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Biochemische und pathophysiologische Aspekte der Hyperammoniämie

Biochemical and pathophysiological aspects of hyperammonaemia

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Summary

1. Ammonia liberated continously in large amounts in muscle, kidney and brain is used immediately for the synthesis of mainly glutamine because of the toxic effects of elevated ammonia concentrations. After glutamine hydrolysis in the liver ammonia serves as substrate for the urea biosynthesis. In ureotelic animals urea is the quantitatively most important product for the elimination of surplus nitrogen.

2. The rate of urea biosynthesis depends on the amount of surplus nitrogen and acts as regulatory factor for the nitrogen balance of the adult organism.

3. Urea cycle abnormalities in liver diseases or inborn enzymatic defects are important factors leading to hyperammonaemia in patients.

4. The hyperammonaemia induces an increase of the rate of hepatic pyrimidine nucleotide biosynthesis as a consequence of an ineffective feedback inhibition of the glutamine-dependent carbamoyl phosphate synthetase.

5. The distribution of ammonia between intra-and extracellular space and the amount of ammonium ions excreted in the urine depend on the pH value. An alkalosis induces an intracellular ammonia load and inhibits the urinary ammonium ion excretion, which is increased in acidosis as one mechanism of proton elimination.

6. The ammonia-induced inhibition of the citric acid cycle caused by an α-ketoglutarate deficiency is one important reason for the neurotoxicity of ammonia, which is the main point in the pathogenesis of hepatic coma.

Zusammenfassung

1. Das ständig in großen Mengen in Muskulatur, Niere und Gehirn freigesetzte Ammoniak wird wegen seiner toxischen Wirkungen am Entstehungsort überwiegend in Form von Glutamin fixiert, um in der Leber als Substrat in die Harnstoffsynthese einzugehen. In Ureoteliern ist Harnstoff die quantitativ bedeutsamste Eliminationsform überschüssigen Stickstoffs.

2. Die Anpassung der Harnstoffsyntheserate an die Menge des im Stoffwechsel überschüssigne Stickstoffs dient der ausgeglichenen Stickstoffbilanz des erwachsenen Organismus.

3. Störungen der Harnstoffsynthese bei Lebererkrankungen oder kongenitalen Enzymdefekten sind als klinisch bedeutsamste Ursachen der Hyperammoniämie anzusehen.

4. Die Hyperammoniämie bewirkt eine Steigerung der Syntheserate von Pyrimidinnucleotiden in der Leber, die durch eine Umgehung der Feedback-Hemmung der Glutamin-abhängigen Carbamoylphosphatsynthetase zustandekommt.

5. Die Ammoniakverteilung zwischen intra- und extrazellulärem Raum und die Ammoniumionenausscheidung im Urin sind pH-abhängig. Eine Alkalose führt zum Ammoniakeinstrom in den Intracellulärraum und zur Hemmung der Ammoniumionenausscheidung im Urin. Die bei Acidose gesteigerte renale Ammoniumionenausscheidung dient gleichzeitig der Elimination von H+-Ionen.

6. Eine wesentliche Ursache der Neurotoxizität des Ammoniaks, die bei der Pathogenese des Coma hepaticum Bedeutung hat, ist die Hemmung des Citratcyclus durch α-Ketoglutaratmangel im Gehirn.

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  1. Medizinische Universitätsklinik Freiburg i. Brsg., Germany

    J. Pausch & W. Gerok

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Herrn Professor Dr. Paul Schölmerich zum 60. Geburtstag gewidmet

Mit Unterstützung durch die Deutsche Forschungsgemeinschaft, Bonn — Bad Godesberg, und die Forschergruppe „Leberkrankheiten“, Freiburg

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Pausch, J., Gerok, W. Biochemische und pathophysiologische Aspekte der Hyperammoniämie. Klin Wochenschr 55, 97–103 (1977). https://doi.org/10.1007/BF01490236

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