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Blood Ammonia
Wayne W. Grody, M.D., Ph.D.
Ammonia, the major nitrogenous product of protein catabolism, is a highly toxic compound, particularly to the brain;1 when blood concentrations are sufficiently elevated, cerebral edema, altered mental status, seizures, coma and death can ensue. Because ammonia is not secreted by the renal tubules, the highly efficient urea cycle evolved to convert it to a nontoxic compound excretable in the urine. The cycle is comprised of five enzymes. The first, carbamylphosphate synthetase, transfers ammonia nitrogen to bicarbonate to form carbamylphosphate; the last enzyme, arginase, hydrolyzes arginine to form ornithine and urea; waste nitrogen is excreted in the urine via the latter compound.
Because the urea cycle enzymes are primarily expressed in the liver, any significant compromise to liver function, whether inherited or acquired, can result in hyperammonemia and consequent hepatic encephalopathy. Most fundamental is inherited deficiency of any of the five enzymes of the urea cycle,2 which can be confirmed by plasma amino acid analysis, specific enzyme assay, or detection of mutations in the causative genes.3 The one X-linked urea cycle disorder, ornithine transcarbamylase deficiency, can be a cause of episodic hyperammonemic encephalopathy in carrier females;4 the other disorders can sometimes present in more chronic or late-onset forms.5 Other inborn errors of metabolism causing hyperammonemia include the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, lysinuric protein intolerance and the organic acidemias and carnitine deficiencies (in which the urea cycle is poisoned as a secondary effect).6,7 Other hyperammonemic conditions that can have a secondary metabolic component include Reye syndrome, valproate administration,8 and transient hyperammonemia of the newborn.
Acquired hyperammonemias can result from overload or bypass of the urea-generating system, as in chemotherapy and ureterosigmoidoscopy. Finally, end-stage liver damage of whatever cause will produce hyperammonemia and hepatic encephalopathy.9
Measurement of blood ammonia is subject to a number of method-dependent variations in normal ranges, and artifacts arising from the collection or transport process. Specimens must be placed on ice for transport to the laboratory in order to inhibit continued metabolism and dispersal. Arterial blood often provides more reliable values than venous blood.10 Frequent serial draws are sometimes required for optimal management and monitoring of treatment.
REFERENCES
- Hawkins RA, Mans AM. Brain metabolism in encephalopathy caused by hyperammonemia. Adv Exp Med Biol 1994;368:11-21.
- Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996;43:127-70.
- Leibundgut EO, Wermuth B, Colombo JP, Liechti-Gallati S. Ornithine transcarbamylase deficiency: characterization of gene mutations and polymorphisms. Hum Mutat 1996;8:333-9.
- Pridmore CL, Clarke JT, Blaser S. Ornithine transcarbamylase deficiency in females: an often overlooked cause of treatable encephalopathy. J Child Neurol 1995;10:369-74.
- Chow WC, Ng HS, Tan IK, Thum TY. Case report: recurrent hyperammonemic encephalopathy due to citrullinemia in a 52 year old man. J Gastroenterol Hepatol 1996;11:621-5.
- Coulter DL. Carnitine deficiency in epilepsy: risk factors and treatment. J Child Neurol 1995;10(Suppl 2):S32-S39.
- Ogier de Baulny H, Slama A, Touati G, Turnbull DM, Pourfarzam M, Brivet M. Neonatal hyperammonemia caused by a defect of carnitine-acylcarnitine translocase. J Pediatr 1995;127:723-8.
- Bohles H, Sewell AC, Wenzel D. The effect of carnitine supplementation in valproate-induced hyperammonemia. Acta Pediatr 1996;85:446-9.
- Ferenci P. Treatment of hepatic encephalopathy in patients with cirrhosis of the liver. Dig Dis 1996;14(Suppl 1):40-52.
- Huizenga JR, Gips CH, Conn HO, Jansen PL. Determination of ammonia in ear-lobe capillary blood is an alternative to arterial blood ammonia. Clin Chem Acta 1995;239:65-70.
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