Pathological Alterations in Ammonia Metabolism

The first human experiments which suggested a toxic effect of ammonia in disease were done by Van Caulaert. The revival and extension of this work by the group led by Davidson (G2) in the Boston City Hospital has stimulated widespread interest in ammonia as a factor in the production of mental symptoms in liver disease. The ability of various factors, such as urea feedings, high-protein diet, cation resins in the ammonia cycle, and amino acids, to induce symptoms of coma in patients with liver disease (G2, M3, M4, P7, S8) made it quite clear that ammonia was associated with the symptom complex called hepatic coma. The severe toxicity of ammonia in animals and the ability of intravenous or oral ammonium salts to provoke episodes of impending liver coma tended to substantiate the clinical impressions. Rapid confirmation of these observations was furnished by the experiments of other groups (Bll, C2, E2, FI). 

The significance of ammonia in clinical disease was broadened markedly when it was discovered that ammonia poisoning might be the mechanism of the cerebral symptoms associated with chronic heart failure. It has been known for a long time that the mental symptoms associated with heart failure could not be correlated with the oxygen supply to the brain, which remains, in most cases, adequate. The work of A. N. Bessman (B4) demonstrated that the ammonia content of the blood was elevated in heart failure, probably due to the chronic passive congestion of the liver which prevented the liver from removing the normally formed ammonia from the portal system. When the blood ammonia fell, the mental symptoms of heart failure were relieved. This has been confirmed by Calkins and Delph (Cl), who studied twenty-six cases of heart failure and found the blood ammonia to be elevated only in the two patients who had mental symptoms. 

It has long been known that the adenylic deaminase of blood is increased in shock (Tl). Seligson s experiments with animals in hemorrhagic shock demonstrated that the peripheral blood ammonia was markedly elevated (N4). Further work with this problem showed that the blood ammonia rises during hemorrhagic shock to tremendous levels and that these levels are compatible with the cerebral symptoms noted in shock (H2). Retransfusion of the bled animal does not cause this ammonia level to return completely to normal, and in fact it remains elevated to toxic levels until the death of the animal. A source of this ammonia has been shown to be the intestinal tract, for the highest rise of ammonia is found in the portal system. 

The most recent addition to the clinical syndromes in which ammonia probably plays a dominant role is hemolytic disease of the newborn. 

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