Ammonia intoxication

The ammonia produced by enteric bacteria and absorbed into portal venous blood and the ammonia produced by tissues are rapidly removed from circulation by the liver and converted to urea. Only traces (10—20 Ig/dL) thus normally are present in peripheral blood. This is essential, since ammonia is toxic to the central nervous system. Should portal blood bypass the liver, systemic blood ammonia levels may rise to toxic levels. This occurs in severely impaired hepatic function or the development of collateral links between the portal and systemic veins in cirrhosis. Symptoms of ammonia intoxication include tremor, slurred speech, blurred vision, coma, and ultimately death. Ammonia may be toxic to the brain in part because it reacts with a-ketoglutarate to form glutamate. The resulting depleted levels of a-ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons. 

All defects in urea synthesis result in ammonia intoxication. Intoxication is more severe when the metabolic block occurs at reactions 1 or 2 since some covalent linking of ammonia to carbon has already occurred if citrulline can be synthesized. Clinical symptoms common to all urea cycle disorders include vomiting, avoidance of high-protein foods, intermittent ataxia, irritability, lethargy, and mental retardation. The clinical features and treatment of all five disorders discussed below are similar. Significant improvement and minimization of brain damage accompany a low-protein diet ingested as frequent small meals to avoid sudden increases in blood ammonia levels. 

In preparation for elective bowel surgery, 1 g of neomycin is given orally every 6-8 hours for 1-2 days, often combined with 1 g of erythromycin base. This reduces the aerobic bowel flora with little effect on anaerobes. In hepatic coma, coliform flora can be suppressed by giving 1 g every 6-8 hours together with reduced protein intake, thus reducing ammonia intoxication. Use of neomycin for hepatic coma has been almost entirely supplanted by lactulose, which is much... 

TThe catabolic production of ammonia poses a serious biochemical problem, because ammonia is very toxic. The molecular basis for this toxicity is not entirely understood. The terminal stages of ammonia intoxication in humans are characterized by onset of a comatose state accompanied by cerebral edema (an increase in the brain s water content) and increased cranial pressure, so research and speculation on ammonia toxicity have focused on this tissue. Speculation centers on a potential depletion of ATP in brain cells. 

Causes and symptoms When liver function is compromised, as a result of genetic defects in one of the urea cycle of hyperammonemia enzymes or to liver disease, hyperammonemia (ammonia intoxication) can occur. 

It is clear, however, that the quantitative difference described by McDermott (M5) is proportional to the amount of destruction and repair present in a particular liver, rather than to a nebulous farrago of complex biochemical changes. We are still dealing with ammonia intoxication in the cases reported. This is not to deny the very real and as yet minimally understood relation of the liver to brain metabolism (vide infra), but it is essential to the development of a lucid picture of disease as a biochemical phenomenon that we do not convert variations of the same process into a multiplicity of syndromes. 

Vivodialysis of patients with hepatic coma and ammonemia can be shown to remove a considerable amount of ammonia (Kl), but the gradient is so small and the rate of the production of ammonia so great that at present vivodialysis is of no value in the treatment of hepatic coma. That it might even be deleterius is suggested by the evidence pointing to a deficiency syndrome in hepatic coma in addition to the ammonia intoxication (B14). 

Because of the risk of ammonia intoxication, neither NH4+ nor NH3 are the main means by which this form of nitrogen is moved around... 

In summary, then, the above short overview indicates that organisms from very early on probably minimized the threat of ammonia intoxication by metabolic mechanisms which serve to limit the amount of free ammonia in cell/body fluids formed in the first place. However, some formation and accumulation are inevitable. In mammals, and other animals that depend upon the urea cycle, this excess NH4+/NH3 together forms the precursor pool for urea synthesis. 

One example of the risk assessment of ammonia intoxication (caused by plant wreck in town conditions) by the PHOENICS CFD model (Mastryukov and Ivanov, 2002 [399]) is presented in Figure 9.20. 

