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. 1988 Dec;82(6):2069–2076. doi: 10.1172/JCI113828

Determinants of hepatic function in liver cirrhosis in the rat. Multivariate analysis.

J Reichen 1, B Egger 1, N Ohara 1, T B Zeltner 1, T Zysset 1, A Zimmermann 1
PMCID: PMC442790  PMID: 3198765

Abstract

We investigated the determinants of hepatic clearance functions in a rat model of liver cirrhosis induced by phenobarbital/CCl4. Aminopyrine N-demethylation (ABT), galactose elimination (GBT), and serum bile acids (SBA) were determined in vivo. The livers were then characterized hemodynamically: intrahepatic shunting (IHS) was determined by microspheres and sinusoidal capillarization by measuring the extravascular albumin space (EVA) by a multiple indicator dilution technique. The intrinsic clearance was determined by assaying the activity of the rate-limiting enzymes in vitro. Hepatocellular volume (HCV) was measured by morphometry. ABT and SBA, but not GBT, differentiated cirrhotic from normal liver. IHS ranged from normal to 10%; all cirrhotic livers showed evidence of sinusoidal capillarization (reduced EVA). The cirrhotic livers showed a bimodal distribution of HCV, HCV being decreased in 50% of the cirrhotic livers. Multivariate analysis showed EVA and portal flow to be the main determinants of microsomal (ABT) and cytosolic (GBT) clearance function; SBA, by contrast, were determined solely by IHS. We conclude that sinusoidal capillarization is the main determinant of hepatic clearance, while serum bile acids reflect intrahepatic shunting. These findings emphasize the importance of alterations of hepatic nutritional flow to explain reduced clearance function in cirrhosis of the liver.

