Barone, M

Coetzee, M

Francavilla, A

Makowka, L

Ove, P

Polimeno, L

Starzl, TE

Van Thiel, DH

PubMed

Name not available

Regulation of liver size and regeneration: Importance in liver transplantation

A. Francavilla

P. Ove

POLIMENO, Lorenzo

M. Coetzee

L. Makowka

DH Van Thiel

TE Starzl

BARONE, Michele

Archivio istituzionale della ricerca - Università di Bari

Regulation of liver size and regeneration: importance in liver transplantation

D-Scholarship@Pitt

Regulation of Liver Size and Regeneration: Importance in Liver Transplantation A. Francavilla, P. Ove, L. Polimeno, M. Coetzee, L. Makowka, M. Barone, D.H. Van Thiel, and T.E. Starzl T HE LIVER, under normal conditions, presents only one mitosis per 1,000 hepa-tocytes, and the cells contain a fair amount of glycogen, lipids, and proteins. Table 1 indicates the two types of factors controlling normal liver physiology. It is very difficult to define the exact role of each of these factors because they are very closely interrelated. The typical alterations induced by a portacaval shunt constitute the best dem-onstration of the existence of these two types· of factors. 1,2 In fact, in addition to the typical signs of atrophy in this model, the presence of regeneration with increases in the number of mitosis from 1.14 to 6 can be observed. The appearance of atrophy and ultrastructural deterioration demonstrates a lowering of fac-tors controlling the size and morphology of the liver, and the latter indicates the appearance of regulating factors of regeneration. In a series of investigations during 1971 to 1977,3'5 we have established that insulin is the main factor that regulates the size, morpholo-gy, and structure of the liver. In fact, a nonhypoglycemic insulin infusion into the ligated left portal vein for four days after an Eck fistula greatly reduced the left lobular From the Departments of Gastroenterology, Univer-sity of Bari, Italy; Anatomy and Cell Biology, Surgery, and Gastroenterology. University of Pittsburgh Health Center; and Veterans Administration Medical Center. Pittsburgh. Supported by research grants from the Veterans Administration; Project Grant No. AM-19961 from the National Institutes of Health. Bethesda, MD: and by Grant No. 885/01 16544 from the Consiglio Nazionale delle Ricerche. Italy. Address reprint requests to A. Francavilla, MD. Veter-ans Administration Hospital, Bldg 6, Circle Dr, Pitts-burgh, PA 15140. ©1988 by Grune & Stratton. Inc. 0041-1345/88/1001-1177$03.00/0 hepatocyte atrophy, preserved the hepatocyte ultrastructure, and increased the cell renewal (mitosis rose from six to 15 per 1,000 cells). This effect was not changed by the addition of glucagon, regardless of the dose. The finding that insulin increased the number of mitoses raised the question of the importance of hor-mones in the regeneration process. After this study, several authors6•10 have described hormonal changes in both rats and dogs, ie, decreases in'insulin, triiodothyronine, thyroxine, and calcitonin levels, whereas glu-cagon and corticosterone levels increase. Fur-thermore, we have recently reported that sex-ual hormones are involved in liver regenera-tion after 70% hepatectomy in rats. ll - D Estrogen levels increase in the serum with a corresponding increase in estrogen receptors, which correlates with the peak of the mitotic index. On the other hand, serum testosterone and androgen receptors display a very signifi-cant decrease. On the basis of these hormonal changes, many speculations have been proposed to attempt to define the role of hormones in liver regeneration. Nevertheless, none of these hypotheses were conclusive for the following reasons: (I) it is possible to prevent the typical insulin-glucagon change after hepatectomy by glucose infusion without affecting liver re-generation in a major way; (2) insulin and Table 1. Factors Regulating liver Size and Regeneration Factors for Li_ Throphism Hepatocyte content Glycogen lipids Vitamins Electrolytes Hepatocyte structures Factors for Li_ Regeneration Rapid activation of hepato-cyte spontaneous re-newal to maintain liver mass constant 494 Transplantation Proceedings, Vol XX. No 1. Suppl 1 (February), 1988: pp 494-497 --- --~------- --~------~---------------------------------LIVER REGENERATION IN LIVER TRANSPLANTATION 495 Table 2. Tissue and Serum Growth Factors Time Name of Purification Molecular Investigator Period Substance (fold) Weight (kd) Tissue factors Blomquist 1957 LaBrecque 1975-19B7 HSS 110,000 14-15 Hatase 1979 30 Starzl 1979 Goldberg 1980-1985 