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Selection of liver-transplant candidates for adult-to-adult living donor liver transplantation as the only surgical option for end-stage liver disease†
Article first published online: 5 APR 2006
Copyright © 2006 American Association for the Study of Liver Diseases
Volume 12, Issue 7, pages 1077–1083, July 2006
How to Cite
Yamashiki, N., Sugawara, Y., Tamura, S., Kaneko, J., Nojiri, K., Omata, M. and Makuuchi, M. (2006), Selection of liver-transplant candidates for adult-to-adult living donor liver transplantation as the only surgical option for end-stage liver disease. Liver Transpl, 12: 1077–1083. doi: 10.1002/lt.20759
Accepted for presentation in part at the 56th Annual Meeting of the American Association for the Study of Liver Diseases.
- Issue published online: 23 JUN 2006
- Article first published online: 5 APR 2006
- Manuscript Accepted: 2 FEB 2006
- Manuscript Received: 30 OCT 2005
- Scientific Research, Ministry of Education, Culture, Sports, Science and Technology, Japan
- Research on HIV/AIDS
- Research on Measures for Intractable Diseases, Ministry of Health, Labor and Welfare, Japan
The selection of living donor liver transplantation (LDLT) recipients in regions where deceased donor liver transplantation (DDLT) is rarely performed might be different from that in other centers at which LDLT is an alternative option to DDLT. Records of adult (age ≥ 18 yr) patients referred to our center were reviewed to analyze the selection process of LDLT candidates. Among the 533 LDLT candidates, 165 (31%) were rejected due to recipient issues. Advanced hepatocellular carcinoma (HCC) was the most common reason for rejection (n = 55). Among the remaining recipients, 120 patients (22%) were rejected due to donor issues. LDLT was eventually performed in 249 (47%) of the evaluated recipients. There are few options for candidates who are unable to find live donors in regions where DDLT is unrealistic. A more effective and precise approach to recipient and donor evaluation should be pursued. Liver Transpl 12:1077–1083, 2006. © 2006 AASLD.
Advances in surgical techniques have led to a worldwide increase in living donor liver transplantation (LDLT).1–6 Graft survival after LDLT among adult patients is comparable to that after deceased donor liver transplantation (DDLT).7–9 The major advantages of performing LDLT over DDLT are a shorter recipient waiting time and therefore a lower rate of mortality while on the waiting list, a nonemergent surgical schedule, and a lower rate of ischemic injury to the donor organ. Donor safety is a concern in LDLT, with a mortality rate of 0.1 to 0.8%10 and an early surgical complication rate of 12 to 29%.11, 12
In Asia, deceased donor organs are extremely rare due to religious and cultural traditions. Thus, LDLT is increasingly performed, and in some Asian countries LDLT is performed more often than DDLT.6, 13 LDLT has led to a reduced mortality rate and a prolonged survival of selected adult patients with end-stage liver disease. In Japan, the first successful adult-to-adult LDLT was performed in 1993, and more than 300 adult-to-adult LDLTs were performed in 2003.9 In contrast, only 28 DDLTs were performed from the time the Organ Transplant Law became effective in 1997 through August 2005.14 Therefore, if the evaluation of a living donor is negative, few options remain for transplant candidates.
For conditions in which DDLT is unrealistic, patients and families place their last hope on the LDLT procedure, and come to the transplant program with high motivation. Public awareness continues to increase, and an increasing number of patients and potential donors are being seen at each transplant program. In an early report15 regarding the patient and donor selection process that focused mainly on pediatric LDLT, 85% of evaluated patients underwent LDLT. Recent reports on adult recipients16–23 are mainly from countries where the number of DDLTs is high. Indication criteria of LDLT both in donors and recipients might differ depending on the availability of deceased donor organs. In this article, we report our experience of evaluating patients and living donors for adult liver transplantation in a setting with scarce availability of deceased donor organs.
PATIENTS AND METHODS
Selection of Subjects
Between January 1996 and March 2005, 533 potential LDLT recipients were evaluated at the University of Tokyo adult-to-adult liver transplantation program. The median age was 51 (18-75) yr. Of the 533 potential recipients, 321 were men and 212 were women. The medical charts of all the candidates referred to our program were reviewed.