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Selected References

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  1. BRADLEY S. E., INGELFINGER F. J., BRADLEY G. P. Hepatic circulation in cirrhosis of the liver. Circulation. 1952 Mar;5(3):419–429. doi: 10.1161/01.cir.5.3.419. [DOI] [PubMed] [Google Scholar]
  2. Bioulac-Sage P., Saric J., Boussarie L., Balabaud C. Congenital portacaval shunt in rats: liver adaptation to lack of portal vein--a light and electron microscopic study. Hepatology. 1985 Nov-Dec;5(6):1183–1189. doi: 10.1002/hep.1840050620. [DOI] [PubMed] [Google Scholar]
  3. Bircher J., Blankart R., Halpern A., Häcki W., Laissue J., Preisig R. Criteria for assessment of functional impairment in patients with cirrhosis of the liver. Eur J Clin Invest. 1973 Jan;3(1):72–85. doi: 10.1111/j.1365-2362.1973.tb00332.x. [DOI] [PubMed] [Google Scholar]
  4. Bircher J., Küpfer A., Gikalov I., Preisig R. Aminopyrine demethylation measured by breath analysis in cirrhosis. Clin Pharmacol Ther. 1976 Oct;20(4):484–492. doi: 10.1002/cpt1976204484. [DOI] [PubMed] [Google Scholar]
  5. Braillon A., Lee S. S., Girod C., Peignoux-Martinot M., Valla D., Lebrec D. Role of portasystemic shunts in the hyperkinetic circulation of the portal hypertensive rat. J Lab Clin Med. 1986 Dec;108(6):543–548. [PubMed] [Google Scholar]
  6. Chojkier M., Groszmann R. J. Measurement of portal-systemic shunting in the rat by using gamma-labeled microspheres. Am J Physiol. 1981 May;240(5):G371–G375. doi: 10.1152/ajpgi.1981.240.5.G371. [DOI] [PubMed] [Google Scholar]
  7. Cohn J. N., Khatri I. M., Groszmann R. J., Kotelanski B. Hepatic blood flow in alcoholic liver disease measured by an indicator dilution technic. Am J Med. 1972 Dec;53(6):704–714. doi: 10.1016/0002-9343(72)90187-8. [DOI] [PubMed] [Google Scholar]
  8. Cruz-Orive L. M., Weibel E. R. Sampling designs for stereology. J Microsc. 1981 Jun;122(Pt 3):235–257. doi: 10.1111/j.1365-2818.1981.tb01265.x. [DOI] [PubMed] [Google Scholar]
  9. Dubuisson L., Bioulac P., Saric J., Balabaud C. Hepatocyte ultrastructure in rats with portacaval shunt. A morphometric study of acinar zones. Dig Dis Sci. 1982 Nov;27(11):1003–1010. doi: 10.1007/BF01391746. [DOI] [PubMed] [Google Scholar]
  10. Farrell G. C., Cooksley W. G., Powell L. W. Drug metabolism in liver disease: activity of hepatic microsomal metabolizing enzymes. Clin Pharmacol Ther. 1979 Oct;26(4):483–492. doi: 10.1002/cpt1979264483. [DOI] [PubMed] [Google Scholar]
  11. Festi D., Morselli Labate A. M., Roda A., Bazzoli F., Frabboni R., Rucci P., Taroni F., Aldini R., Roda E., Barbara L. Diagnostic effectiveness of serum bile acids in liver diseases as evaluated by multivariate statistical methods. Hepatology. 1983 Sep-Oct;3(5):707–713. doi: 10.1002/hep.1840030514. [DOI] [PubMed] [Google Scholar]
  12. Goresky C. A., Bach G. G., Nadeau B. E. On the uptake of materials by the intact liver. The transport and net removal of galactose. J Clin Invest. 1973 May;52(5):991–1009. doi: 10.1172/JCI107300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gross J. B., Jr, Reichen J., Zeltner T. B., Zimmermann A. The evolution of changes in quantitative liver function tests in a rat model of biliary cirrhosis: correlation with morphometric measurement of hepatocyte mass. Hepatology. 1987 May-Jun;7(3):457–463. doi: 10.1002/hep.1840070308. [DOI] [PubMed] [Google Scholar]
  14. Groszmann R., Kotelanski B., Cohn J. N., Khatri I. M. Quantitation of portasystemic shunting from the splenic and mesenteric beds in alcoholic liver disease. Am J Med. 1972 Dec;53(6):715–722. doi: 10.1016/0002-9343(72)90188-x. [DOI] [PubMed] [Google Scholar]
  15. Hansen B. A., Poulsen H. E. The capacity of urea-N synthesis as a quantitative measure of the liver mass in rats. J Hepatol. 1986;2(3):468–474. doi: 10.1016/s0168-8278(86)80058-7. [DOI] [PubMed] [Google Scholar]
  16. Henderson J. M., Millikan W. J., Jr, Wright-Bacon L., Kutner M. H., Warren W. D. Hemodynamic differences between alcoholic and nonalcoholic cirrhotics following distal splenorenal shunt--effect on survival? Ann Surg. 1983 Sep;198(3):325–334. doi: 10.1097/00000658-198309000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Huet P. M., Goresky C. A., Villeneuve J. P., Marleau D., Lough J. O. Assessment of liver microcirculation in human cirrhosis. J Clin Invest. 1982 Dec;70(6):1234–1244. doi: 10.1172/JCI110722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Huet P. M., Villeneuve J. P. Determinants of drug disposition in patients with cirrhosis. Hepatology. 1983 Nov-Dec;3(6):913–918. doi: 10.1002/hep.1840030604. [DOI] [PubMed] [Google Scholar]
