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. 1997 Feb 15;99(4):692–700. doi: 10.1172/JCI119213

Metabolic effects of liver transplantation in cirrhotic patients.

L Luzi 1, G Perseghin 1, E Regalia 1, L P Sereni 1, A Battezzati 1, D Baratti 1, E Bianchi 1, I Terruzzi 1, H Hilden 1, L C Groop 1, A Pulvirenti 1, M R Taskinen 1, L Gennari 1, V Mazzaferro 1
PMCID: PMC507852  PMID: 9045872

Abstract

To assess whether liver transplantation (LTx) can correct the metabolic alterations of chronic liver disease, 14 patients (LTx-5) were studied 5+/-1 mo after LTx, 9 patients (LTx-13) 13+/-1 mo after LTx, and 10 patients (LTx-26) 26+/-2 months after LTx. Subjects with chronic uveitis (CU) and healthy volunteers (CON) were also studied. Basal plasma leucine and branched-chain amino acids were reduced in LTx-5, LTx-13, and LTx-26 when compared with CU and CON (P < 0.01). The basal free fatty acids (FFA) were reduced in LTx-26 with respect to CON (P < 0.01). To assess protein metabolism, LTx-5, LTx-13, and LTx-26 were studied with the [1-14C]leucine turnover combined with a 40-mU/m2 per min insulin clamp. To relate changes in FFA metabolism to glucose metabolism, eight LTx-26 were studied with the [1-14C]palmitate and [3-3H]glucose turnovers combined with a two-step (8 and 40 mU/m2 per min) euglycemic insulin clamp. In the postabsorptive state, LTx-5 had lower endogenous leucine flux (ELF) (P < 0.005), lower leucine oxidation (LO) (P < 0.004), and lower non-oxidative leucine disposal (NOLD) (P < 0.03) with respect to CON (primary pool model). At 2 yr (LTx-26) both ELF (P < 0.001 vs. LTx-5) and NOLD (P < 0.01 vs. LTx-5) were normalized, but not LO (P < 0.001 vs. CON) (primary and reciprocal pool models). Suppression of ELF by insulin (delta-reduction) was impaired in LTx-5 and LTx-13 when compared with CU and CON (P < 0.01), but normalized in LTx-26 (P < 0.004 vs. LTx-5 and P = 0.3 vs. CON). The basal FFA turnover rate was decreased in LTx-26 (P < 0.01) and CU (P < 0.02) vs. CON. LTx-26 showed a lower FFA oxidation rate than CON (P < 0.02). Tissue glucose disposal was impaired in LTx-5 (P < 0.005) and LTx-13 (P < 0.03), but not in LTx-26 when compared to CON. LTx-26 had normal basal and insulin-modulated endogenous glucose production. In conclusion, LTx have impaired insulin-stimulated glucose, FFA, and protein metabolism 5 mo after surgery. Follow-up at 26 mo results in (a) normalization of insulin-dependent glucose metabolism, most likely related to the reduction of prednisone dose, and, (b) maintenance of some alterations in leucine and FFA metabolism, probably related to the functional denervation of the graft and to the immunosuppressive treatment.

