A quarter century of liver transplantation : Learning from livers

Liver transplantation has emerged as a powerful tool to incre;ise the understanding of ph ysio logical and paLhophysio lngical processes in the liver. Transplantation for metabolic d iseases with resolution of the disease process has been the ultimate proof of the hepatic source of the defect. Recurrence of the primary disease in Lhe liver following transplantation ha~ furthcreJ understanding of the pathogenesis of hepatitis and the cell biology o( hepmobiliary tumours. The role of genetics and immune factors in the pathogenesis of alcoholic I iver disease may be clarified with the increasing numbers of patients transplanted for alcohol ic cirrhos is. Normal gallbladde r mnti Ii ty in the denervated transplanted liver questions the role of neuronal influences on gallbladder function. Finally, experimen tal liver transplantation in animals has been used as a tool to tudy metabolic problems. Can J Gastroenterol 1989;3(4): 162-164

RESUME: La greffe du fo ie s'est nveree un ouril puissnnt pour ameliorer notre comprehension des fonc tio ns physio logiq ues er physiopnthologiques du foie.La greffe effeccucc dans le but de traiter les maladies mctaboliques et qui se tradu it par la resolu tion du processus morbide, est bien la preuve ultimc de l'origine h.epatique du probleme.La reprise de la ma lad ie primai re dans le fo ie apres la tran~plantation nous permet de mieux con nni'tre la pathogcnese de l'hcpatite et la biologie cellula ire des lllmeur~ hepatobilia ires.Le role des facteurs genctiques er im mun itaires dans la parhogenese de la cirrho~c de Laennec peut fa re clarific avec le no mbre crois ant de transplantcs rraites pour c irrhose alcoo liquc.La mo tilite normale de la vcsicu le bi liairc clans le fo ie transplante dencrve oblige a rcmettre en q uestio n le role des influe nces neuronales sur la fonction Jc la vesic ul e. Enfin, la greffe experim enrale du fo ie chez les animaux a servi d'instrument a l'ctude des probleme:, metaboliques.that it has allo wed us to und erstand in more detai l man y ph ys iological <1nd path ophysio lngic<1 I processes in the li ver.In this review, some of these lessons that have been learned from a quarter ccmury of li ver trnmplanrnrion wi ll be presented.Liver transplantation to correct ,1 congeni rn l defec t in metabolism that has o riginated in the I ive r has resul ted in some specrncular c ures of o nce fa tal and untreatable di5eases ( 2).T ah le I lisrs mewholic diseases which can he t reared by li ver trnnsplanratinn.Type II

