Patient Selection in Liver Transplant: When Is It the Right Time to List?

Abstract

Progress in liver transplant during the past 2 decades has offered an increasing number of patients a better chance of survival and an improved quality of life; however, it has also created a widening gap between organ availability and demand. A brief survey of the Organ Procurement and Transplantation Network data from the Scientific Registry of Transplant Recipients database at the time of this report shows that, as of June 2007, 1-year survival after liver transplant was 82.1% for adults and 86.2% for children (based on almost 15,000 patients who underwent transplant).1OPTN: Organ Procurement and Transplantation Network OPTN Web site.http://www.optn.orgGoogle Scholar However, in 2006, the last year for which data are available, only 6600 of 11,000 new patients placed on the liver transplant list received a new graft. The number of patients on the waiting list at the end of the year was largely unchanged from that at the beginning (ie, approximately 17,300).22006 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994-2006. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association. Ann Arbor, MI; 2006.Google Scholar These figures suggest that approximately 4500 patients (only 450 of whom actually improved to the point of being removed from the list) died, deteriorated, or were taken off the list for other reasons. In early 2002, the Model for End Stage Liver Disease (MELD) scoring system was implemented to allocate liver grafts in a more systematic, objective manner. This system stratifies patients based on their probability of death within 3 months, using 3 laboratory parameters (total serum bilirubin concentration, international normalized ratio, and serum creatinine concentration) to generate a score reflective of the patients' status.3Malinchoc M Kamath PS Gordon FD Pien CJ Rank J ter Borg PC A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.Hepatology. 2000; 31: 864-871Crossref PubMed Scopus (2118) Google Scholar, 4Kamath PS Wiesner RH Malinchoc M et al.A model to predict survival in patients with end-stage liver disease.Hepatology. 2001; 33: 464-470Crossref PubMed Scopus (3764) Google Scholar With the exception of acute liver failure (and in some specific instances, such as hepatocellular carcinoma [HCC], hepatopulmonary syndrome, and metabolic syndrome), the MELD system has proven to be valuable, and its implementation has decreased waiting list mortality.5Freeman Jr, RB The model for end-stage liver disease comes of age.Clin Liver Dis. 2007; 11: 249-263Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 6Austin MT Poulose BK Ray WA Arbogast PG Feurer ID Pinson CW Model for end-stage liver disease: did the new liver allocation policy affect waiting list mortality?.Arch Surg. 2007; 142: 1079-1085Crossref PubMed Scopus (53) Google Scholar Because a few patients with a relatively satisfactory MELD score nonetheless have a poor clinical status, the liver transplant community continues to try to adapt or modify the basic formula to take such exceptions into account. The method used to select patients for the liver transplant waiting list, however, has received less systematic study. A report by Aranda-Michel et al,7Aranda-Michel J Dickson RC Bonatti H Crossfield JR Keaveny AP Vasquez AR Patient selection for liver transplant: 1-year experience with 555 patients at a single center.Mayo Clin Proc. 2008; 83: 165-168PubMed Scopus (12) Google Scholar published in this issue of Mayo Clinic Proceedings, attempts to elucidate the patient selection process and to clarify how and when patients should be placed on the list based on their MELD score. This study focuses on the patients who were presented to the Liver Transplant Selection Committee at a single large transplant center, Mayo Clinic's site in Jacksonville, FL, in 2005; in that year, 246 liver transplants were performed.1OPTN: Organ Procurement and Transplantation Network OPTN Web site.http://www.optn.orgGoogle Scholar It assesses the policies used in selecting which patients to list, ie, their absolute need for liver transplant and the odds that they would actually be offered a liver graft. Early studies on the implementation of the MELD score showed that a score of 15 was the cutoff between risk/benefit ratios for liver transplant.8Merion RM Schaubel DE Dykstra DM Freeman RB Port FK Wolfe RA The survival benefit of liver transplantation.Am J Transplant. 2005; 5: 307-313Crossref PubMed Scopus (649) Google Scholar Although the point is not specifically made by Aranda-Michel et al, the current allocation policy is to offer liver grafts first to those with a MELD score of greater than 15 in each of the United Network of Organ Sharing (UNOS) regions.9Organ Procurement and Transplant Network policy 3.6. Allocation of livers. September 18, 2007. OPTN Web site.http://www.optn.org/PoliciesandBylaws2/policies/pdfs/policy_8.pdfGoogle Scholar On the 2006 national patient list, approximately 42% of all newly listed patients vs 52% of all listed patients had a MELD score of less than 15.22006 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994-2006. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association. Ann Arbor, MI; 2006.Google Scholar Of those patients who eventually underwent a transplant in the same year, only 23% had a MELD score of less than 15.22006 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994-2006. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association. Ann Arbor, MI; 2006.Google Scholar According to the article by Aranda-Michel et al, more than half (53%, 295/555) of the patients presented to the Liver Transplant Selection Committee at Mayo Clinic's site in Jacksonville, FL, were initially denied placement on the transplant list. Of these 295 patients, 150 (51%) were denied list placement because their disease stage was considered too early.7Aranda-Michel J Dickson RC Bonatti H Crossfield JR Keaveny AP Vasquez AR Patient selection for liver transplant: 1-year experience with 555 patients at a single center.Mayo Clin Proc. 2008; 83: 165-168PubMed Scopus (12) Google Scholar Of the 295 patients who were initially denied, only 37 (13%) were later re-presented to the selection committee, and most were accepted for listing. It is interesting to note that, of the 150 patients whose disease stage was considered too early, only 13 (9%) were subsequently listed during the study period (most likely when their clinical status worsened), with an additional 26 (17%) listed in the follow-up period. Aranda-Michel et al do not specify the average MELD score of patients whose disease stage was considered too early, but we can infer that most had a score of less than 15. Of the patients who were accepted for listing, the average MELD score was 21. Patients who were listed with a MELD score of less than 15 were likely either clinically sicker than their actual score implied or had been assigned a higher score based on an HCC exception or on an appeal to the regional review board. Transplant practitioners who are responsible for placing patients on transplant lists face many challenges. One of them is the evolving concept of listing and performing transplants on patients with HCC. The Milan criteria, established more than 10 years ago and currently used by UNOS for listing or excluding patients with HCC, are widely considered to need revision.10Mazzaferro V Regalia E Doci R et al.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5670) Google Scholar On the basis of criteria originally put forth by the University of California at San Francisco, several studies have pushed the limit of transplantability to a single HCC lesion of up to 6.5 cm or 2 to 3 lesions (none with a diameter larger than 3 cm) with a total diameter of less than 8 cm.11Yao FY Ferrell L Bass NM et al.Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.Hepatology. 2001; 33: 1394-1403Crossref PubMed Scopus (1765) Google Scholar, 12Yao FY Ferrell L Bass NM et al.Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria.Liver Transpl. 2002; 8: 765-774Crossref PubMed Scopus (376) Google Scholar, 13Roayaie K Feng S Allocation policy for hepatocellular carcinoma in the MELD era: room for improvement?.Liver Transpl. 2007; 13: S36-S43Crossref PubMed Scopus (62) Google Scholar Additionally, a large population of patients receiving bridge therapy (chemoembolization, radiofrequency ablation, or, more rarely, resection) for tumors were originally outside the Milan criteria but fell within the criteria once the tumor was down-staged.14Majno P Giostra E Mentha G Management of hepatocellular carcinoma on the waiting list before liver transplantation: time for controlled trials?.Liver Transpl. 2007; 13: S27-S35Crossref PubMed Scopus (37) Google Scholar Patients who do not meet the current UNOS criteria but do meet the University of California at San Francisco criteria could arguably petition for placement on a transplant list, especially if their tumor had been down-staged. Aranda-Michel et al do not specifically describe their criteria for excluding patients with HCC, but they can be presumed to have followed current regulations. In their study, 10% of patients were denied because the tumor did not meet their institutional criteria. One wonders how many of these patients would have been eligible for transplant if they had been followed by a transplant team early on in their disease, when the tumor was either not yet present or had dimensions that did not exceed the exclusion criteria. Also of note are the increasing age of patients at transplant and the expected progression of their comorbidities. Obesity, cardiac disease, pulmonary disease, and diabetes, coupled with preexisting or worsening renal insufficiency, have a key role in patient selection. In the study of Aranda-Michel et al, 15% of patients were excluded because of substantial comorbid illnesses. The authors do not specify which comorbid illnesses were more frequent; however, a trend seems to exist to “push the envelope” for transplant in increasingly sicker patients, even if this would mean that patients who had been previously denied ultimately underwent transplant. The renal transplant literature provides a telling example: potential kidney graft recipients who were significantly obese underwent successful gastric bypass surgery to reduce their body mass index and thereby improve their chances of transplant.15Alexander JW Goodman H Gastric bypass in chronic renal failure and transplant.Nutr Clin Pract. 