Mayo Clin Proc. • February 2008;83(2):140-142 • www.mayoclinicproceedings.com140

EDITORIAL

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

EDITORIAL

Address correspondence to Gennaro Selvaggi, MD, Miami Transplant Insti-tute, University of Miami Miller School of Medicine, Suite 507, Highland Profes-sional Bldg, 1801 NW 9th St, Miami, FL 33136 (GSelvaggi@med.miami.edu).

© 2008 Mayo Foundation for Medical Education and Research

Mayo ClinicProceedings

February 2008Volume 83Number 2

See alsopage 165

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

Progress in liver transplant during the past 2 decades hasoffered an increasing number of patients a better

chance of survival and an improved quality of life; how-ever, it has also created a widening gap between organavailability and demand. A brief survey of the Organ Pro-curement and Transplantation Network data from the Sci-entific Registry of Transplant Recipients database at thetime of this report shows that, as of June 2007, 1-yearsurvival after liver transplant was 82.1% for adults and86.2% for children (based on almost 15,000 patients whounderwent transplant).1 However, in 2006, the last year forwhich data are available, only 6600 of 11,000 new patientsplaced on the liver transplant list received a new graft. Thenumber of patients on the waiting list at the end of the yearwas largely unchanged from that at the beginning (ie, ap-proximately 17,300).2 These figures suggest that approxi-mately 4500 patients (only 450 of whom actually improvedto the point of being removed from the list) died, deterio-rated, 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 livergrafts in a more systematic, objective manner. This systemstratifies patients based on their probability of death within3 months, using 3 laboratory parameters (total serum bi-lirubin concentration, international normalized ratio, andserum creatinine concentration) to generate a score reflec-tive of the patients’ status.3,4 With the exception of acuteliver failure (and in some specific instances, such as hepa-tocellular carcinoma [HCC], hepatopulmonary syndrome,and metabolic syndrome), the MELD system has proven tobe valuable, and its implementation has decreased waitinglist mortality.5,6 Because a few patients with a relativelysatisfactory MELD score nonetheless have a poor clinicalstatus, the liver transplant community continues to try toadapt or modify the basic formula to take such exceptionsinto account.

The method used to select patients for the liver trans-plant waiting list, however, has received less systematicstudy. A report by Aranda-Michel et al,7 published in thisissue of Mayo Clinic Proceedings, attempts to elucidate thepatient selection process and to clarify how and whenpatients should be placed on the list based on their MELDscore. This study focuses on the patients whowere presented to the Liver Transplant Selec-tion Committee at a single large transplantcenter, Mayo Clinic’s site in Jacksonville, FL,in 2005; in that year, 246 liver transplants were performed.1

It assesses the policies used in selecting which patients tolist, ie, their absolute need for liver transplant and the oddsthat they would actually be offered a liver graft.

Early studies on the implementation of the MELD scoreshowed that a score of 15 was the cutoff between risk/benefit ratios for liver transplant.8 Although the point is notspecifically made by Aranda-Michel et al, the current allo-cation policy is to offer liver grafts first to those with aMELD score of greater than 15 in each of the UnitedNetwork of Organ Sharing (UNOS) regions.9 On the 2006national patient list, approximately 42% of all newly listedpatients vs 52% of all listed patients had a MELD score ofless than 15.2 Of those patients who eventually underwent atransplant in the same year, only 23% had a MELD score ofless than 15.2

According to the article by Aranda-Michel et al, morethan half (53%, 295/555) of the patients presented to theLiver Transplant Selection Committee at Mayo Clinic’ssite in Jacksonville, FL, were initially denied placement onthe transplant list. Of these 295 patients, 150 (51%) were

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EDITORIAL

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

denied list placement because their disease stage was con-sidered too early.7 Of the 295 patients who were initiallydenied, only 37 (13%) were later re-presented to the selec-tion committee, and most were accepted for listing. It isinteresting to note that, of the 150 patients whose diseasestage was considered too early, only 13 (9%) were subse-quently listed during the study period (most likely whentheir clinical status worsened), with an additional 26 (17%)listed in the follow-up period. Aranda-Michel et al do notspecify the average MELD score of patients whose diseasestage was considered too early, but we can infer that mosthad a score of less than 15. Of the patients who were ac-cepted for listing, the average MELD score was 21. Patientswho were listed with a MELD score of less than 15 werelikely either clinically sicker than their actual score impliedor had been assigned a higher score based on an HCCexception or on an appeal to the regional review board.

