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Aim: To study the hepatic clearance of a glycoprotein (rat plasma kallikrein) by the liver of rats with experimental decompensated cirrhosis., Material and Methods: Cirrhosis was induced by intragastrically administration of carbon tetrachloride 520 mg/kg/week, during 16-19 weeks. After this period, each liver was isolated, exsanguinated and perfused at 37 degrees C with 10nM rat plasma kallikrein (RPK)., Results: 58% of the animals died during the treatment and the remaining developed prostration, ascites, jaundice and bleeding; at the end of the treatment period serum aminotransferases were not altered and serum albumin decreased. The liver histology showed cirrhosis. RPK clearance rate of the cirrhosis group (5.4 +/- 0.9 pmol/g liver/10 min) was significantly lower (p < 0.05) than that of the control group (13.5 +/- 2.7 pmol/g liver/10 min)., Conclusion: The development of cirrhosis is associated with a decreased hepatic clearance of a glycoprotein which endocytosis is mediated by a receptor.

We have previously reported that the endocytosis of rat plasma kallikrein (RPK) by hepatocytes is a calcium-independent and beta-galactoside-dependent mechanism. We now report the clearance of RPK by the liver of four groups of rats: normal, inflamed (48 h ex-turpentine) and two groups chronically treated with CCl4 (52 mg/kg per week, intragastrically, for 9-12 weeks). Each liver was isolated, exsanguinated and perfused at 37 degrees C with 30 mL of BSA-Krebs-Henseleit-bicarbonate medium containing 10 nmol/L RPK. Although all rats received the same mild CCl4 treatment, the liver histology showed that they evolved either to severe hepatitis (serum alanine aminotransferase [ALT] 4852 +/- 885 U/L, parenchymatous necrosis in the perivenous region) or to compensated cirrhosis (serum ALT 209 +/- 42 U/L, vigorous fibrous encircling regeneration nodules); neither jaundice nor ascites was noted. The results show that serum albumin was not altered among the groups and that: the acute-phase response by itself (inflamed group) increased RPK clearance rate (3.01 +/- 0.59 mL/min) as compared with the normal group (1.85 +/- 0.14 mL/min); the CCl4 treatment, although induced an acute-phase response, decreased (P < 0.01) RPK clearance rates (0.80 +/- 0.11 mL/min hepatitis group and 0.98 +/- 0.10 mL/min cirrhosis group). These findings suggest that the hepatic clearance rate of plasma kallikrein is an early indicator of liver injury.

The liver synthesizes prokallikrein and is the main organ to clear the active enzyme (plasma-kallikrein) from circulation. This clearance, a receptor-mediated endocytosis, is calcium-independent and not affected by the blockade of Kupffer cells. The effects of endothelial cells blockade and of acetaminophen intoxication on the clearance of 10 nM rat plasma-kallikrein (RPK) by the isolated, exsanguinated and perfused rat liver are now reported. Endothelial cells blockade obtained by the addition of large excess (30 uM) of formaldehyde-treated serum albumin to the perfusion fluid does not affect the hepatic clearance of RPK (the half-lives of hepatic uptake were 15.5 +/- 1.0 min in the absence versus 16.5 +/- 1.4 min in the presence of the treated protein, p > 0.05). Some livers were perfused 24 hours after acetaminophen intoxication: 6.6 mmol/kg given i.p. after a 42-hour period of fast. Hepatocyte injury suggested by elevated aminotransferase activity (ALT 10 times control value, AST 30 times control value), acute phase inflammatory response (serum alpha 2-macroglobulin increase) and reduced synthetic function (serum albumin decrease), was confirmed histologically and only zone 3 hepatocytes were necrotic. A 66-hour period of fast does not affect by itself the hepatic clearance of RPK (16.9 +/- 1.3 min of half-life of hepatic uptake) when compared with the control group (15.5 +/- 1.0 min, p > 0.05). On the other hand the RPK clearance by the livers of rats previously intoxicated with acetaminophen was markedly deficient (the half-life of hepatic uptake was 39.2 +/- 3.2 min). These findings suggest that RPK is internalized by hepatocytes, preferentially by those of the perivenular zone of the hepatic acinus.

1. The clearance of plasma kallikrein by the isolated and perfused liver of rats chronically intoxicated with ethanol was studied. Alcohol was added to the diet as 36% of total calories, and the animals were kept on this diet for 5-7 weeks. 2. The hepatic clearance of plasma kallikrein by these rats (uptake half-life, 15 +/- 2 min; N = 3) was similar to that observed in the control groups (normal diet, uptake half-life, 14 +/- 2 min; N = 5, or normal diet with sucrose added as 36% of total calories, uptake half-life, 16 +/- 3 min; N = 4). 3. These results provided indirect evidence that the endocytosis mechanism of plasma kallikrein by the liver differs from that described for glycoproteins which use the galactosyl receptor, since liver endocytosis via this latter system is reduced by chronic alcohol intoxication.

To evaluate quali-quantitatively ischemic liver injury due to acute cardiocirculatory failure (ischemic hepatitis), and its real clinical signification, 200 out of 1165 autopsy records with ACF clinical diagnosis were selected; 33/200 (16.5%) shown centrilobular necrosis without inflammatory component, accompanied or not by midzonal compromise. Grade IV centrilobular necrosis (50-100% involved lobules) was present in 96.9%, with 15.5% associated midzonal pattern, and 21.2% of confluent type; 2 additional cases with isolated midzonal necrosis (5.7%) were seen. Only six patients (3.0% of ACF patients, and 18.2% of those with histological injury) shown overt clinical liver disease, one of them with a fulminant hepatitis picture (0.5% of ACF, and 3.0% of patients with ischemic necrosis). Bilirubin levels were 3.4-10.2 mg%, and aminotransferases rose up to 540 times over their seric superior normal limits. Centrilobular necrosis involved 100% of lobules in all cases.

The authors measure the concentration of urea and arginase activity at pH 6.5 and 9.7 in the rat liver at intervals during the administration thioacetamide (TAM) at a dose of 50 mg per kg of body weight and per day. The values obtained correlate the amount of urea and the arginase activity at pH 6.5 and 9.7 during TAM administration for the intervals comprised between 1-12 days and 12-30 days. These results suggest that the concentration of liver urea depends mainly of the level at arginase activity, which is regulated by the proton concentration of the internal environment.

We report the clearance of rat plasma kallikrein (RPK) by the perfused livers of normal rats and from others at 2 and 4 days after subcutaneous injection of turpentine oil. RPK removal from the perfusate follows a logarithmic curve (y = a+b lnx) and from this equation its half-life of removal can be calculated. RPK clearance rate followed the potential equation y = axb. Both the half-life of RPK removal and RPK clearance rates were similar in the 3 groups of perfused livers. We conclude that, at the initial concentration of RPK used (approximately 3 nM), its liver clearance is not affected during the acute-phase response to inflammation.