References
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References

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Further Reading

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Keywords

hyperammonemia, elevated serum ammonia level, ammoniemia, elevated ammonia levels, urea, adult-onset genetic disorders of the urea cycle, alpha-amino group, a-amino group, hepatic urea cycle, waste nitrogen, extrahepatic tissues, mitochondrial dysfunction, N -acetylglutamate, NAG, adenosine diphosphate, ADP, adenosine triphosphate, ATP, total free ammonia, glutamine, N -methyl D-aspartate, NMDA, gamma-aminobutyric acid, GABA, astroglial glutamate transporter molecules, astrocytes, membrane permeability transition phenomenon, hepatic encephalopathy, ornithine transcarbamylase deficiency, OTC, hepatic necrosis, N -acetylglutamate synthetase, arginase deficiency, carbamyl phosphate synthetase, CPS, citrullinemia, argininosuccinic acid synthase deficiency, citrullinuria, argininosuccinate lyase deficiency, ASA, argininosuccinic aciduria, argininosuccinase deficiency, hyperargininemia, familial argininemia

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Contributor Information and Disclosures

Author

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Disclosure: MDS Pharma Salary Employment

Medical Editor

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Leonard G Feld, MD, PhD, MMM, FAAP, Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center
Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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