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Selected References

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  1. Abumrad N. N., Rabin D., Diamond M. P., Lacy W. W. Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. Metabolism. 1981 Sep;30(9):936–940. doi: 10.1016/0026-0495(81)90074-3. [DOI] [PubMed] [Google Scholar]
  2. Aki K., Ogawa K., Ichihara A. Transaminases of branched chain amino acids. IV. Purification and properties of two enzymes from rat liver. Biochim Biophys Acta. 1968 Jun 4;159(2):276–284. doi: 10.1016/0005-2744(68)90076-4. [DOI] [PubMed] [Google Scholar]
  3. Bismuth H., Castaing D., Ericzon B. G., Otte J. B., Rolles K., Ringe B., Sloof M. Hepatic transplantation in Europe. First Report of the European Liver Transplant Registry. Lancet. 1987 Sep 19;2(8560):674–676. doi: 10.1016/s0140-6736(87)92453-6. [DOI] [PubMed] [Google Scholar]
  4. Block K. P., Heywood B. W., Buse M. G., Harper A. E. Activation of rat liver branched-chain 2-oxo acid dehydrogenase in vivo by glucagon and adrenaline. Biochem J. 1985 Dec 1;232(2):593–597. doi: 10.1042/bj2320593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Castellino P., Luzi L., Simonson D. C., Haymond M., DeFronzo R. A. Effect of insulin and plasma amino acid concentrations on leucine metabolism in man. Role of substrate availability on estimates of whole body protein synthesis. J Clin Invest. 1987 Dec;80(6):1784–1793. doi: 10.1172/JCI113272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Castellino P., Solini A., Luzi L., Barr J. G., Smith D. J., Petrides A., Giordano M., Carroll C., DeFronzo R. A. Glucose and amino acid metabolism in chronic renal failure: effect of insulin and amino acids. Am J Physiol. 1992 Feb;262(2 Pt 2):F168–F176. doi: 10.1152/ajprenal.1992.262.2.F168. [DOI] [PubMed] [Google Scholar]
  7. Cavallo-Perin P., Cassader M., Bozzo C., Bruno A., Nuccio P., Dall'Omo A. M., Marucci M., Pagano G. Mechanism of insulin resistance in human liver cirrhosis. Evidence of a combined receptor and postreceptor defect. J Clin Invest. 1985 May;75(5):1659–1665. doi: 10.1172/JCI111873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cobelli C., Saccomani M. P., Tessari P., Biolo G., Luzi L., Matthews D. E. Compartmental model of leucine kinetics in humans. Am J Physiol. 1991 Oct;261(4 Pt 1):E539–E550. doi: 10.1152/ajpendo.1991.261.4.E539. [DOI] [PubMed] [Google Scholar]
  9. Frayn K. N. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983 Aug;55(2):628–634. doi: 10.1152/jappl.1983.55.2.628. [DOI] [PubMed] [Google Scholar]
  10. Gillison S. L., Bartlett S. T., Curry D. L. Synthesis-secretion coupling of insulin. Effect of cyclosporin. Diabetes. 1989 Apr;38(4):465–470. doi: 10.2337/diab.38.4.465. [DOI] [PubMed] [Google Scholar]
  11. Groop L. C., Bonadonna R. C., DelPrato S., Ratheiser K., Zyck K., Ferrannini E., DeFronzo R. A. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest. 1989 Jul;84(1):205–213. doi: 10.1172/JCI114142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Groop L. C., Bonadonna R. C., Shank M., Petrides A. S., DeFronzo R. A. Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. J Clin Invest. 1991 Jan;87(1):83–89. doi: 10.1172/JCI115005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heslin M. J., Newman E., Wolf R. F., Pisters P. W., Brennan M. F. Effect of hyperinsulinemia on whole body and skeletal muscle leucine carbon kinetics in humans. Am J Physiol. 1992 Jun;262(6 Pt 1):E911–E918. doi: 10.1152/ajpendo.1992.262.6.E911. [DOI] [PubMed] [Google Scholar]
  14. Horber F. F., Horber-Feyder C. M., Krayer S., Schwenk W. F., Haymond M. W. Plasma reciprocal pool specific activity predicts that of intracellular free leucine for protein synthesis. Am J Physiol. 1989 Sep;257(3 Pt 1):E385–E399. doi: 10.1152/ajpendo.1989.257.3.E385. [DOI] [PubMed] [Google Scholar]