Transplant practitioners who are responsible for placingpatients on transplant lists face many challenges. One ofthem is the evolving concept of listing and performingtransplants on patients with HCC. The Milan criteria, es-tablished more than 10 years ago and currently used byUNOS for listing or excluding patients with HCC, arewidely considered to need revision.10 On the basis of crite-ria originally put forth by the University of California atSan Francisco, several studies have pushed the limit oftransplantability to a single HCC lesion of up to 6.5 cm or 2to 3 lesions (none with a diameter larger than 3 cm) with atotal diameter of less than 8 cm.11-13 Additionally, a largepopulation of patients receiving bridge therapy (chemo-embolization, radiofrequency ablation, or, more rarely,resection) for tumors were originally outside the Milancriteria but fell within the criteria once the tumor was down-staged.14 Patients who do not meet t he current UNOS criteriabut do meet the University of California at San Franciscocriteria could arguably petition for placement on a trans-plant list, especially if their tumor had been down-staged.Aranda-Michel et al do not specifically describe their crite-ria for excluding patients with HCC, but they can be pre-sumed to have followed current regulations. In their study,10% of patients were denied because the tumor did notmeet their institutional criteria. One wonders how many ofthese patients would have been eligible for transplant ifthey had been followed by a transplant team early on intheir disease, when the tumor was either not yet present orhad dimensions that did not exceed the exclusion criteria.

Also of note are the increasing age of patients at trans-plant 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 specifywhich comorbid illnesses were more frequent; however, atrend seems to exist to “push the envelope” for transplant inincreasingly sicker patients, even if this would mean thatpatients who had been previously denied ultimately under-went transplant. The renal transplant literature provides atelling example: potential kidney graft recipients who weresignificantly obese underwent successful gastric bypasssurgery to reduce their body mass index and thereby im-prove their chances of transplant.15 Similarly, in the fieldof pulmonary hypertension, aggressive perioperative in-travenous treatment with prostaglandin analogues hasbeen used to sustain patients through subsequent livertransplant, thereby achieving acceptable survival.16 Ex-panding the candidate pool will only increase the gap be-tween organ availability and need.

The most important point made by Aranda-Michel et alis the need for early referral at any given stage of liverdisease. Using a multispecialty approach to evaluation,liver transplant surgeons and transplant hepatologists canoptimize medical therapy from the moment of referral tothe transplant center until transplant. Viral hepatitis can betreated, if deemed appropriate. The specialty team canperform adequate surveillance for HCC and other cirrho-sis-related complications, such as hepatopulmonary syn-drome or pulmonary hypertension. Social issues (such asalcohol or narcotics addiction, family support, and insur-ance coverage) can be followed longitudinally to ensureoptimal postoperative adherence and improve long-termgraft and patient survival.

The concept of minimal listing criteria, whereby anypatient who meets such criteria is referred for listing, wasstudied at Mayo Clinic before the implementation of theMELD system.17 The process-outcome analysis at that timeshowed an increase both in the number of registered pa-tients and in the rate of first-time patient referral. In thecurrent MELD era, it is reasonable to believe that listingonly when a patient has a definite chance to receive an offerfor transplant can reduce in-list waiting times, while con-comitantly increasing the average MELD score on the list.Conversely, no penalty is paid for placing a patient on thelist even if he/she has a low score because the MELD sys-tem does not give any weight to time spent on the list, otherthan for patients with the same score.

One could argue that keeping a long list of active pa-tients with low MELD scores could burden the system.However, many patients can experience a sudden decom-pensation of their liver disease, which would rapidly in-crease their MELD score. If such patients have completedand updated their clinical evaluations and are already listedfor transplant, the liver transplant center would need onlyto update the score in the national system, avoiding undue

Mayo Clin Proc. • February 2008;83(2):140-142 • www.mayoclinicproceedings.com142

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For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

time lapses. In contrast, listing after such rapid decompen-sation could be delayed for patients who have been deniedpreviously because their disease stage was too early and somight not have completed all necessary tests for listing (eg,cardiac status clearance by a stress echocardiogram). Inthe end, the most important concept advanced by Aranda-Michel et al is that patients should be referred early andfollowed up by a team of liver transplant specialists. Alltests necessary for the workup could be updated periodi-cally so as not to delay placement on the active transplantlist; placement on the list would depend instead on theinternal policies of each center.

