The Model for End-Stage Liver Disease (MELD) score was originally developed to assess the short-term prognosis among patients undergoing transjugular intrahepatic portosystemic shunting.1 The validity of the MELD score was subsequently evaluated and confirmed as a disease severity index in patients with end-stage liver disease (ESLD).2–4 In 2002, the United Network for Organ Sharing (UNOS) implemented MELD to prioritize organ allocation in patients with chronic liver disease awaiting liver transplantation.5 Studies investigating the implications of the MELD index have found that a high pretransplant MELD score is inversely correlated with posttransplant survival in deceased donor liver transplantation (DDLT). However, this issue continues to be debated.4, 6–11
In living donor liver transplantation (LDLT), the graft size and pretransplant disease severity are important factors for patient survival post-transplant.12–15 The outcome of adult-to-adult living donor liver transplantation (ALDLT) has been shown to be poorer than that of pediatric LDLT as well as DDLT in a matched cohort. This poorer outcome is thought to be due to the frequent use of small-for-size grafts (SFSGs) in ALDLT.14, 16 For this reason, the use of ALDLT in very ill recipients remains controversial. However, more recently, the outcome of ALDLT has improved, and ALDLT using an SFSG has been attempted even in severely ill patients at experienced transplant centers.
Here we examined the outcome of recipients with high pretransplant MELD scores and a SFSGs < 0.8% of graft-versus-recipient weight ratio (GRWR). In addition, the factors associated with posttransplant patient survival were assessed.
1-YSR, 1-year patient survival rate; ALDLT, adult-to-adult living donor liver transplantation; DDLT, deceased donor liver transplantation; ESLD, end-stage liver disease; GRWR, graft-versus-recipient weight ratio; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; MHV, middle hepatic vein; SD, standard deviation; SFSG, small-for-size graft; UNOS, United Network for Organ Sharing.
PATIENTS AND METHODS
Between February 1999 and December 2005, 215 consecutive adult recipients (age > 18 years) underwent ALDLT at Seoul National University Hospital. Forty-eight recipients who were diagnosed as having ESLD not related to hepatitis B virus (HBV) were excluded from this study for standardization purposes. There were 167 HBV-infected adult recipients enrolled in this study.
The study subjects included 121 men and 46 women who ranged in age from 21 to 65 years (mean, 48.3 ± 8.1 years). The UNOS status was 1 in 1 patient, 2A in 29 patients, and 2B or 3 in 147 patients. The Child-Turcotte-Pugh classification was class A in 9 patients, class B in 31 patients, and class C in 136 patients. The MELD scores at the time of transplant ranged from 7 to 48 (mean, 22.8 ± 9.3). The MELD score was calculated purely on the basis of liver disease severity, and an additional point for hepatocellular carcinoma (HCC) was not allotted. HCC was diagnosed in 78 patients (46.7%). Pretransplant HBV DNA was positive in 77 patients (46.1%), and hepatitis e antigen was positive in 75 patients (44.9%).
On the basis of the MELD score at the time of transplant, the recipients were divided into group L (low MELD score ≤ 25, n = 105) and group H (high MELD score > 25, n = 62). The mean MELD scores were 17.0 ± 4.4 in group L and 32.6 ± 6.6 in group H. To analyze the risk associated with the graft size in very ill patients, the patients were divided into 4 groups as follows: group Hs (high MELD score > 25 and SFSG; GRWR < 0.8%, n = 11), group Hn (high MELD score > 25 and a normal-size graft; GRWR ≥ 0.8%, n = 51), group Ls (low MELD score ≤ 25 and SFSG; GRWR < 0.8%, n = 18), and group Ln (low MELD score ≤ 25 and a normal-size graft; GRWR ≥ 0.8%, n = 87).
The definitions used for complications were adapted from the Clavien grading system for negative outcomes.17–19 Grade 1 and 2 complications were minor problems. Grade 1 included minor risk events that did not require therapy other than immunosuppressors, analgesics, antipyretic, anti-inflammatory, antiemetic, and drugs required for urinary retention, lower urinary tract infection, arterial hypertension, hyperlipidemia, or transient hyperglycemia. Grade 2 complications were potentially life-threatening but did not require invasive interventions. Complications that were greater than grade 3 were major complications requiring invasive interventions (grade 3) or leading to lasting disability or organ dysfunction that was either difficult to control or had a significant risk of leading to graft failure (grade 4) or death (grade 5).
