Biamed & Phartnacother (1992) 46.79-83 Q Elsevier, Paris

79

Dosslet

Liver transplantation: the challenges of the 1990s B Dousset, D Houssin Cfinique Chirurgicale, Hapital Cochin. 27 rue du Eawbourg Saint-Jacques, 75674 Paris Cedex 14, prance (Received 15 November 1991; accepted 22 January 1992)

Summary - An enormous increase in liver transplantation has been observed over the last decade since it now represents a suitable therapeutic option for patients with end-stage liver disease. The overall one-year survival rate is about 75% for adults and 85% for children, when fulminant hepatic failure and malignancies are excluded. Such improvements in both survival and quality of life are due to many concurrent factors: better timing and selection; development of the UW solution for liver prese~ation; improvement in operative management including surgical technique, veno-venous bypass and cellsaver: progress in intensive care management of immunosupressed patients. Nevertheless, the increasing demand for tivers is now confronting the transplant teams with organ shortage, for which the introduction of graft reduction, hepatic biparition and living-related donation will contribute to alleviate the scarcity of donors. As a consequence of the increasing number of long-term survivors, greater efforts are now being directed towards the long-term outcome after liver transplantation: disease recurrence, the need for permanent immunosuppression and the quality of rehabilitation will become the challenges of the 1990s before reaching the next step towards multiple organ transplantation. liver transptan~tion R6sumi - Transplantation Mpatique: le dCfi des amAs 1990. Le de’veloppement imporrant de la transplantation hepatique au cows de la derniere decennie s’expbque par I’ame’lioration constante des rhsultats. puisqu’crcuteller?lerlt 75To des ad&es et 85% des enfants son? vivants UR an apt-es la greffe si l’on e.rclue les tumeurs et les hepatites fulminantes. Ces progres son? dus ci plusieurs PlPments: la meifleure selection des malades et In meilleure defir;itiou du moment de l’indication: 1‘uti~isation de ia .~o~l~tio?lde Wisco?ls~rt pour la pr~se~~~~tirj?td ‘organe: I *atit~lioration de la r~a~~i~~~ation p~ri-op~rato~re incluant i’uti~isation du shunr vei~~o-~~ei?tet~~, du cell-saver et de l’aprotit~iize: les progres de la r~a~rimution post-op~ratoire des itnmunodkprimis. Cependant Ia demande croissants de greffons expose la piupart des Pquipes a une penurie relative d’organes pour laquelle I’utilisatinn de foies reduits. des foies partagbs ou provenant de donneur vivant semble pouvoir att&wer cette carence. L’apparitinn de survivants de longue d&e rend ne’cessaire I’e’valuation des benefices d long terme de la transplantation hepatique: !a prdvention de In rhcidive de la maladie initiale. les progres de l’innnunosuppression et I’ame’lioration de la qualite de la vie apr& Ia greffe d$inissent /es objectifs futurs avant de franchir I’etape suivante de la gt~fle musty-or~ane. transplantation hCpattque

Whereas 530 liver transplants took place up to 1984 in Europe, 6 398 have been undertaken since then, more than 3,000 of which have been performed during’ihe last 2 years at 72 centers [lo]. The reasons for such an escalation are evident since the i-year survival rate is about 75% for adults and 85% for children, excluding transplants for fulminant hepatic failure and malignancies [IO, 291. Thus, the increasing number of liver

transplantations has been mirrored by a gradual improvement in both survival and quality of life. However, although there are several explanations for these improved results, the transplant teams are now confronted with new problems caused by the increasing number of candidates and longterm survivors. Since the introduction of cyclosporine in the early 1980s the most significant change in recent

SO years was in patient selection and the recognition of those who would truly benefit from transplantation_ For example, we now try to avoid grafting in end-stage cirrhotic patients with cachexia, spontaneous ascitic fluid infection and refractory hepato-renal syndrome, whose life expectation does not exceed a few weeks, since it is now clear that most of these candidates will not benefit from a n*w liver. For the same reasons, in fulminant hepatic failure, the recent establishment of early prognosis criteria [22] should allow transplantation before the onset of multi-organ failure and therefore increase post-transplant survival rate. There is now general agreement on the liver disenses which make the patient eligible for liver transplantation and, moreover, on the appropriate timing for patient referral. Primary biliary cirrhosis is a chronic cholestatic disease with a predictable course according to the bilirubin level, for which transplantation can be offered with excellent results before the onset of severe hepatic insufficiency In primary sclerosing cholangitis, a symptomatic patient with advanced liver disease is a primary indication for liver transplantation and any attempt to repair surgically or to stent a biliary stricture may compromise the outcome of a subsequent liver transplant. In the same manner, in biliary atresia where the failure of the kasai procedure results in early symptomatic cirrhosis transplantation should be performed before liver decompensation without further surgical biliary drainage.