Some centers might prefer to apply a more restrictiveapproach, listing only patients with MELD scores of 15 orhigher, as advocated by Aranda-Michel et al. Others mightprefer instead to list most patients presented to their selec-tion committee, even those with scores lower than theaccepted MELD of 15. As long as longitudinal follow-upby the transplant team is performed, there will be an advan-tage for all patients with end-stage liver disease; that ad-vantage could in turn lead to a lower mortality rate.

Gennaro Selvaggi, MDMiami Transplant InstituteUniversity of Miami Miller School of MedicineMiami, FL

1. OPTN: Organ Procurement and Transplantation Network. OPTN Website. http://www.optn.org. Accessed January 7, 2008.

2. 2006 Annual Report of the U.S. Organ Procurement and TransplantationNetwork and the Scientific Registry of Transplant Recipients: Transplant Data1994-2006. Department of Health and Human Services, Health Resources andServices Administration, Healthcare Systems Bureau, Division of Transplanta-

tion, Rockville, MD; United Network for Organ Sharing, Richmond, VA;University Renal Research and Education Association, Ann Arbor, MI; 2006.

3. Malinchoc M, Kamath PS, Gordon FD, Pien CJ, Rank J, ter Borg PC. Amodel to predict poor survival in patients undergoing transjugular intrahepaticportosystemic shunts. Hepatology. 2000;31(4):864-871.

4. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predictsurvival in patients with end-stage liver disease. Hepatology. 2001;33(2):464-470.

5. Freeman RB Jr. The model for end-stage liver disease comes of age. ClinLiver Dis. 2007;11(2):249-263.

6. Austin MT, Poulose BK, Ray WA, Arbogast PG, Feurer ID, Pinson CW.Model for end-stage liver disease: did the new liver allocation policy affectwaiting list mortality? Arch Surg. 2007;142(11):1079-1085.

7. Aranda-Michel J, Dickson RC, Bonatti H, Crossfield JR, Keaveny AP,Vasquez AR. Patient selection for liver transplant: 1-year experience with 555patients at a single center. Mayo Clin Proc. 2008;83(2):165-168.

8. Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port FK, WolfeRA. The survival benefit of liver transplantation. Am J Transplant. 2005;5(2):307-313.

9. Organ Procurement and Transplant Network policy 3.6. Allocation oflivers. September 18, 2007. OPTN Web site. http://www.optn.org/PoliciesandBylaws2/policies/pdfs/policy_8.pdf. Accessed January 7, 2008.

10. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for thetreatment of small hepatocellular carcinomas in patients with cirrhosis. N EnglJ Med. 1996;334(11):693-699.

11. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellu-lar carcinoma: expansion of the tumor size limits does not adversely impactsurvival. Hepatology. 2001;33(6):1394-1403.

12. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellu-lar carcinoma: comparison of the proposed UCSF criteria with the Milancriteria and the Pittsburgh modified TNM criteria. Liver Transpl. 2002;8(9):765-774.

13. Roayaie K, Feng S. Allocation policy for hepatocellular carcinoma in theMELD era: room for improvement? Liver Transpl. 2007;13(11)(suppl 2):S36-S43.

14. Majno P, Giostra E, Mentha G. Management of hepatocellular carci-noma on the waiting list before liver transplantation: time for controlled trials?Liver Transpl. 2007;13(11)(suppl 2):S27-S35.

15. Alexander JW, Goodman H. Gastric bypass in chronic renal failure andtransplant. Nutr Clin Pract. 2007;22(1):16-21.

16. Vater Y, Martay K, Dembo G, Bowdle TA, Weinbroum AA. Intraopera-tive epoprostenol and nitric oxide for severe pulmonary hypertension duringorthotopic liver transplantation: a case report and review of the literature. MedSci Monit. 2006 Dec;12(12):CS115-CS118. Epub 2006 Nov 23.

17. Talwalkar JA, Kim WR, Rosen CB, Kamath PS, Wiesner RH. Effects ofminimal listing criteria on waiting list registration for liver transplantation: aprocess-outcome analysis. Mayo Clin Proc. 2003;78(4):431-435.