Selection of Recipients
Patients less than 65 yr of age and referred with a history of end-stage liver disease, fulminant hepatic failure, hepatocellular carcinoma (HCC), or metabolic or congenital liver disease were considered for liver transplantation. Institutional inclusion criteria for patients with HCC were as follows: no more than 5 nodules, each sized ≤5 cm. Extrahepatic metastasis and vascular invasion were contraindications for transplantation. Patients with alcoholic liver disease were required a 6-month period of abstinence.
The other conditions that were absolute contraindications for LDLT were pulmonary hypertension, uncontrollable cardiac failure, uncontrollable respiratory failure, and uncontrollable infectious disease. LDLT with ABO-incompatible donors for adult patients was not performed at our hospital. Indication for all evaluated candidates is shown in Table 1.
|Factors||Total (n = 533)||LDLT (n = 249)||Rejected (n = 284)||P value|
|Age (yr) (median, range)||51 (18-75)||51 (18-65)||51 (18-75)||0.258|
|Primary biliary cirrhosis||66||51||15||<0.001|
|Fulminant hepatic failure||60||26||34||0.338|
|Primary sclerosing cholangitis||18||8||10||0.519|
|HBV and HCV coinfection||2||0||2||0.283|
Selection of Donors for LDLT
Donor evaluation was scheduled primarily by the surgeon according to our center's protocol (Table 2). At the initial visit, a detailed presurgical process of evaluation, donor risk, and follow-up schedule were explained by the transplant physician, and a booklet explaining the donation procedure was given to each potential donor and recipient. All potential donors were interviewed independently by the transplant coordinator (registered nurse). Our criteria for living donors (listed in Table 2) were as follows: healthy individual between 20 and 65 yr of age; no significant medical history or abdominal surgery; and no history of viral hepatitis. Donor candidates within 3 degrees of consanguinity or the spouse of the recipient were considered for the operation, and any deviation from this criteria was discussed on a case-by-case basis by both the transplant team and the institutional ethics board.
|Interviewed by transplant coordinator|
|Confirmed of voluntarism becoming living donor|
|Age ≥ 20 and ≤ 65 yr|
|Within 3 degrees of consanguinity or spouse|
|Long-term relationship with recipient|
|Screened by transplant surgeons|
|No significant medical history|
|No viral hepatitis|
|ABO-compatible or identical|
|Consultation for psychiatric evaluation (if necessary)|
|Complete blood count, blood type, hepatitis serology, liver function tests, coagulation, erythrocyte segimentation rate, urinalysis, iron, serum ferritin, transferring, ceruloplasmin, α1-antitrypsin level, and blood oxygen saturat ion, cytomegalovirus antibody (immunoglobulin G), Epstein-Barr virus antibody (immunoglobulin G), antinuculear antibody, human immunodeficiency antibody, adult T cell leukemia antibody, Alpha-fetoprotein, CEA|
|FOBT (age > 40 yr)|
|Chest X-ray, electrocardiogram, pulmonary function tests|
|Enhanced CT scan of abdomen|
|Liver biopsy (when body mass index >25 and/or bright liver by abdominal ultrasound)|
|Gastrointestinal endoscopy (age > 40 yr)|
|Colonoscopy (when FOBT positive and/or CEA positive)|
|Treadmill test (age > 40 yr)|
|Three dimensional CT*|
|HLA typing/cross match|
|Indocyanine green retention rate at 15 minutes|
|Final informed consent|
After confirming the voluntary decision to become a live donor, the second phase of the evaluation was performed. This process included blood tests, a chest X-ray, electrocardiogram, and pulmonary function tests. For donor candidate older than 40 yr of age, serum tumor markers and fecal occult blood test were added. Abdominal computed tomography scan with intravenous contrast was performed to rule out anatomic or medical contraindications.
If the donor cleared this phase, then the third phase began. Liver biopsy was performed when a fatty liver was suspected. A treadmill test and endoscopy were performed in donors older than 40 yr of age. Colonoscopy was also performed when a fecal occult blood test and/or serum carcinoembryonic antigen were positive. When eligibility was confirmed, angiography was performed as part of the third phase. In January 2004, angiography was replaced with three-dimensional computed tomography. Because of this change, most donor evaluation processes are now performed on an outpatient basis.