  15. Irving C. S., Wong W. W., Shulman R. J., Smith E. O., Klein P. D. [13C]bicarbonate kinetics in humans: intra- vs. interindividual variations. Am J Physiol. 1983 Aug;245(2):R190–R202. doi: 10.1152/ajpregu.1983.245.2.R190. [DOI] [PubMed] [Google Scholar]
  16. Jaskiewicz K., Voigt M. D., Robson S. C. Distribution of hepatic nerve fibers in liver diseases. Digestion. 1994;55(4):247–252. doi: 10.1159/000201156. [DOI] [PubMed] [Google Scholar]
  17. Kjaer M., Keiding S., Engfred K., Rasmussen K., Sonne B., Kirkegård P., Galbo H. Glucose homeostasis during exercise in humans with a liver or kidney transplant. Am J Physiol. 1995 Apr;268(4 Pt 1):E636–E644. doi: 10.1152/ajpendo.1995.268.4.E636. [DOI] [PubMed] [Google Scholar]
  18. Lautt W. W. Afferent and efferent neural roles in liver function. Prog Neurobiol. 1983;21(4):323–348. doi: 10.1016/0301-0082(83)90016-3. [DOI] [PubMed] [Google Scholar]
  19. Lee J. A., Ahmed Q., Hines J. E., Burt A. D. Disappearance of hepatic parenchymal nerves in human liver cirrhosis. Gut. 1992 Jan;33(1):87–91. doi: 10.1136/gut.33.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Luzi L., Battezzati A., Perseghin G., Bianchi E., Terruzzi I., Spotti D., Vergani S., Secchi A., La Rocca E., Ferrari G. Combined pancreas and kidney transplantation normalizes protein metabolism in insulin-dependent diabetic-uremic patients. J Clin Invest. 1994 May;93(5):1948–1958. doi: 10.1172/JCI117186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Luzi L., Castellino P., Simonson D. C., Petrides A. S., DeFronzo R. A. Leucine metabolism in IDDM. Role of insulin and substrate availability. Diabetes. 1990 Jan;39(1):38–48. doi: 10.2337/diacare.39.1.38. [DOI] [PubMed] [Google Scholar]
  22. Luzi L., Groop L. C., Perseghin G., Taskinen M. R., Hilden H., Bianchi E., Terruzzi I., Dodesini A. R., Di Carlo V., Pozza G. Effect of pancreas transplantation on free fatty acid metabolism in uremic IDDM patients. Diabetes. 1996 Mar;45(3):354–360. doi: 10.2337/diab.45.3.354. [DOI] [PubMed] [Google Scholar]
  23. Luzi L., Hering B. J., Socci C., Raptis G., Battezzati A., Terruzzi I., Falqui L., Brandhorst H., Brandhorst D., Regalia E. Metabolic effects of successful intraportal islet transplantation in insulin-dependent diabetes mellitus. J Clin Invest. 1996 Jun 1;97(11):2611–2618. doi: 10.1172/JCI118710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Luzi L., Petrides A. S., De Fronzo R. A. Different sensitivity of glucose and amino acid metabolism to insulin in NIDDM. Diabetes. 1993 Dec;42(12):1868–1877. doi: 10.2337/diab.42.12.1868. [DOI] [PubMed] [Google Scholar]
  25. Luzi L., Secchi A., Facchini F., Battezzati A., Staudacher C., Spotti D., Castoldi R., Ferrari G., Di Carlo V., Pozza G. Reduction of insulin resistance by combined kidney-pancreas transplantation in type 1 (insulin-dependent) diabetic patients. Diabetologia. 1990 Sep;33(9):549–556. doi: 10.1007/BF00404143. [DOI] [PubMed] [Google Scholar]
  26. MacGilchrist A. J., Reid J. L. Impairment of autonomic reflexes in cirrhosis. Am J Gastroenterol. 1990 Mar;85(3):288–292. [PubMed] [Google Scholar]
  27. Martin R. J., Bernardis L. L. Characterization of tissue enzyme activities in rats with dorsomedial hypothalamic lesions and their sham-operated controls. Physiol Behav. 1980 May;24(5):855–858. doi: 10.1016/0031-9384(80)90140-7. [DOI] [PubMed] [Google Scholar]
