Laboratory Studies

The following tests should be performed after a patient is found to be hyperammonemic:

Arterial blood gas analysis: This study determines acid-base status; respiratory alkalosis strongly suggests a urea cycle defect; it is the result of hyperventilation due to stimulation of the central respiratory drive.
Serum amino acid tests
- Glutamine and alanine levels are increased in all urea cycle defects except for arginase deficiency.
- Citrulline level is decreased mildly in CPS/NAGS and OTC deficiencies but increased markedly in AS deficiency and moderately in AL deficiency.
- Arginine level is increased markedly in arginase deficiency but decreased mildly in all the other enzyme deficiencies of the urea cycle.
- Argininosuccinic acid level is increased markedly in AL deficiency.
Urinary orotic acid tests: The level is increased markedly in OTC deficiency and mildly in other enzyme deficiencies except for CPS/NAGS deficiency, in which it is decreased mildly.
Urinary ketone tests: Presence of ketosis indicates an organic acidemia.
Plasma and urinary organic acid tests: These levels screen for the presence of an organic acidemia that may be causing the hyperammonemia.
Enzyme assays: Assays performed on tissue specimens obtained by percutaneous liver biopsy can determine diagnosis in cases of CPS, NAGS, and OTC deficiency. Enzyme assays are also performed on red blood cells (for arginase deficiency), fibroblast from skin biopsy (ASS, ASL, and HHH), and intestinal mucosa (CPS, OTC). Enzyme analysis has largely been replaced by genetic analysis. It is still indicated in selected cases with negative genetic testing or if genetic testing is not available.^[2]
DNA mutation analysis is the method of choice in confirming the diagnosis of UCD as it is clinically available for all genes of the urea cycle.^[2]
Heterozygote identification in OTC-deficient pedigrees
- Allopurinol loading test: This test establishes the carrier status of women at risk for OTC deficiency. After a loading dose of allopurinol, urinary orotidine excretion is measured; it is increased greatly in carriers.
- DNA analysis: Several techniques are available to determine the presence of a mutation at the OTC locus.
Antenatal diagnosis: All urea cycle defects can be diagnosed antenatally by different techniques including, DNA analysis on chorionic villus or amniotic fluid cells, measurements of amniotic fluid metabolites or enzyme activities in the amniotic cells, chorionic villi, fetal liver, and fetal erythrocytes.^[2]

Neuroimaging

CT or MRI of the brain may show cerebral edema in acute hyperammonemia (see image below).^[24]The classic MR finding in patients with chronic liver disorders is hyperintense signal in the globus pallidum on T1-weighted images due to increased tissue concentration of manganese.

CT scan of cerebral edema caused by hyperammonemia. Republished with permission of American Society of Neuroradiology from U-King-Im JM, Yu E, Bartlett E, Soobrah R, Kucharczyk W. Acute hyperammonemic encephalopathy in adults: imaging findings. AJNR Am J Neuroradiol. 2011 Feb;32(2):413-8; permission conveyed through Copyright Clearance Center, Inc.

MR spectroscopy shows an elevated glutamine/glutamate peak coupled with decreased myoinositol and choline signals.^{[25, 26]}

Multiple strokelike lesions have been reported as MRI findings in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria.^[27]

A newer imaging technique involving diffusion tensor imaging reveals damage to corticospinal tracts in patients with arginase deficiency.^[28]

Histologic Findings

The most consistent neuropathologic change in encephalopathies with hyperammonemia is prominent Alzheimer type II astrogliosis.

Treatment & Management

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Media Gallery

CT scan of cerebral edema caused by hyperammonemia. Republished with permission of American Society of Neuroradiology from U-King-Im JM, Yu E, Bartlett E, Soobrah R, Kucharczyk W. Acute hyperammonemic encephalopathy in adults: imaging findings. AJNR Am J Neuroradiol. 2011 Feb;32(2):413-8; permission conveyed through Copyright Clearance Center, Inc.

of 1

Author

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Gurjot Singh MD Candidate, Aureus University School of Medicine

Gurjot Singh is a member of the following medical societies: American Academy of Family Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nicholas Lorenzo, MD, CPE, MHCM, FAAPL Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Former Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, CPE, MHCM, FAAPL is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association for Physician Leadership

Disclosure: Nothing to disclose.

Chief Editor

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Medical Director, Tulane Center for Autism and Related Disorders, Tulane University School of Medicine; Pediatric Neurologist and Epileptologist, Ochsner Hospital for Children; Professor of Neurology, Louisiana State University School of Medicine

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, American Medical Association, American Neurological Association, Association of Military Surgeons of the US, Child Neurology Society, Southern Pediatric Neurology Society

Disclosure: Nothing to disclose.

Additional Contributors

J Stephen Huff, MD, FACEP Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD, FACEP is a member of the following medical societies: American Academy of Neurology, American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Elena Crisan, MD Neurology Staff, Department of Neurology, Edwards Hines Veterans Affairs Hospital; Assistant Professor of Neurology, Loyola University Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Kazi Imran Majeed, MD to the development and writing of this article.