The primary endpoint was the 1-year patient survival rate (1-YSR). Patients were followed for a mean of 32.6 ± 23.6 months (range, 0-91.2 months).
Donors and Grafts
Donors were selected according to a protocol described elsewhere.20–23 The selected donors were 120 men and 47 women; 69 patients were gender-mismatched. The mean age ranged from 16 to 52 years (mean, 30.1 ± 9.0 years). Among the 167 donors, 3 donors (1.8%) were older than 50. The most common donors were the patients' offspring (44.9%), followed by other relatives (19.8%), spouses (13.8%), siblings (11.4%), and unrelated donors (10.2%). There were no ABO-mismatched cases. Among the 167 grafts, 140 were right livers, and 27 were left livers. Among the 140 right livers, 60 cases (43.8%) drained the middle hepatic vein (MHV) or its branches. This was also present in 26 cases (96.3%) among 27 left livers. The graft weights measured on the back table ranged from 265 to 1060 g (mean, 662.3 ± 152 g), and the GRWR ranged from 0.54% to 2.58% (mean, 1.04% ± 0.24%). An SFSG with a GRWR < 0.8% was used in 29 patients (17.4%). The surgical procedures have been described elsewhere.22–25 The mean operation time for the recipients was 569.5 ± 135.4 (330-1060) minutes; the cold and warm ischemic times were 76.7 ± 36.2 (15-228) and 45.6 ± 18.3 (17-203) minutes, respectively.
All values are expressed as means ± the standard deviation. The categorical variables were compared with Fisher's exact test, and the continuous variables were compared with the nonparametric Mann-Whitney U test. We used the Kaplan-Meier method with the log-rank test for the analysis of patient survival. The variables reaching statistical significance by univariate analysis were then included in the multivariate analysis. For multivariate analyses, we used the Cox proportional hazards regression method with a stepwise procedure to determine the adjusted survival rates. A P value < 0.05 was considered significant. Statistical analyses were performed with SPSS 10.0 statistical software (SPSS, Inc., and Microsoft Corp., Chicago, IL).
Preoperative Clinical Data
The preoperative characteristics of the patients, donors, and grafts according to groups L and H are summarized in Table 1. For the recipients, the distribution of male gender (74.2% versus 71.4%), age (47.7 ± 8.9 versus 49.5 ± 7.7 years), body weight (65.3 ± 10.4 versus 64.4 ± 10.2 kg), pretransplant hepatitis B e antigen positivity (51.6% versus 42.9%), pretransplant HBV DNA positivity (43.5% versus 45.7%), and waiting time to transplant (121.2 ± 232.6 versus 159.4 ± 323.2 days) were similar in comparisons of groups H and L (P > 0.05). However, patients with the diagnosis of HCC were more common in group L (61.0%) than in group H (22.6%; P = 0.000). A history of complications of ESLD before transplantation was more frequent in group H than in group L; in group H, uncontrolled ascites (50.0%), hepatic encephalopathy (64.5%), and spontaneous bacterial peritonitis (48.4%) were more common than in group L (27.6%, 30.5%, and 27.6%; P < 0.05). The severity of disease immediately before transplantation was more grave in group H than in group L in terms of UNOS status 1 or 2A (40.3% versus 4.8%) and Child-Turcotte-Pugh grade C (100% versus 70.4%; P < 0.05).
Table 1. Clinical Features of the Recipients in Adult-to-Adult Liver Transplantation
Total (n = 167)
Group L (n = 105)
Group H (n = 62)
Abbreviations: HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; MHV, middle hepatic vein; SD, standard deviation.