For the same reasons, surgeons should remember that any abdominal intervention in a cirrhotic patient may substantially compromise the outcome of a subsequent liver transplant. Moreover, if sclerotherapy fails in controlling varicose bleeding, meso-caval shuut should be indicated, as it avoids porta hepatis dissection and it can easily be ligated during transplant [2]. The timing for transplantation is not as easy to determine for non-cholestatic cirrhosis such as post-necrotic, auto-immune or alcoholic cirrhosis, since they do not usually follow a predictable course. In these indications, transplantation will be considered in patients who present with recurrent variceal bleeding, intractable ascitis or encephalopathy despite adequate treatment, with a pool quality of life and an estimated survival time of less than one year. In addition to the former criteria, a period of abstinence of at least 3 to 6 months and a psychiatric evaluation should be required before considering patients with alcoholic liver disease as suitable candidates for liver replacement [ 191.

Transplantation for liver malignancies has been d~s~ppojnti~lg with a 2-year survival rate of abont 30%, mainly due to tumor recwrence [23, 263. For this reasoa, liver transplantation for cancer should be considered after a rigorous assessment only if the tumor is confined to the liver. Furthermore, if during liver transplant evidence is found of extra-hepatic spread by frozen sections, the procedure should probably be aborted. Indirectly, one of the most contributive advances in liver transplantation in the past 3 years has been the development of the University of Wisconsin’s (VW) solution for organ preservatin; which allows an increase of up to 20 hours in cold ischemic time without adversely affecting the quality of organ storage [ I?‘]. From now on, liver replacement can be performed as a semielective procedure during daylight hours, thus avoiding the adverse effects of night surgery and simplifying logistics. The beneficial effects of an extended preservation time are multiple, since it allows liver retrieval from greater distances, better sharing of organs and longer ‘back-table’ preparation for graft reduction or bipartition. Surprisingly, apart from increasing experience in the management of technical problems such as anatomical variations, portal thrombosis or previous porto-systemic shunts, there have been very few changes in the surgical technique itself since the beginning of the transplant era. Nevertheless, the introduction in adults of veno-venous bypass, which minimises fluid support and maintains cardiac output during the anhepatic phase, has contributed to reducing the adverse effects of vascular exclusion on renal function and fluid balance [28]. Moreover, the use of the cell saver has limited the risks of majar blood replacement [S]. Progress in surgical management has also been matched by improved postoperative care, leading to an earlier diagnosis and to better management of the various post-operative complications [ 181. The improved results of liver transplantation are now transforming the management of chronic liver diseases. since every patient might become a suitable candidate for liver replacement. As a consequence of this tremendous expansion in liver grafting, the transplant teams now have to face the problem of an increasing shortage of organs, for which there are several coflcurrent solutions. The number of potential donors could be further increased by legal and cultural adaptation in many countries. Progress in transplanl surgery has un-

