Activities of urea-cycle enzymes in chronic liver disease.

The activities of urea-cycle enzymes were measured in liver biopsies of patients suffering from chronic-persistent hepatitis (CPH), chronic-active hepatitis (CAH) and liver cirrhosis. Most of the activities of urea-cycle enzymes did not differ in the case of CPH as compared to controls. Chronic-active hepatitis and liver cirrhosis are associated with a significant (p less than 0.05) decrease of enzyme activity as compared to normal persons. Most of the urea-cycle enzymes are significantly decreased in patients with CAH in comparison with CPH. No significant differences can be demonstrated in the case of CAH as compared to patients with complete cirrhosis. In conclusion, progression of chronic liver disease is associated with increasing alterations of enzyme activities catalyzing a liver specific metabolic pathway. The decrease of the activities of the key enzymes of the urea cycle (Carbamylphosphate-Synthetase and Arginino-succinate-Synthetase) is nearly identical both in CAH and liver cirhosis, although CAH may be a reversible disease. Therefore, marked alterations in the metabolic pathway of ammonia detoxification seem to preceed the histological manifestation of irreversible liver damage.

Influence of steroids on urea-cycle enzymes in chronic human liver disease.

Activities of Krebs-Henseleit enzymes were determined in liver biopsies of normal persons and in patients suffering from alcoholic hepatitis and chronic active hepatitis. Prednisone was administered for five days in falling dosis (1.5 mg-0.5 mg/kg/body weight) to patients with alcoholic hepatitis and to controls. Patients with chronic active hepatitis received 15-20 mg prednisone daily for more than three months. In healthy persons prednisone did not influence the activities of Krebs-Henseleit enzymes. In patients with alcoholic hepatitis most of the urea-cycle enzymes are significantly decreased (p is less than 0.05) when compared to controls. After glucocorticoid administration enzyme activities remained unchanged. Activities of most of the urea-cycle enzymes are significantly (p is less than 0.05) decreased in untreated patients with chronic active hepatitis. In some of these patients, glucocorticoid administration was associated with a remission as proved by clinical, biochemical and histological data. Activities of the rate-limiting enzymes of the urea-cycle (ASAS, CPS) increased significantly in these patients. By contrast, alterations of enzyme activities could not be observed in patients who failed to respond favourably to steroid treatment.

[Intracellular localisation of urea-cycle enzymes in liver (author's transl)]. / Intrazelluläre Lokalisation von Enzymen des Krebs-Henseleit-Cyclus in der Leber

Enzymes of the Krebs-Henseleit urea-cycle were localized by means of differential centrifugation and fractional tissue extraction in rat liver and in human liver. Argininosuccinatlyase (ASAL) and Argininosuccinatsynthetase (ASAS) represent enzymes of the soluble cytoplasmic fraction. Ornithine-ketoacid-transaminase(OKT), carbamyl-phosphate-synthetase (CPS) and ornithine-carbamyl-transferase (OCT) are localized in the mitochondrial and nuclei fractions of the liver cell. Most of the arginase activity is bound to subcellular structures (probably to nuclei). A small portion of arginase-activity was found in the soluble cytoplasmatic fraction. The enzymes of the Krebs-Henseleit urea-cycle are equally distributed in rat liver and in human liver. Differences in the subcellular localisation of (mitochondrial) enzymes in human liver could be attributed to mitochondrial breakage during tissue preparation and do not represent in-vivo conditions.

[Intrahepatic cholestasis due to N-propyl ajmaline]. / Intrahepatische Cholestase durch N-Propyl-Ajmalin

In two patients intrahepatic cholestasis and cholestatic liver disease probably due to N-propyl ajmaline were observed. In both cases there was a four-week-interval between the first ingestion of the drug and the onset of jaundice. In one case with rigors there was a temporary rise in temperature and cholestasis. In the other there was a two to three week prodromal period of pruritus and gastro-intestinal symptoms. Both cases were characterised by blood and pronounced tissue eosinophilia in the periportal zones, a marked increase of cholestatic and hepatic cell enzymes, serum bilirubin and cholesterol, a moderate increase in erythrocyte sedimentation rate and absence of leucocytosis. Pathological laboratory findings returned to normal spontaneously within 5 weeks in one case and within two weeks under steroid therapy in the other.