Hepatopoietin 13,000 38 Terblanche 1980 Francavilla 1981-1987 HSS 38,000 15-50 Schwarz 1985 14-25 Weberman 1984 Fleig 1986 Serum factors Morley 1973 400,000 26 Michalopoulos 1984-1986 HPTA 120 HPTB 3 Russell 1984 65 Nakamura 1984 Hepatotrophin 20,000 120 Goldberg 1980-1985 Hepatopoietin 13,000 38 Diaz-Gil 1986 HP 83,000 64 Abbreviations: HPTA, hapatopoietin A; HPTB, hepatopoietin B; HP, hepatic DNA-synthesis promoter. glucagon in vitro do not affect hepatocyte proliferation; (3) triiodothyronine, thyroxine, calcitonin, and sex hormones in vitro do not show particular activity on hepatocyte prolif-eration; (4) the administration of all these hormones in animals after hepatectomy has never provided consistent data on liver regen-eration; and finally (5) and even of further importance are the results we have obtained by transplanting small livers into much larger recipients. A rapid growth of small livers occurs during the first day after transplanta-tion, which is similar to that observed after partial hepatectomy. None of the typical hor-monal alterations observed after hepatectomy occurred during this process. Because hormonal changes did not provide any conclusive answers as related to liver regeneration, in 1975 several investigations on growth factors in serum and tissue were ini-tiated. Table 2 illustrates the growth factors that have been partially isolated from serum l4-19 and liver. 19-32 As reported in Table 2, we have been working on the extraction and purifica-tion of hepatic stimulator substance (HSS) Table 3. Steps in the Purification of HSS and Chemical and Physicochemical Properties of Fraction F'60 Obtained From Weanling Rat Liver Protein Injected DNA Resistant to in Each Rat Synthesis Neuroam- Purification Material (mg/2mL) (cpm/mg DNA)- Heat Trypsin inidase (fold) Cytosol 75 43,350 ± 8,820t 65 0 C supernatant 20 56,720 ± 10,24Ot 6 OH-F 10 66,350 ± 11 ,350t 15 30Kd 2_75 63,520 ± 13,220t 102 F,OG 0.003 54,380 ± 10,200 100% 30% 100% 38,100 -[3H)thymidine incorporation in a 40% hepatectomized rat injected with phosphate-buffered saline was 16,500 cpm/mg DNA. The numbers are the averages from no less than 20 different rats ± SD. tSignificantly different from controls, P < .05. 496 "0 '" "' '" o ~ #. ~~ .00 '" " ...JZ 20 10 ~~ PM~* Q)c::t K<:K"Dw1MM~* ~;l ~ (; g 50 .. .<: 0._ I- (; E r-1uc' ~_r..<:.!:. 00 1.7 3.4 6.8 L:... . *pc::O.05 HSS ~/lMM gr.b.w. Fig 1. Dose response curve in 40% hepatectomized rats injected with FlIo' F,IO was injected intraperitone-ally six hours after operation. ['HIThymidine incorpora-tion. percentage of labeled nuclei and percentage of mitosis were determined 24 hours after operation .• P < .05. since 1980. HSS was first described by LaBrecque and Pesch20 in the cytosol of par-tially hepatectomized rats and subsequently identified in canine liver by Starzl et al. 22 Table 3 reports the steps in the purification and the physicochemical characteristics of the active chromatographic fraction, referred to as FIso. that is obtained from weanling rat liver cytosol using fast protein liquid chromatogra-phy (FPLC) apparatus. This fraction stimu-lated DNA synthesis in hepatocytes in a dose-dependent regimen when injected in 40% hepatectomized rats (Fig 1). The activity of this fraction is organ specific but not species specific.33 Similar to the findings with hormones, the considerable knowledge .obtained on growth factors has not yet resulted in any conclusive theory on liver regeneration. A better under-standing of this process is clinically very important, not only for cases of liver damage but also for hepatic transplantation. It has been observed that in clinical liver transplantation a liver from a small donor, occasionally transplanted into a much larger recipient, rapidly increases in size and achieves a size comparable to that of a normal liver for that particular recipient in a period of 2 weeks. These phenomena have been exten-FRANCAVILLA ET AL 300% 200% 100% 0.0. lIo.o. ,, __ " __ _ o qi-~~~~_~_~ __ 2 4 8 10 14 18 22 Days after transplantation Fig 2. Change in liver volume after transplantation. The growth of a small-for-size liver transplanted in a large recipient 1.1 and the growth of a normal liver transplanted in a recipient of similar size 1il.1 are expressed as a percentage of the initial volume. sively studied in dogs in which small-for-size livers were transplanted into larger recip-ients. 