  28. Matthews D. E., Schwarz H. P., Yang R. D., Motil K. J., Young V. R., Bier D. M. Relationship of plasma leucine and alpha-ketoisocaproate during a L-[1-13C]leucine infusion in man: a method for measuring human intracellular leucine tracer enrichment. Metabolism. 1982 Nov;31(11):1105–1112. doi: 10.1016/0026-0495(82)90160-3. [DOI] [PubMed] [Google Scholar]
  29. Mazzaferro V., Regalia E., Doci R., Andreola S., Pulvirenti A., Bozzetti F., Montalto F., Ammatuna M., Morabito A., Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996 Mar 14;334(11):693–699. doi: 10.1056/NEJM199603143341104. [DOI] [PubMed] [Google Scholar]
  30. McCullough A. J., Glamour T. Differences in amino acid kinetics in cirrhosis. Gastroenterology. 1993 Jun;104(6):1858–1865. doi: 10.1016/0016-5085(93)90671-x. [DOI] [PubMed] [Google Scholar]
  31. McCullough A. J., Mullen K. D., Tavill A. S., Kalhan S. C. In vivo differences between the turnover rates of leucine and leucine's ketoacid in stable cirrhosis. Gastroenterology. 1992 Aug;103(2):571–578. doi: 10.1016/0016-5085(92)90849-t. [DOI] [PubMed] [Google Scholar]
  32. Miles J., Glasscock R., Aikens J., Gerich J., Haymond M. A microfluorometric method for the determination of free fatty acids in plasma. J Lipid Res. 1983 Jan;24(1):96–99. [PubMed] [Google Scholar]
  33. Millikan W. J., Jr, Henderson J. M., Galloway J. R., Warren W. D., Matthews D. E., McGhee A., Kutner M. H. In vivo measurement of leucine metabolism with stable isotopes in normal subjects and in those with cirrhosis fed conventional and branched-chain amino acid-enriched diets. Surgery. 1985 Sep;98(3):405–413. [PubMed] [Google Scholar]
  34. Morgan M. Y., Marshall A. W., Milsom J. P., Sherlock S. Plasma amino-acid patterns in liver disease. Gut. 1982 May;23(5):362–370. doi: 10.1136/gut.23.5.362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Morrison W. L., Bouchier I. A., Gibson J. N., Rennie M. J. Skeletal muscle and whole-body protein turnover in cirrhosis. Clin Sci (Lond) 1990 Jun;78(6):613–619. doi: 10.1042/cs0780613. [DOI] [PubMed] [Google Scholar]
  36. Navasa M., Feu F., García-Pagán J. C., Jiménez W., Llach J., Rimola A., Bosch J., Rodés J. Hemodynamic and humoral changes after liver transplantation in patients with cirrhosis. Hepatology. 1993 Mar;17(3):355–360. [PubMed] [Google Scholar]
  37. O'Keefe S. J., Abraham R. R., Davis M., Williams R. Protein turnover in acute and chronic liver disease. Acta Chir Scand Suppl. 1981;507:91–101. [PubMed] [Google Scholar]
  38. Odessey R., Goldberg A. L. Leucine degradation in cell-free extracts of skeletal muscle. Biochem J. 1979 Feb 15;178(2):475–489. doi: 10.1042/bj1780475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pagano G., Cavallo-Perin P., Cassader M., Bruno A., Ozzello A., Masciola P., Dall'omo A. M., Imbimbo B. An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects. J Clin Invest. 1983 Nov;72(5):1814–1820. doi: 10.1172/JCI111141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Palestine A. G., Nussenblatt R. B., Chan C. C. Side effects of systemic cyclosporine in patients not undergoing transplantation. Am J Med. 1984 Oct;77(4):652–656. doi: 10.1016/0002-9343(84)90356-5. [DOI] [PubMed] [Google Scholar]
  41. Pennington J. C., Jr Quality of life following liver transplantation. Transplant Proc. 1989 Jun;21(3):3514–3516. [PubMed] [Google Scholar]
  42. Petrides A. S., Groop L. C., Riely C. A., DeFronzo R. A. Effect of physiologic hyperinsulinemia on glucose and lipid metabolism in cirrhosis. J Clin Invest. 1991 Aug;88(2):561–570. doi: 10.1172/JCI115340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Petrides A. S., Luzi L., Reuben A., Riely C., DeFronzo R. A. Effect of insulin and plasma amino acid concentration on leucine metabolism in cirrhosis. Hepatology. 1991 Sep;14(3):432–441. [PubMed] [Google Scholar]
