Review Article Severe hyperammonaemia in adults not explained by liver disease Valerie Walker Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, C Level MP 8, South Block, Southampton Hospital, Tremona Road, Southampton SO16 6YD, UK Email: [email protected] Abstract Ammonia is produced continuously in the body. It crosses the blood–brain barrier readily and at increased concentration it is toxic to the brain. A highly integrated system protects against this: ammonia produced during metabolism is detoxified temporarily by incorporation into the non-toxic amino acid glutamine. This is transported safely in the circulation to the small intestine, where ammonia is released, carried directly to the liver in the portal blood, converted to non-toxic urea and finally excreted in urine. As a result, plasma concentrations of ammonia in the systemic circulation are normally very low ( ,40 mmol/L). Hyperammonaemia develops if the urea cycle cannot control the ammonia load. This occurs when the load is excessive, portal blood from the intestines bypasses the liver and/or the urea cycle functions poorly. By far, the commonest cause is liver damage. This review focuses on other causes in adults. Because they are much less common, the diagnosis may be missed or delayed, with disastrous consequences. There is effective treatment for most of them, but it must be instituted promptly to avoid fatality or long-term neurological damage. Of particular concern are unsuspected inherited defects of the urea cycle and fatty acid oxidation presenting with catastrophic illness in previously normal individuals. Early identification of the problem is the challenge. Ann Clin Biochem 2012; 49: 214–228. DOI: 10.1258/acb.2011.011206 Introduction Ammonia is produced continuously in the body. It crosses the blood–brain barrier readily and at increased concen- tration it is toxic to the brain. A highly integrated system protects against this: ammonia produced during metab- olism is detoxified temporarily by incorporation into the non-toxic amino acid glutamine. This is transported safely in the circulation to the small intestine, where ammonia is released, carried directly to the liver in the portal blood, con- verted to non-toxic urea and finally excreted in urine. As a result, plasma concentrations of ammonia in the systemic circulation are normally very low ( ,40 mmol/L). Hyperammonaemia develops if the urea cycle cannot control the ammonia load. This occurs when the load is excessive, portal blood from the intestines bypasses the liver and/or the urea cycle functions poorly. By far, the com- monest cause at all ages is liver damage associated with abnormal liver function, often with portosystemic shunting. This review focuses on other causes in adults. Because they are much less common, diagnosis may be missed or delayed, with disastrous consequences. There is effective treatment for most of them, but it must be instituted promptly to avoid fatality or long-term neurological damage. Of particular concern is the inherited urea cycle defect (UCD), ornithine transcarbamylase deficiency. There is an escalating number of reports of fatal hyperam- monaemic crises in previously asymptomatic adults who could have made a good recovery had the diagnosis been made at presentation. Ammonia: sources and detoxification by glutamine and the urea cycle Ammonia Ammonia is generated during metabolism in all organs. Large amounts are produced in skeletal muscle, particularly during exercise, mainly from deamidation of adenosine monophosphate, with some from amino acid catabolism. These processes and glutamate dehydrogenase activity con- tribute to ammonia production in the brain. 1,2 Another important source is release from the kidneys during the pro- duction of ammonia to buffer H þ ions in urine. Glutamine is taken up from the blood and metabolized by phosphate- dependent glutaminase in the proximal tubular cells, releas- ing ammonia. Normally, approximately 30% of total renal ammonia is excreted with H þ ions. The other 70% is released into the circulation. This situation changes dramati- cally with acute disturbances of acid–base balance: the This article was prepared at the invitation of the Clinical Sciences Reviews Committee of the Association of Clinical Biochemistry. Annals of Clinical Biochemistry 2012; 49: 214–228
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