2007; 22: 16-21Crossref PubMed Scopus (85) Google Scholar Similarly, in the field of pulmonary hypertension, aggressive perioperative intravenous treatment with prostaglandin analogues has been used to sustain patients through subsequent liver transplant, thereby achieving acceptable survival.16Vater Y Martay K Dembo G Bowdle TA Weinbroum AA Intraoperative epoprostenol and nitric oxide for severe pulmonary hypertension during orthotopic liver transplantation: a case report and review of the literature.Med Sci Monit. 2006 Dec; 12 (Epub 2006 Nov 23.): CS115-CS118PubMed Google Scholar Expanding the candidate pool will only increase the gap between organ availability and need. The most important point made by Aranda-Michel et al is the need for early referral at any given stage of liver disease. Using a multispecialty approach to evaluation, liver transplant surgeons and transplant hepatologists can optimize medical therapy from the moment of referral to the transplant center until transplant. Viral hepatitis can be treated, if deemed appropriate. The specialty team can perform adequate surveillance for HCC and other cirrhosis-related complications, such as hepatopulmonary syndrome or pulmonary hypertension. Social issues (such as alcohol or narcotics addiction, family support, and insurance coverage) can be followed longitudinally to ensure optimal postoperative adherence and improve long-term graft and patient survival. The concept of minimal listing criteria, whereby any patient who meets such criteria is referred for listing, was studied at Mayo Clinic before the implementation of the MELD system.17Talwalkar JA Kim WR Rosen CB Kamath PS Wiesner RH Effects of minimal listing criteria on waiting list registration for liver transplantation: a process-outcome analysis.Mayo Clin Proc. 2003; 78: 431-435Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar The process-outcome analysis at that time showed an increase both in the number of registered patients and in the rate of first-time patient referral. In the current MELD era, it is reasonable to believe that listing only when a patient has a definite chance to receive an offer for transplant can reduce in-list waiting times, while concomitantly increasing the average MELD score on the list. Conversely, no penalty is paid for placing a patient on the list even if he/she has a low score because the MELD system does not give any weight to time spent on the list, other than for patients with the same score. One could argue that keeping a long list of active patients with low MELD scores could burden the system. However, many patients can experience a sudden decompensation of their liver disease, which would rapidly increase their MELD score. If such patients have completed and updated their clinical evaluations and are already listed for transplant, the liver transplant center would need only to update the score in the national system, avoiding undue time lapses. In contrast, listing after such rapid decompensation could be delayed for patients who have been denied previously because their disease stage was too early and so might not have completed all necessary tests for listing (eg, cardiac status clearance by a stress echocardiogram). In the end, the most important concept advanced by Aranda-Michel et al is that patients should be referred early and followed up by a team of liver transplant specialists. All tests necessary for the workup could be updated periodically so as not to delay placement on the active transplant list; placement on the list would depend instead on the internal policies of each center. Some centers might prefer to apply a more restrictive approach, listing only patients with MELD scores of 15 or higher, as advocated by Aranda-Michel et al. Others might prefer instead to list most patients presented to their selection committee, even those with scores lower than the accepted MELD of 15. As long as longitudinal follow-up by the transplant team is performed, there will be an advantage for all patients with end-stage liver disease; that advantage could in turn lead to a lower mortality rate. Patient Selection for Liver Transplant: 1-Year Experience With 555 Patients at a Single CenterMayo Clinic ProceedingsVol. 83Issue 2PreviewLiver transplant (LT) has revolutionized the management of end-stage liver disease in the past 2 decades. The institution of the Model for End-Stage Liver Disease scoring system for organ allocation has de-emphasized recipient waiting time, but its effect on patients' referral to liver transplant centers is unclear. The aim of this retrospective study was to analyze the outcome of patients referred for liver transplant in a 12-month period (January 1, 2005, through December 31, 2005) after the institution of the new scoring system. Full-Text PDF