81

doubtedly contributed in alleviating the scarcity of organs. In infants, where the organ shortage is particularly critical, the introduction of reducedsize grafts from adult donors has drastically decreased mortality among children on the waiting list [l]. Hepatic bipartition, using one liver for 2 recipients, has been successfully performed in both children and ad&s requiring emergency ~ans~la~tation [9_ 151, Recently, living-related liver transplants, using the left liver lobe of a parent, have been performed with non negligible morbidity in donors, raising the ethical question of single organ donation from living donors [3]. Another solution which could extend the availability of organs is the use of ABU-in~ompatibIe grafts. However, only 40% of the ABO-incompatible grafts are still functioning 2 months after transplantation, clearly indicating that such grafts should be avoided except for emergency cases f13]. Finally, the rising demand for liver transplantation resulting in an increased time on the waiting-list, may lead to reconsideration of cases with a well-established poor prognosis such as tumors, or end-stage cirrhosis. It is a subject of debate as to whether a compatible liver should be offered in priority to the sickest patient, or to the one W&Ysould benefit the most from the graft. Although the aim of attaining a one-year survival rate of 90% or more after elective liver replacement has become realistic, persistent challenges still remain for the next decade. The increasing number of long-term survivors is now opening up a new area of late ~ompli~ations_ Disease recurrence i7] is well established for tumors [23, 261, liver disease related to B virus [27], Budd-Chiari syndrome [ 141 and has been reported with no further evidence for primary biliary cirrhosis [25] and chronic active auto-immune hepatitis [20]. The recent identi~~ation of hepatitis C virus will probably lead to the recognition of graft viral reinfestation and disease recurrence [4]. In tumors, except for incidental carcinomas detected in native livers [ 161, neither a rigorous assessment nor the use of chemotherapy have been able to prevent a si~~ifi~~t rate of recurrence. The long-term results of major cluster excision for liver mafignancies are still awaited. However, new chemotherapy protocols may in future reduce the rate of recurrence in selected patients. In B virus-related liver disease, the imanti-HBV immunousing munoprophylaxis globulins tends to transiently protect the graft without preventing viral reinfestation in most cases [27]. The combination of long-term im-

munoprophylaxis

using human anti-HBV monnand sew anti-viral agents may decrease the rate of viral recurrence in infected recipients and reeds to be evaluated in prospective trials [211. In Budd-Chiari syndrome, unless there is a well-established cirrhosis, most of the patients can benefit from a meso-systemic shunt. Nevertheless, in the case of liver transplant, anticoagulation therapy should be instituted to prevent rechrombosis, In addition to disease recurrence, the need for permanent immunosuppression in long-term survivors will surely become the greatest concern in the near future, not only as regards long-term graft function but also quality of life. Thus, mmplant patients remain exposed to late infections and to adverse side-effects of steroids and cyclosporine such as hypertrichosis, hypertension and nephrotoxicity. Furthermore, the increased risk of de 820~0 malignancies in long-term immunosuppressed patients, which has been mainly reported for kidney transplantation, is likely to extend to liver recipients with prolonged followUP ~241. donaX antibodies

Therefore, the recent arrival of new generations of immunosuppressors has raised expectations. A murine monoclonal antibody (OKT3) has been shown to efficiently treat refractory rejection but also induces an adverse humoral immune response and is consequently ilot appropriate for long-term immunosuppression [S]. A new agent, FKSOS, has been reported to be suitable for prophylactic immunosuppression and to reduce both incidence and severity of acute rejection without serious side-effects [32]. Nevertheless, these positive preliminary results have to be confirmed by a larger series of patients in controlled prospective trials on cyclosporine, which are currently being run both in Europe and the United States. Finally, liver transplantation could benefit in future from other conceptual approaches. Auxiliary partial liver transplant, used either as a temporary support for acute hepatic failure until native liver recovery or as permanent assistance for metabolic disorders, has been reported 1311 and may in future become another therapeutic Option for liver failure. Furthermore, the combined advance in preservation and immunosuppression is now paving the way towards the next step in multiple organ transplanta~on. Liver-kidney I1 1i* liver-small bowel I 121, heart-lung-liver I61 and [30] have ail been cluster transplantations achieved with success, but their application

82 should be carefully considered especially with regard to quality of life after ~ansp~antati#~. The benefits of the liver transplant revolution are enormous, since it constitutes the only therapeutic option for patients with fatal liver disease and has encouraged progress in all aspects of preservation, management of liver disease, hepato-bi~i~y surgery and ~mmunosuppression. However, due- to the vast irtcrease in candidates, the transplant teams are now confronted with the problem of organ shortage and with the need for stricter prognostic criteria in order to prevent potential wastage. Although liver transplantation still cannot be considered as routine therapy, the initial phase of develupment has now been reached with encouraging results. We now have to face the forthcoming challenge of increasing the one-year survival rate especially in critical groups of patients, while bearing in mind the rational evaluation of long-term benefits.

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