TABLE 1 Metabolic diseases treated by liver transplantation
Type II hypercholesterolemia (3) Hemophilia A (4) Hemophilia B (5) Combined hemophilia A and B (unpublished data) Primary hyperoxaluria (6) WIison's disease (7) Tyrosinemia ( 8) Crigler-Najjar syndrome I ( 9) Protoporphyria ( 10) Byler•s disease (10) Alpha 1-antitrypsin deficiency ( 11) Glycogen storage diseases ( 12) Seo-blue histiocyte syndrome ( 13) Niemann-Pick disease ( 14) hypercholcstcrt1lcmi;1 i~ a cunditiun ll'hich is cc1uscd hy ,, lack of low Jen~it y lipoprotein (LDL) receptor~ in t he liver.In this condiri,m the liver is histological ly normal and the end organ is usually the heart with ea rly coronary .irccrydisea~e.Successful transplantnrion of the li ver to restore the receptors to clear th<' lipids from the circul ation along with transplnnt a1 io n of the damaged h art has resu lted in a cure of this congeni ta l cond ition (3).Simi larly, the well knmvn morbidity a nd mnr-1ali1y associated wi th he moph ilia h,we been cured by liver transplantation (4,5).This confirms t hat fac tor Vlll coagulant activity, whic h ,s deficient in hemophilia, is dependent on the liver tor signifi cant production .Correction of th e miss ing hepcltic e n:y me in primary h yperoxalu ri a by liver rransplantmion 111 conjunction with a renal trnn •plant ro correct the damaged organ is anothe r exampl e n ( a cure for a rrevious ly inc urahlc disea~e (6).
These examples illustrate how orthotopic I iver transplanta tion for a ,uspected hepatic defect is the ultimate rronf of the original hypothes i:.fo r the pathogenesb of the disease.Wilson 's Jisease, a congenital d isorder in copper metabolism that results in copper overload in the li ver and brain, can he cured by liver tran:,plan ta t ion.A lthough many patients with Wilson's disease will not requ ire tra nsplantation because of lifelong tre,Hment wit h copper chelating age nr~.some pnt icnt:, still present with refrnctory end srnge li ver d i:,ease, acute fulminant hepatic failure or di~ab ling neurological deficits.A lthough a defect in hepatic hi liary copper excretion was postulated, successful I ivcr trnnsplantatinn in the:,e patients confi rmed th e hepatic ha:,b for the disease, and the :,pecrnLu lar neumlogical recovery following t ransplan tation in some patient:, ( 7, 15) suggested that the new liver Clluld facilitate the clearance of residual copper from the central nervous system.
A n ot h e r way in which liver transplantation has enhanced the understanding of ba:,ic liver ~lisease:, i:, by the nb:,ervation:, on the recurrence of primary ll\•er diseases fo ll owing transplantation.Early reports suggested that primary biliary ci rrhosis recu rred tdlowing tran:,plantation ( 16).However , because o f the histnll>gic.11simila ri ty hetween chronic graft rejection and primary hiliary cirrhosis, it is most d ifficu lt to prove a rec urrence of this dbea:,e.Recurrence of autoimmune ch roni c active hepatitis has been documenred (17,18).This raises th e question of whether circulati ng antihodie:, interact with normal ;:uuigens in the ne\\' liver or alternatively may suggest a viral etilllogy to this condition.T he persistence of antimiroc ho ndria l antibodies fo llowing liver transplantation in patien ts with primary biliary cirrhosis docs nm result in disease recurrence a nd suggests that thb antibod y is not directly involved in the pathogenesis of the disease.1-lepatitb B wi ll always recur in a transplanted patient but t he cli n ical sequclae of th e recurrence of viremia is unpredictable ( I 9).This observatiun confirms that extrahepatic reservoirs of hepatitis B virus exist and long te rm fo llow-up of these immunosuppressed patients will add to the understanding of rhe complex interre lationship between hepatitis B vi rus and th e immune sys tem.
The recurrence of hepatic tumours fo ll owi ng transplan tation has been disappointing.Primary hepat()cellular carcinoma has a recurrence rate of 70% at one year and cholangincarcmoma has heen reported to have a 100% recurre nce rate ( 15.20).Best resu lts fo r rumnurs have been for the Cibrolamcllar variant of hc patoce llula r carcinnma Liver transplantation: Learning fro m livers a nd fo r m icroscop 1c tumours d 1scovered incidentally fi.lll owing the removal of a cirrhnric li ver (2 1 ).The observation that the rrampla nted liver can he the !:lite of recurre nce !>uggests that the resi du a l malignant ce ll s have a preference for the mi lieu pwvided hy th e hepatic m1crostructurc.The high incidence of recurrent tumour also emphasizes the limitations of conventional screening proced ures for metastatic d isease prior to I ransplantation.The increased risk of malignancy in l iver transplant pat iL•nts on c h ronic 1mmunosuppressinn has abo illustrated the ro le nf immunological survcillnncc 111 the development of neopln,tic disenst'.In particular, the developmen t ot lymphoprol ifcrativc disease thm regresses fol lowing cessation of imm L mosuppressinn (22) may have implications in the etiology of these conditions since vira l markers have been found in a variety of lymphomas.
Recently, a large series ,if patients t mnsplanred for alcoholic ci rrl•w~is wa~ reported ( 2 3 ).Although the authors have suggested that pre-selection of ,ib~tinent patients together with the ordeal of transplantation has resulted in a group of patients with no relapscs to ,ilcnhol abuse, a ~kcptic would suggcM that eventual ly some of these patient:, wi ll return to alcohol use and abuse.Since the gen eu c aspec ts of suscept i bi Ii t y 10 alcohnl have heen emphasized (24) it wi ll be ot great interest to sec if the transpl an ted liver will be injured by alcohol abuse.Furthermore, there ha:, been evidence that both cell med iated and hun1llral immune factors may play a role in the pathogenes is of alcnholic liver disease (25,26) a nd so the effects of long term immunosuppression will he of interest in the alcoholic tran~plant patient.As well as irs ro le in h e lping w e luci d a te the pathogenesis of a num ber of liver d ise,1ses, liver tramplanta tion has also clari fi ed und erstandi n g o f b as ic physiologic processes.For example, it h as heen traditional teaching that ga llbladder contractility is regulated hy neuronal inn uences and gastrointc~rina I hormones.The nhervation 1hat the denervarcd gn llhladder, which has hce n t ra nsplan ted with the liv e r, n:sronds normally to hunnon,11 stimuli rn1ses Jnuhts ahnu1 the rel,nin: 1mport.1nce of neurngenic slimul, (27).Furthermore, several tn1mrl:111r raucn1s have suffered (rom hil ia ry colic (ol lnwing the I ran,rlant ( unpuhl,shl,J data).The pnin pa1hway, fl,r the denervated gnllbladJer are nu1 well unJerslllml.