Immunosuppression, Organ Allocation, and Other Issues in Liver Transplantation

Since the last Seminars in Liver Disease devoted to liver transplantation, there have been major advances in many aspects of organ transplantation, including immunosuppression and the selection and management of patients. However, there are several unresolved issues and new issues that have surfaced with changes in how and whom we transplant. This issue of Seminars addresses some of these controversies.

The first article illustrates this well. It is an overview of current immunosuppression, which has expanded considerably since the 1990s, although corticosteroids remain central to both initial immunosuppression at most transplant centers and to the treatment of rejection. Hirose and Vincenti describe newer antiproliferatives and antilymphocyte antibodies directed at T cell function and discuss promising agents for the future. Although the reader will recognize some old faces, the transplant team now has a greater armamentarium of drugs to tailor individual therapy.

The second article, by Biggins and Bambha, addresses issues resulting from recent changes in how donor organs are selected. The model for end-stage liver disease (MELD) is now used to select recipients and resulted from the determination that allocation of donor livers should be based solely upon liver disease severity and risk of mortality while awaiting transplantation. This allocation system replaced the Child-Turcotte-Pugh severity system, which was also based on whether the patient was hospitalized and how long the patient had been on the waiting list. While achieving the desired outcome of decreasing pretransplantation mortality, the use of MELD has left underserved some patients, who have decreased survival because of factors other than those manifest in the MELD score (e.g., ascites). This article also highlights that when there is a scarce resource, equitable distribution is extremely difficult. This has led many centers to expand the use of potential donors who otherwise would not have been considered. In the next article, Renz et al discuss extended-donor criteria, including the use of older donors, the risks of hypernatremia or steatosis in the donor, donation after cardiac death, and the use of partial liver transplantation. They highlight the importance of careful evaluation of the donor and the need for thorough discussion with the recipient about potential risks and informed consent. Kulkarni and Cronin subsequently discuss problems associated with the ethics of liver transplantation and make note of the downside of the new MELD allocation system and its regional variation. The articles by Biggins and Renz should be read together with this article to develop a broader picture of problems associated with ethics and donor allocation, as they address and expand many of these issues with figures and tables showing regional variation in donor and recipient size and severity of disease. The ethical aspects of living donation present additional problems that, unfortunately, were not addressed in any depth in these articles.

Transplantation of patients with hepatocellular carcinoma (HCC) has changed markedly over the past decade. HCC was initially a contraindication to liver transplantation, but a landmark study from Milan challenged this view and resulted in criteria allowing successful transplantation of patients with small lesions. However these criteria are now being strongly challenged. We chose to highlight the issues in a “debate” between Yao and Llovet. In separate articles, each discusses the use of expanded criteria and “down-staging” as a modality to successful transplantation in patients with HCC. Yao takes the position from the University of California at San Francisco (UCSF) that successful down-staging can be achieved under stringent new criteria. He has included the current United Network for Organ Sharing (UNOS) criteria, the proposed criteria and the UCSF protocol, and independent evaluation by other sites. Llovet et al note that no randomized controlled studies have ever been undertaken in HCC (unlike nearly all other cancers) and that the results are inconsistent between centers. His article highlights preoperative modalities, lead time bias, the limited success of therapies for HCC, and the limited reporting of long-term outcomes for extended indications. Reading the two articles together reveals the problems associated with drawing conclusions from studies that are inconsistent and lack standardization of approach and reporting. Indeed, in several instances, the same articles are used to make different points by each author! Given the biologic variability of tumors, it is not surprising that a “one size fits all” approach is not ideal. In addition, the articles highlight the problem of preoperative assessment of lesion number and size by increasingly sensitive radiologic techniques. Evaluation by biologic characteristics is even more difficult preoperatively but may be of more value than size determination. Transplantation of patients with HCC has benefited from the introduction of an exemption from MELD criteria. Given the scarce resource of donors, many may be resistant to extending the criteria for transplanting patients with HCC. Widespread acceptance may require validation by multiple centers.

This issue also considers new approaches to specific problems; there are four articles that focus on specific diseases and their management. The first is a superb update on an old problem, new therapies for hepatorenal syndrome, by Arroyo et al. Hepatorenal syndrome is a common complication of cirrhosis, is associated with a poor prognosis, and is not restricted to liver transplant centers. This article details effective treatments that may allow better treatment for patients, which may translate into possible referral to and benefit from liver transplantation. This article will be useful to the practicing gastroenterologist as much as to the transplant hepatologist and demystifies a complicated management problem. Krowka discusses portopulmonary hypertension, a difficult and uncommon problem, considered a contraindication to successful liver transplantation. Much of the current thinking has resulted from work performed at his center, and the tables outline diagnosis and the successful approach to management of portopulmonary syndrome. Roland and Stock address transplantation in patients with HIV. Although this is extraordinarily difficult given the interaction between medications, a dedicated multidisciplinary approach has led to outcomes similar to those of transplant patients without HIV infection, a truly remarkable recent advance. The majority of such liver transplants are being undertaken under the auspices of an NIH study to learn and refine new management strategies by optimizing interactions between surgeons, hepatologists, HIV infectious disease specialists, and pharmacologists. Finally, Sharma and Lok have provided an excellent update on viral hepatitis and liver transplantation, outlining the excellent outcomes for hepatitis B and the challenges for management of hepatitis C infection. Although newer nucleos(t)ide analogs have revolutionized the peritransplantation management of the HBV infection, we await such specific HCV therapies to make major progress in hepatitis C peritransplantation management.

Overall, this issue will be used by those at liver transplant centers as well as fellows, gastroenterologists, and referring physicians to explain some of the changing faces of successful liver transplant management and to better manage some aspects of end-stage liver disease.