Age, years (mean ± SD)
48.3 ± 8.1
49.5 ± 7.7
47.7 ± 8.9
Body weight, kg (mean ± SD)
64.8 ± 10.2
64.4 ± 10.2
65.3 ± 10.4
Waiting time to transplantation, days
145.6 ± 293.1
159.4 ± 323.2
121.2 ± 232.6
Donor and graft factors
Donor gender (male:female)
Donor age, years (mean)
30.1 ± 9.0
30.2 ± 9.2
30.0 ± 8.7
Cytotoxic antibody (negative:positive)
Graft weight, g (mean)
662 ± 152
668.7 ± 160.3
651.1 ± 139.4
Graft versus recipient weight ratio, %
1.04 ± 0.24
1.05 ± 0.26
1.02 ± 0.28
Proportion of a small-for-size graft
Graft type (right:left)
MHV tributary drainage
Operative time, minutes (mean)
569.5 ± 135.4
572.0 ± 143.7
565.1 ± 120.6
Ischemic time, minutes (mean)
76.7 ± 36.2
77.9 ± 33.1
74.8 ± 41.0
45.6 ± 18.3
43.5 ± 19.8
49.0 ± 15.0
Follow-up duration, months (mean)
32.6 ± 23.6
30.9 ± 21.7
35.5 ± 26.5
Donor male gender (67.7% versus 74.3%), age (30.0 ± 8.7 versus 30.2 ± 9.2 years), cytotoxic antibody positivity (3.2% versus 3.8%), graft weight (651.1 ± 139.4 versus 668.7 ± 160.3 g), GRWR (1.02% ± 0.28% versus 1.05% ± 0.26%), right liver graft (83.9% versus 83.8%), proportion of SFSG (17.7% versus 17.1%), MHV drainage (44.3% versus 57.3%), operation time (565.1 ± 120.6 versus 572.0 ± 143.7 minutes), cold ischemic time (74.8 ± 41.4 versus 77.9 ± 33.1 minutes), and warm ischemic time (49.0 ± 15.0 versus 43.5 ± 19.8 minutes) were similar in comparisons of groups H and L (P > 0.05).
Outcome of ALDLT According to the MELD Scores
The postoperative complications are noted in Table 2. The most common posttransplant minor complication was posttransplant diabetes mellitus in 42 cases, followed by nephrotoxicity (n = 37), acute cellular rejection (n = 22), neurotoxicity (n = 19), infection (n = 17), ileus (n = 15), intraperitoneal bleeding (n = 8), pneumonia (n = 7), prolonged ascites (n = 6), recurrence of hepatitis without graft failure (n = 6), portal vein stenosis (n = 4), hepatic artery stenosis (n = 3), and others (n = 5). There were 102 cases of minor complications that developed among 51 patients in group L and 89 cases among 42 patients in group H. The most common major complications were biliary complications in 39 cases, followed by intraperitoneal bleeding (n = 22), infection (n = 16), pneumonia (n = 13), fluid collection (n = 12), nephrotoxicity (n = 10), HCC recurrence (n = 10), prolonged ascites (n = 9), neurotoxicity (n = 7), hepatic artery obstruction (n = 5), hepatic vein stenosis (n = 5), primary nonfunction (n = 3), and others (n = 9). Eighty-eight major complications developed among 49 patients in group L,and 72 developed among 39 patients in group H. There was no significant difference in the rate of posttransplant complications between the 2 groups (P > 0.05). However, the mean posttransplant hospital stay was longer in group H (47.6 ± 36.8 days) than in group L (33.3 ± 21.9 days; P = 0.000).
Table 2. Posttransplant Complications According to the Model for End-Stage Liver Disease Scores
Group L (n = 105)
Group H (n = 62)
Abbreviations: HCC, hepatocellular carcinoma.
Minor complications (P = 0.044)
102 cases among 51 patients (48.6%)
89 cases among 42 patients (67.7%)
Posttransplant diabetes mellitus (n = 42)
Nephrotoxicity (n = 37)
Acute cellular rejection (n = 22)
Neurotoxicity (n = 19)
Infection (n = 17)
Ileus (n = 15)
Intraperitoneal bleeding (n = 8)
Pneumonia (n = 7)
Prolonged ascites (n = 6)
Recurrence of hepatitis B (n = 6)
Portal vein stenosis (n = 4)
Hepatic artery stenosis (n = 3)
Hepatic vein stenosis (n = 2)
Biliary complication (n = 2)
Compression fracture of spine (n = 1)
Major complications (P = 0.599)
79 cases among 49 patients (46.7%)
72 cases among 37 patients (59.7%)
Biliary complication (n = 39)
Intraperitoneal bleeding (n = 22)
Infection (n = 16)
Pneumonia (n = 13)
Fluid collection (n = 12)
Nephrotoxicity (n = 10)
HCC recurrence (n = 10)
Prolonged ascites (n = 9)
Neurotoxicity (n = 7)
Hepatic artery obstruction (n = 5)
Hepatic vein stenosis (n = 5)
Primary nonfunction (n = 3)
Portal vein stenosis (n = 2)
Chronic rejection (n = 2)
Intestinal obstruction (n = 1)
Intracranial hemorrhage (n = 1)
Aplastic anemia (n = 1)
Graft-versus-host disease (n = 1)
Colonic perforation (n = 1)
There was no case of retransplantation, even for graft failure, because of the scarce availability of DDLT in Korea.