  19. Kardel T., Ramsöe K., Nörby Rasmussen S. Preoperative liver function tests correlated with encephalopathy after porta-caval anastomosis. Scand J Gastroenterol. 1975;10(1):29–32. [PubMed] [Google Scholar]
  20. Keiding S., Chiarantini E. Effect of sinusoidal perfusion on galactose elimination kinetics in perfused rat liver. J Pharmacol Exp Ther. 1978 May;205(2):465–470. [PubMed] [Google Scholar]
  21. Klotz U., Avant G. R., Hoyumpa A., Schenker S., Wilkinson G. R. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest. 1975 Feb;55(2):347–359. doi: 10.1172/JCI107938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  23. Lauterburg B. H., Bircher J. Expiratory measurement of maximal amino-pyrine demethylation in vivo: effect of phenobarbital, partial hepatectomy, protacaval shunt and bile duct ligation in the rat. J Pharmacol Exp Ther. 1976 Feb;196(2):501–509. [PubMed] [Google Scholar]
  24. Lindskov J. The quantitative liver function as measured by the galactose elimination capacity. I. Diagnostic value and relations to clinical, biochemical, and histological findings in patients with steatosis and patients with cirrhosis. Acta Med Scand. 1982;212(5):295–302. [PubMed] [Google Scholar]
  25. Lo M. W., Silber B., Riegelman S. An automated HPLC method for the assay of propranolol and its basic metabolites in plasma and urine. J Chromatogr Sci. 1982 Mar;20(3):126–131. doi: 10.1093/chromsci/20.3.126. [DOI] [PubMed] [Google Scholar]
  26. MEIER P., ZIERLER K. L. On the theory of the indicator-dilution method for measurement of blood flow and volume. J Appl Physiol. 1954 Jun;6(12):731–744. doi: 10.1152/jappl.1954.6.12.731. [DOI] [PubMed] [Google Scholar]
  27. Mannes G. A., Stellaard F., Paumgartner G. Increased serum bile acids in cirrhosis with normal transaminases. Digestion. 1982;25(4):217–221. doi: 10.1159/000198835. [DOI] [PubMed] [Google Scholar]
  28. Mannes G. A., Thieme C., Stellaard F., Wang T., Sauerbruch T., Paumgartner G. Prognostic significance of serum bile acids in cirrhosis. Hepatology. 1986 Jan-Feb;6(1):50–53. doi: 10.1002/hep.1840060110. [DOI] [PubMed] [Google Scholar]
  29. McLean E. K., McLean A. E., Sutton P. M. Instant cirrhosis. An improved method for producing cirrhosis of the liver in rats by simultaneous administration of carbon tetrachloride and phenobarbitone. Br J Exp Pathol. 1969 Oct;50(5):502–506. [PMC free article] [PubMed] [Google Scholar]
  30. Miescher G., Paumgartner G., Preisig R. Portal-systemic spill-over of bile acids: a study of mechanisms using ursodeoxycholic acid. Eur J Clin Invest. 1983 Dec;13(6):439–445. doi: 10.1111/j.1365-2362.1983.tb00126.x. [DOI] [PubMed] [Google Scholar]
  31. Monroe P. S., Baker A. L., Schneider J. F., Krager P. S., Klein P. D., Schoeller D. The aminopyrine breath test and serum bile acids reflect histologic severity in chronic hepatitis. Hepatology. 1982 May-Jun;2(3):317–322. doi: 10.1002/hep.1840020305. [DOI] [PubMed] [Google Scholar]
  32. Ohkubo H., Okuda K., Iida S., Ohnishi K., Ikawa S., Makino I. Role of portal and splenic vein shunts and impaired hepatic extraction in the elevated serum bile acids in liver cirrhosis. Gastroenterology. 1984 Mar;86(3):514–520. [PubMed] [Google Scholar]
  33. Pessayre D., Lebrec D., Descatoire V., Peignoux M., Benhamou J. P. Mechanism for reduced drug clearance in patients with cirrhosis. Gastroenterology. 1978 Mar;74(3):566–571. [PubMed] [Google Scholar]
  34. Pirttiaho H. I., Sotaniemi E. A., Ahlqvist J., Pitkänen U., Pelkonen R. O. Liver size and indices of drug metabolism in alcoholics. Eur J Clin Pharmacol. 1978 Mar 17;13(1):61–67. doi: 10.1007/BF00606684. [DOI] [PubMed] [Google Scholar]
  35. Poupon R. Y., Poupon R. E., Lebrec D., Le Quernec L., Darnis F. Mechanisms for reduced hepatic clearance and elevated plasma levels of bile acids in cirrhosis. A study in patients with an end-to-side portacaval shunt. Gastroenterology. 1981 Jun;80(6):1438–1444. [PubMed] [Google Scholar]