Mastryukov, B.S., and Ivanov, A.V. (2002) Risk assessment of ammonia intoxication caused by plant wreck in town conditions, Moscow State Institute of Steel and Alloys, PHOENICS Journal 14,1, art. 24 MSISA. 

Cedrangolo et al (C5) and De Lorenzo (Dl) also postulated an alternative pathway on the basis of their experimental results on rats. The animals were injected with a-methyl aspartate, a specific inhibitor for argininosuccinate synthetase. No effect on urea excretion was observed, but there was complete inhibition of urea synthesis from citrulline in liver homogenates prepared from injected animals, as well as increased susceptibility to ammonia intoxication. However, this inhibition was not confirmed by Crokaert and Baroen (C15, C16, C17), although they did confirm the lack of any effect on urea excretion. The experimental basis for this suggestion is therefore in doubt. 

Lysine Intolerance with Periodic Ammonia Intoxication... 

CIO. Colombo, J. P., Richterich, R., Donath, A., Spahr, A., and Rossi, E., Congenital lysine intolerance with periodic ammonia intoxication. Lancet i, 1014-1015 (1964). 

C12. Corbeel, L. M., Colombo, J. P., Van Sande, M., and Weber, A., Periodic attacks of lethargy in a baby with ammonia intoxication due to a congenital defect in ureo-genesis. Arch. Dis. Childhood 44, 681-687 (1969). 

Ammonia intoxication due to a congenital detect in urea ssnnthesis. J. Pediat. 66 1039-1040 (1964). Abstr. 

Salvatore, F., Cimino, F., d Ayello-Caracciolo, M., and Cittadini, D., Mechanism of the protection by L-ornithine-n-aspartate mixture and by L-arginine in ammonia intoxication. Arch. Biochcm. Biophys. 107, 499-503 (1964). 

Shih, V. E., Efron, M. L., and Moser, H. W., Hyperornithinemia and homo-citrullinuria with ammonia intoxication, myoclonic seizures and mental retardation. Amer. J. Bis. Child. 117, 83-92 (1969). 

J/ tion of NHJ is excessive (i.e., greater than 60 /rM) in blood. Elevated concentrations of ammonia are serious the consequences of ammonia intoxication include lethargy, tremors, slurred speech, blurred vision, protein-induced vomiting (vomiting caused by the consumption of dietary protein), coma, and death. 

Other substances to which people have been exposed have been shown to alter the toxic effects of ammonia. Methionine sulfoximine, administered by intraperitoneal injection, suppressed the tonic convulsions produced by intravenous injection of ammonium chloride in mice (Hindfelt and Plum 1975 Warren and Schenker 1964). Intraperitoneal injection of alpha-methylglutamic acid also exerts a protective effect against hyperammonemia in rats (Lamar 1970). Nicotinohydroxamic acid and neomycin administered orally reduce blood ammonia levels and increase excretion of urea in treated rats (Haiada et al. 1985). Ethanol exerted a protective effect on acute ammonia intoxication in mice (O Connor et al. 

Sodium benzoate decreased urea production in ammonia challenged rats (Maswoswe et al. 1986) and hyperammonemic mice (O Connor et al. 1987). Valproate, a widely used antiepileptic dmg, has a hyperammonemic effect in Wistar rats (Ferrier et al. 1988) and may therefore predispose to ammonia intoxication. Ammonia interferes with the metabolism of pent-4-enoic acid in cultured rat hepatocytes and may dramatically potentiate its toxicity (Coude and Grimber 1984). 

Persons who suffer from severe liver or kidney disease may be susceptible to ammonia intoxication, as it is chiefly by the actions of these organs that NH/ is biotransformed and excreted (Cordoba et al. 1998 Gilbert 1988 Jeffers et al 1988) individuals with hereditary urea cycle disorders are also at risk (Schubiger et al. 1991). In these individuals, the levels produced endogenously are sufficient to produce toxicity. Levels that are likely to be encountered in the environment, with the exception of those resulting from high-level accidental exposures, are insignificant, due to the low absorption rate, in comparison with levels produced within the body (WHO 1986). 

---