Ethical and Financial Consideration
At any time during the evaluation process potential donors could contact the transplant coordinator directly via telephone or e-mail, and express any conflicts or complaints. If necessary, potential donors were seen by unrelated surgeons, physicians, or psychiatrists for assessment of psychosocial problems.
The medical expenses of LDLT have been covered by national health insurance for patients with biliary atresia, Budd-Chiari syndrome, cholestatic liver diseases, Alagille syndrome, and congenital metabolic diseases. From 2004 onward, adult patients with fulminant hepatic failure, liver cirrhosis, hepatocellular carcinoma meeting the Milan criteria,24 polycystic liver disease, and Caroli's disease were also added for insurance coverage. The expenses of donor evaluation and surgery were covered by insurance only if LDLT was performed for insurance-covered disorders. The costs of evaluation for rejected donors were not covered. All patient-donor pairs not meeting institutional and insurance criteria were reviewed by the institutional ethics board for final approval.
Differences between groups were analyzed by independent-groups t-test for continuous variables and chi-squared test for categorical variables.
Patient Characteristics and Overall Outcome After Referral
A total of 533 potential LDLT recipients were evaluated (Table 1). Male patients were more frequently rejected than female patients (P = 0.026). Patients with primary biliary cirrhosis had LDLT more frequently than others (P < 0.001). In contrast, patients with alcoholic liver disease were prone to be rejected (P = 0.003). Overall outcome of these patients is shown in Figure 1. Of these, 165 patients (31%) were rejected due to recipient issues. Among the 368 recipients who were deemed suitable for LDLT, 70 patients (19%) were unable to find suitable donors during the screening period. During further donor evaluation, 49 additional patients were excluded due to donor issues. As a result, 249 patients received LDLT at our hospital from their children (n = 106; 43%), siblings (n = 47; 19%), spouses (n = 44; 18%), parents (n = 33; 13%), or other individuals (n = 19; 7%).
Reasons for Rejection Due to Recipient Issues
The reasons for rejection due to recipient issues are summarized in Table 3. Fifteen patients declined to undergo LDLT, and 8 refused to undergo evaluation due to financial reasons.
|Declined to undergo LDLT||15 (3)|
|Financial reasons||8 (2)|
|Medically not indicated||142 (48)|
|Advanced HCC||55 (15)|
|Advanced disease including multiorgan failure||28 (11)|
|Advanced age (>65 yr)||14 (5)|
|Too early for LDLT||12 (1)|
|Uncontrolled infectious diseases||11 (6)|
|Medical comorbidity unrelated to ESLD||10 (6)|
|Not abstaining from alcohol||1 (0)|
|Spontaneous recovery from FHF||8 (2)|
|Resectable HCC||1 (1)|
|Severe stenosis of hepatic artery||1 (1)|
|Noncompliance with treatment||1 (0)|
A total of 142 patients were medically denied. Of those, 55 patients had HCC beyond our inclusion criteria; multiple nodules exceeding the institutional criteria without extrahepatic progression (n = 35), portal vein invasion (n = 8), extrahepatic metastasis (n = 7), rupture of HCC (n = 3), tumor seeding (n = 1), and invasion to inferior vena cava (n = 1).
A total of 28 patients were deemed too ill for LDLT. Usually, these patients had multiorgan failure other than liver disease at the time of referral. Of these, 17 died before the patient was transferred to our hospital due to the following reasons: varices rupture (n = 6), liver failure (n = 5), fulminant hepatic failure complicated with multiple organ failure (n = 4), intracranial bleeding (n = 1), and respiratory failure (n = 1). Ten patients with a volunteer donor died before completing donor evaluation due to liver failure. The remaining patient-donor pair was rejected due to pulmonary hypertension.