  36. Ranek L., Andreasen P. B., Tygstrup N. Galactose elimination capacity as a prognostic index in patients with fulminant liver failure. Gut. 1976 Dec;17(12):959–964. doi: 10.1136/gut.17.12.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Reichen J., Arts B., Schafroth U., Zimmermann A., Zeltner B., Zysset T. Aminopyrine N-demethylation by rats with liver cirrhosis. Evidence for the intact cell hypothesis. A morphometric-functional study. Gastroenterology. 1987 Oct;93(4):719–726. doi: 10.1016/0016-5085(87)90433-1. [DOI] [PubMed] [Google Scholar]
  38. Reichen J., Hoilien C., Le M., Jones R. H. Decreased uptake of taurocholate and ouabain by hepatocytes isolated from cirrhotic rat liver. Hepatology. 1987 Jan-Feb;7(1):67–70. doi: 10.1002/hep.1840070115. [DOI] [PubMed] [Google Scholar]
  39. Reichen J., Le M. Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver. J Clin Invest. 1986 Aug;78(2):448–455. doi: 10.1172/JCI112596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rowland M., Benet L. Z., Graham G. G. Clearance concepts in pharmacokinetics. J Pharmacokinet Biopharm. 1973 Apr;1(2):123–136. doi: 10.1007/BF01059626. [DOI] [PubMed] [Google Scholar]
  41. Sato N., Kamada T., Shichiri M., Hayashi N., Matsumura T., Abe H., Hagihara B. The levels of the mitochondrial and microsomal cytochromes in drinkers' livers. Clin Chim Acta. 1978 Aug 1;87(3):347–351. doi: 10.1016/0009-8981(78)90177-8. [DOI] [PubMed] [Google Scholar]
  42. Schneider J. F., Baker A. L., Haines N. W., Hatfield G., Boyer J. L. Aminopyrine N-demethylation: a prognostic test of liver function in patients with alcoholic liver disease. Gastroenterology. 1980 Dec;79(6):1145–1150. [PubMed] [Google Scholar]
  43. Schröder R., Müller O., Bircher J. The portacaval and splenocaval shunt in the normal rat. A morphometric and functional reevaluation. J Hepatol. 1985;1(2):107–123. doi: 10.1016/s0168-8278(85)80760-1. [DOI] [PubMed] [Google Scholar]
  44. Shin-Buehring Y. S., Osang M., Ziegler R., Schaub J. A simple assay for galactokinase using DEAE-cellulose column chromatography. Clin Chim Acta. 1977 Jan 3;74(1):1–5. doi: 10.1016/0009-8981(77)90379-5. [DOI] [PubMed] [Google Scholar]
  45. Shreeve W. W., Shoop J. D., Ott D. G., McInteer B. B. Test for alcoholic cirrhosis by conversion of [14C]- or [13C]galactose to expired CO2. Gastroenterology. 1976 Jul;71(1):98–101. [PubMed] [Google Scholar]
  46. TYGSTRUP N. Determination of the hepatic galactose elimination capacity after a single intravenous injection in man: the reproducibility and the influence of uneven distribution. Acta Physiol Scand. 1963 Jun-Jul;58:162–172. doi: 10.1111/j.1748-1716.1963.tb02638.x. [DOI] [PubMed] [Google Scholar]
  47. Varin F., Huet P. M. Hepatic microcirculation in the perfused cirrhotic rat liver. J Clin Invest. 1985 Nov;76(5):1904–1912. doi: 10.1172/JCI112186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Villeneuve J. P., Infante-Rivard C., Ampelas M., Pomier-Layrargues G., Huet P. M., Marleau D. Prognostic value of the aminopyrine breath test in cirrhotic patients. Hepatology. 1986 Sep-Oct;6(5):928–931. doi: 10.1002/hep.1840060520. [DOI] [PubMed] [Google Scholar]
  49. Villeneuve J. P., Wood A. J., Shand D. G., Rogers L., Branch R. A. Impaired drug metabolism in experimental cirrhosis in the rat. Biochem Pharmacol. 1978;27(22):2577–2581. doi: 10.1016/0006-2952(78)90330-1. [DOI] [PubMed] [Google Scholar]
  50. Vorobioff J., Bredfeldt J. E., Groszmann R. J. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am J Physiol. 1983 Jan;244(1):G52–G57. doi: 10.1152/ajpgi.1983.244.1.G52. [DOI] [PubMed] [Google Scholar]
  51. Wood A. J., Villeneuve J. P., Branch R. A., Rogers L. W., Shand D. G. Intact hepatocyte theory of impaired drug metabolism in experimental cirrhosis in the rat. Gastroenterology. 1979 Jun;76(6):1358–1362. [PubMed] [Google Scholar]
  52. Zysset T., Tlach C. Altered liver function in diabetes: model experiments with aminopyrine in the rat. J Pharmacol Exp Ther. 1987 Jan;240(1):271–276. [PubMed] [Google Scholar]
  53. Zysset T., Tlach C. Aminopyrine pharmacokinetics in the rat may depend on hepatic blood flow. Drug Metab Dispos. 1986 Sep-Oct;14(5):625–626. [PubMed] [Google Scholar]

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