  44. Rizza R. A., Mandarino L. J., Gerich J. E. Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol. 1981 Jun;240(6):E630–E639. doi: 10.1152/ajpendo.1981.240.6.E630. [DOI] [PubMed] [Google Scholar]
  45. Robinson K. A., Boggs K. P., Buse M. G. Okadaic acid, insulin, and denervation effects on glucose and amino acid transport and glycogen synthesis in muscle. Am J Physiol. 1993 Jul;265(1 Pt 1):E36–E43. doi: 10.1152/ajpendo.1993.265.1.E36. [DOI] [PubMed] [Google Scholar]
  46. STEELE R. Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci. 1959 Sep 25;82:420–430. doi: 10.1111/j.1749-6632.1959.tb44923.x. [DOI] [PubMed] [Google Scholar]
  47. Shanbhogue R. L., Bistrian B. R., Lakshman K., Crosby L., Swenson S., Wagner D., Jenkins R. L., Blackburn G. L. Whole body leucine, phenylalanine, and tyrosine kinetics in end-stage liver disease before and after hepatic transplantation. Metabolism. 1987 Nov;36(11):1047–1053. doi: 10.1016/0026-0495(87)90024-2. [DOI] [PubMed] [Google Scholar]
  48. Shevach E. M. The effects of cyclosporin A on the immune system. Annu Rev Immunol. 1985;3:397–423. doi: 10.1146/annurev.iy.03.040185.002145. [DOI] [PubMed] [Google Scholar]
  49. Shimazu T. Central nervous system regulation of liver and adipose tissue metabolism. Diabetologia. 1981 Mar;20 (Suppl):343–356. [PubMed] [Google Scholar]
  50. Shimazu T. Neuronal regulation of hepatic glucose metabolism in mammals. Diabetes Metab Rev. 1987 Jan;3(1):185–206. doi: 10.1002/dmr.5610030109. [DOI] [PubMed] [Google Scholar]
  51. Shimazu T. Reciprocal innervation of the liver: its significance in metabolic control. Adv Metab Disord. 1983;10:355–384. doi: 10.1016/b978-0-12-027310-2.50019-0. [DOI] [PubMed] [Google Scholar]
  52. Shulman G. I., Rothman D. L., Jue T., Stein P., DeFronzo R. A., Shulman R. G. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990 Jan 25;322(4):223–228. doi: 10.1056/NEJM199001253220403. [DOI] [PubMed] [Google Scholar]
  53. Starzl T. E., Demetris A. J., Van Thiel D. Liver transplantation (1). N Engl J Med. 1989 Oct 12;321(15):1014–1022. doi: 10.1056/NEJM198910123211505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tessari P., Biolo G., Inchiostro S., Orlando R., Vettore M., Sergi G. Leucine and phenylalanine kinetics in compensated liver cirrhosis: effects of insulin. Gastroenterology. 1993 Jun;104(6):1712–1721. doi: 10.1016/0016-5085(93)90650-2. [DOI] [PubMed] [Google Scholar]
  55. Tessari P., Nosadini R., Trevisan R., De Kreutzenberg S. V., Inchiostro S., Duner E., Biolo G., Marescotti M. C., Tiengo A., Crepaldi G. Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin-dependent diabetes mellitus. Evidence for insulin resistance involving glucose and amino acid metabolism. J Clin Invest. 1986 Jun;77(6):1797–1804. doi: 10.1172/JCI112504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Tomas F. M., Munro H. N., Young V. R. Effect of glucocorticoid administration on the rate of muscle protein breakdown in vivo in rats, as measured by urinary excretion of N tau-methylhistidine. Biochem J. 1979 Jan 15;178(1):139–146. doi: 10.1042/bj1780139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Vilstrup H., Bucher D., Krog B., Damgård S. E. Elimination of infused amino acids from plasma of control subjects and of patients with cirrhosis of the liver. Eur J Clin Invest. 1982 Jun;12(3):197–202. doi: 10.1111/j.1365-2362.1982.tb00993.x. [DOI] [PubMed] [Google Scholar]
  58. Zoli M., Marchesini G., Dondi C., Bianchi G. P., Pisi E. Myofibrillar protein catabolic rates in cirrhotic patients with and without muscle wasting. Clin Sci (Lond) 1982 Jun;62(6):683–686. doi: 10.1042/cs0620683. [DOI] [PubMed] [Google Scholar]

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