A total of 11 patients had uncontrolled infectious disorders: sepsis (n = 3), bacterial pneumonia (n = 2), fungal infection (n = 2), endocarditis (n = 1), sinusitis (n = 1), tuberculosis (n = 1), and Pneumocystis carinii pneumonia (n = 1). Another 10 had medical comorbidity unrelated to end-stage liver disease, including neoplasms (n = 5), uncontrolled psychiatric disorders (n = 2), severe obesity with uncontrolled adrenal disease (n = 1), interstitial pneumonia (n = 1), and benign hepatic tumor (n = 1).
Among the 12 rejected patients with alcoholic liver disease, only 1 patient was rejected because of failure to abstain from alcohol. Four were rejected for previously-referenced reasons; declination, varices rupture, too early, and medical comorbidity. The other 7 were rejected for donor issues.
Of the 169 patients who were rejected due to recipient-related issues, the initial screening of volunteer donors was started in 53 cases. The donor evaluation was discontinued as soon as the recipient withdrew.
Reasons for Rejection Due to Donor Issues
Reasons for rejection due to donor issues are summarized in Table 4. A total of 119 candidates were rejected due to donor issues. During phase 1, 70 patients were rejected; 45 had no volunteer donor and 25 had candidates not suitable for donor operation. During phases 2 and 3, donor suitability was considered medically contraindicated in 26 potential donors. In addition, 23 donors withdrew from the program during and after formal evaluation.
|Rejection at Phase 1 evaluation||70|
|No volunteer donor||45|
|Marked physique discrepancy between recipient and donor||3|
|Under regal age||2|
|Over 65 yr old||2|
|Hepatitis B virus carrier||2|
|Significant medical history||2|
|Rejection at Phases 2 or 3 evaluation||26|
|Inappropriate liver volume||13|
|Chronic hepatitis C, Colon cancer||1|
|Abnormal liver function||1|
|Bronchial asthma, poorly controlled||1|
|Refusal to donate||23|
|Before or during medical evaluation||18|
Recipient Outcome after Rejection for LDLT
Of 142 patients who were denied LDLT for medical reasons, 9 sought out another transplant program: 2 received LDLT in Japan and 1 received DDLT abroad (Fig. 1). Among the 119 transplant candidates who were rejected due to donor-related issues, 8 patients registered for the DDLT list; 1 received a DDLT, 1 received a domino transplantation at our center, 3 died, and 3 awaited for DDLT. Seven patients underwent DDLT at centers abroad, and 1 with an ABO-mismatched volunteer donor underwent LDLT at another center in Japan.
In this analysis, 249 (47%) of the referred potential recipients underwent LDLT. This ratio is higher than those (15-30%) of previous reports.16, 18, 19 The differences are partly due to differences in availability of deceased donors. In most of the centers, potential transplant candidates were primarily registered for the DDLT waiting list, and were offered LDLT as an alternative. In contrast, patients in our study may have already been selected by their referring physician according to the availability of potential donors. The selection bias might have reduced the rejection ratio in our hospital (Table 5).
|Reference No.||16||17||18||19||20||21||22||23||Current study|
|Analysis was on recipients or donors||Recipients||Recipients||Donors and recipients||Recipients||Donors||Donors||Donors||Donors||Recipients|
|No. of patients evaluated||100||51*||297||121||533|
|Rejection due to recipient issue||51 (51%)||0||101 (34%)||60 (50%)||165 (31%)|
|Patient declined||4 (4%)||NA||8 (3%)||36 (30%)||15 (3%)|
|Patient underwent DDLT||8 (8%)||6 (12%)||15 (5%)||14 (12%)||1 (0.2%)|
|Unable to find donor||24 (24%)||26 (51%)||0†||17 (14%)||45 (8%)|
|Donor not suitable||10 (10%)||5 (10%)||107 (55%)||23 (19%)||74 (14%)|
|No. of LDLTs||15 (15%)||21 (41%)||89 (30%)||21 (17%)||249 (47%)|
|No. of donors evaluated||622||126||66||148||85|
|Donor declined||NA||2 (2%)||10 (15%)||NA||NA|
|Psychosocial issue||26 (4%)||2 (2%)||NA||7 (8%)||NA|
|No. of donors undergoing surgery||89 (14%)||35 (28%)‡||15 (23%)||46 (31%)||27 (32%)|
A total of 165 (31%) candidates were rejected due to recipient issues and this proportion was comparable with other studies.16, 18, 19 Advanced HCC was the most common reason for rejection in the present analysis. Tumor number and size are restricted by our inclusion criteria, but not in the other LDLT programs in Japan25, 26 or in other countries.17, 27 Among the patients rejected due to advanced HCC in our program, some sought other institutions at home and abroad. The next most common cause of rejection was poor general condition, including multiorgan failure other than liver disease. The indications for LDLT are similar to those for DDLT, which is in contrast with Western countries where a balance needs to be achieved between the candidate's liver disease severity and the adequacy of a partial graft for transplantation. Russo and Brown28 proceeded with LDLT in candidates with Model for End-Stage Liver Disease scores between 11 and 25.