34 In Fig 2, the increase in the volume of a small liver transplanted in a larger animal is compared with that of a normal-for-size liver transplanted into a dog of suitable size. A great increase in thymidine kinase, orni-thine, and decarboxylase levels and in the percentage of mitoses was detected only in the ~ 500 0. 400 2 300 :5 200 0> ~ 100 a 0 Plasma Insulin Plasma Glucagon ~~~~~--~~--~--~-012 4 6 8 1.0 15 20 25 30 Time Post Transplant (days) Fig 3. Plasma insulin and plasma glucagon levels in the two groups of animals: •• small-for-size liver trans-planted in large recipient: o. normal liver transplanted in a recipient of similar size. -----------------------------------LIVER REGENERATION IN LIVER TRANSPLANTATION small liver transplanted in a host of a larger size. This indicates an active hepatocyte pro-liferation. Figure 3 compares the insulin glu-cagon changes observed in both models. Despite a different rate of hepatocyte prolifer-ation, the hormonal changes observed were similar but at the same time different from the levels observed in a regenerating liver induced by partial hepatectomy.3 In this experiment, the lack of specific hormonal changes suggests that the role of hormones in liver regeneration has to be reevaluated, and it raises the question of the existence of inhibitors as additional factors of 497 liver growth regulation. A small liver, when transplanted into a large animal, might be unable to produce enough inhibitor substance to keep a normal plasma concentration. Therefore, regeneration could be seen as a complex mechanism in which the initiating key is the plasma concentration of inhibitors. This possibility even further complicates the already complex view of the regeneration pro-cess. In fact, we know only a few pieces of the puzzle that are responsible for the complex system of regeneration, and even more dis-couraging, we do not fully understand how all these pieces fit together. REFERENCES 1. Fisher ER, Fisher B: Lab Invest 12:929, 1963 2. Putnam CW, Porter KA, Starzl TE: Ann Surg 184:155,1976 3. Starzl TE, Porter KA, Putnam CW: Lancet 2:1241, 1975 4. Starzl TE, Porter KA, Watanabe R, et al: Lancet 1:821,1976 5. Starzl TE, Francavilla A, Halgrimson CG, et al: Surg Gynecol Obstet 137:179, 1973 6. Bucher NLR, Patel U, Cohen S: In Porter R, Whelan J: Hepatotrophic Factors. CIBA Foundation Symposium No 55. Amsterdam, Elsevier, 1978, p 95 7. Bucher NLR, Swaffield MN: Proc Nat! Acad Sci USA 72:1157,1975 8. Lelfert HL, Koch KS, Moran T, et al: Gastroen-terology 78:1470,1979 9. Starzl TE, Porter KA, Francavilla JA, et al: In Porter R, Whelan J: Hepatotrophic Factors. CIBA Foun-dation Symposium No. 55. Amsterdam, Elsevier, 1978, p 111 10. Francavilla A, Porter KA, Benichou J, et al: J Surg Res 25:409, 1978 11. Francavilla A, DiLeo A, Eagon PK, et al: Gastro-enterology 86:552,1984 12. Francavilla A, Eagon PK, DiLeo A, et al: Gastro-enterology 91:182,1986 13. Francavilla A, Eagon PK, DiLeo A, et al: Gastro-enterology 91:1263,1986 . 14. Morley CGD, Kingdon HS: Biochim Biophys Acta 308:260, 1973 15. Michalopoulos G, Houck KA, Dolan ML, et al: Cancer Res 44:4414, 1984 16. Nakamura T, Nowa K, Ichihara A: Biochem Biophys Res Commun 122:1450, 1984 17. Russell WE, McGowan JA, Bucher NRL: J Cell Physiol 119:183, 1984 18. Nakamura N, Teramoto H, Ichihara A: Proc Natl Acad Sci USA 83:6489,1986 19. Diaz-Gil JJ, Escartin P, Garcia-Canero R, et al: Biochem J 235:49,1986 20. LaBrecque DR, Pesch LA: J Physiol 248:273, 1975 21. Hatase 0, Fujii T, Kuramitsu M, et al: Acta Med Okayama 33:73,1979 22. Starzl TE, Terblanche J, Porter KA, et al: Lancet 1:127,1979 23. Terblanche J, Porter KA, Starzl TE, et al: Surg Gynecol Obstet 151:538, 1980 24. LaBrecque DR, Bachur NR: Am J Physiol 242:281,1982 25. LaBrecque DR, Steele G, Fogerty S: Fed Proc 42:438, 1983 26. LaBrecque DR, Wilson M, Fogerty S: Exp Cell Res 150:419, 1984 27. Francavilla A, Ove P, Van Thiel DH, et al: Horm Metab Res 16:237, 1984 28. Francavilla A, Ove P, Polimeno L, et al: Hepatol-ogy 5:922,1985 29. Fleig WE, Lehmann H, Wagner H, et al: Hepatol-ogy 3:19,1986 30. Schwarz LC, Makowka L, Falk JA, et al: Ann Surg 202:296, 1985 31. LaBrecque DR, Wilson M, Rinderknecht C, et al: Hepatology 6:505, 1986 32. LaBrecque DR, Steele G, Fogerty S, et al: Hepa-tology 7:100,1987 33. Francavilla A, Ove P, Polimeno L, et al: Cancer Res 47:5600,1987 34. Kam G, Lynch S, Svanas G, et al: Hepatology 7:362, 1983 

Regulation of liver size and regeneration: importance in liver transplantation.

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Regulation of liver size and regeneration: importance in liver transplantation.

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