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 μmol/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.