After identifying the 368 potential recipients suitable for LDLT, we then investigated donor issue for rejection. Of the 368 patients, 249 (68%) underwent procedure. In contrast to previous reports16, 17 in which approximately half of the LDLT candidates had no potential donor, only 70 (19%) of 368 patients were rejected due to the lack of suitable donor candidates. There is usually a higher number of potential donors than recipients; the ratio of donors and adult recipients is 2.1.18 Our analysis lacked this information because we identified primary donor candidates who were formally evaluated at our center. In many cases, 1 donor candidate was already selected among multiple family members at the time of referral.
The major causes of donor rejection were medical contraindication and refusal. The medical evaluation process has been reported by different authors, and is divided into 3 to 6 phases.16, 18–23, 29 The noninvasive initial screening process excludes 20 to 40% of potential donors.18, 20, 22, 23 The percentage of donors who undergo the operation among candidates varies from 14 to 32%.18, 20–23 In a review of transplant programs in the United States, an average of 45% of evaluated donors was eventually accepted.10 This percentage was based on a questionnaire survey, however, and might not reflect the entire cohort of the potential donors evaluated.
In the present study, refusal to donate occurred in 23 cases; 18 of them refused to donate during the evaluation and 5 declined after completion of the medical evaluation for donation. It is difficult to determine if the donors changed their mind for psychosocial reasons. At the initial screening, potential donors with psychosocial problems required psychiatric consultation. During the evaluation process, coordinators were open to donor question or complaints. Published reports also suggest that refusal occurs during all phases of the evaluation. Valentin-Gamazo et al.18 reported that psychologic evaluation is required twice for all potential donors during the evaluation process. In their series, 26 donors rejected the surgery after psychologic assessment; 21 were excluded after the first consultation, and 5 after the second consultation. In Trotter et al.,16 2 potential donors refused donation after it was determined that they were medically acceptable for donation. These results suggest that the autonomy of the decision of the donor should be protected even after completing the entire evaluation process. In contrast, the recipient and family are coerced to some degree after being informed about LDLT, and thus it remains uncertain as to whether physicians should offer liver transplantation to all potential patients. While surgical techniques and perioperative procedures continue to be refined, the importance of a precise approach to psychosocial problems in donors should be pursued.
In summary, we report the process of the recipient evaluation for LDLT and its outcome in a single-center experience. Although approximately half of the evaluated patients successfully underwent LDLT in our program, the patients we evaluated were already selected before referral, specifically after decision making to be a donor among family members. To save more patients requiring liver transplantation who are not able to find living donors, the role of DDLT should be reacknowledged in our society.
- 5Advances in adult living donor liver transplantation: a review based on reports from the 10th anniversary of the adult-to-adult living donor liver transplantation meeting in Tokyo. Liver Transpl 2004; 10: 715–720., .
- 7Data from US transplant organization. Available at: http://www.ustransplant.org/annual_reports/, accessed on September 27, 2005.
- 9The Japanese Liver Transplantation Society. Liver transplantation in Japan: Registry by the Japanese Liver Transplantation Society. Jpn J Transplant 2004; 39: 634–642. [in Japanese]
- 14Data from The Japan Society for Transplantation, http://www.asas.or.jp/jst/factbook/2004/index.html [in Japanese], accessed on August 21, 2005.
- 22Donor evaluation, donor risks, donor outcome, and donor quality of life in adult-to-adult living donor liver transplantation. Liver Transplant 2002; 8: 829–837., , , , , , et al.