The hospital mortality rates in groups L and H were 6.7% (7/105) and 12.9% (8/62), respectively; the late mortality rates not including hospital mortality were 13.3% (14/105) and 8.1% (5/62; P > 0.05). The causes of deaths were graft failure (n = 6), HCC recurrence (n = 9), sepsis (n = 5), and gastrointestinal bleeding (n = 1) in group L (n = 21) and graft failure (n = 4), HCC recurrence (n = 1), sepsis (n = 4), heart failure due to portopulmonary hypertension (n = 1), graft-versus-host disease (n = 1), intraoperative death due to cardiac arrest (n = 1), and a traffic accident (n = 1) in group H.
The 1-YSR was 86.7% in group L and 83.8% in group H (P = 0.564; Fig. 1A). The multivariate analysis showed that the predictors of the 1-YSR included the pretransplant diagnosis of HCC (odds ratio, 2.517; 95% confidence interval, 1.054-6.011; P = 0.038) and the year of the transplant with respect to the center's experience (odds ratio, 9.941; 95% confidence interval, 1.806-54.732; P = 0.008).
We reanalyzed and compared the outcome without the patients accompanying HCC, and the overall 1-YSR was similar in comparisons of group L (n = 41, 90.2%) and group H (n = 48, 91.7%; P = 0.847; Fig. 1B). The multivariate analysis without the patients accompanying HCC showed that GRWR was a predictor of the 1-YSR (odds ratio, 0.005; 95% confidence interval, 0.000-0.323; P = 0.013).
Outcome of ALDLT in Patients with High MELD Scores and SFSGs
In the subgroup analysis based on both the MELD scores and graft size (Fig. 2A), the 6-month patient survival rates were lower in group Hs (72.7%) than in groups Hn (86.3%), Ls (83.3%), and Ln (95.4%; P = 0.023). However, the 1-YSR was similar among these 4 groups (72.7% in group Hs, 86.3% in group Hn, 77.8% in group Ls, and 88.5% in group Ln; P = 0.278).
The survival outcome without the patients accompanying with HCC was reanalyzed and compared among groups Hs (n = 10), Hn (n = 38), Ls (n = 11), and Ln (n = 30; Fig. 2B). The 6-month patient survival rate was similar among these 4 groups (80.0% in group Hs, 97.4% in group Hn, 81.8% in group Ls, and 96.7% in group Ln; P = 0.075). The 1-YSR was similar among the 4 groups (80.0% in group Hs, 94.7% in group Hn, 72.7% in group Ls, and 96.7% in group Ln; P = 0.072).
Since the implementation of the MELD system by UNOS in February 2002, the patient mortality on the waiting list and the overall number of patients waiting for liver transplantation have decreased. Although the MELD system has been very successful for DDLT, there continues to be debate about the posttransplant outcome of patients with high MELD scores.26 Because patients with high MELD scores have more severe acute illness, they have a more complicated intraoperative and postoperative course26–28 and require a high level of pretransplant care.
Theoretically, a partial liver graft that is unable to meet the metabolic demands of a large recipient is an additional risk factor for a poor posttransplant outcome in critically ill patients with high MELD scores. This is because the small partial graft itself may result in liver dysfunction or failure. Therefore, there is limited information on the effect of pretransplant MELD scores on posttransplant outcome in ALDLT. In 2003, Hayashi et al.28 were the first to report that there was no correlation between the posttransplant 1-YSR in ALDLT and the pretransplant MELD score among 62 adult recipients. However, the mean MELD score in that study was low, even for the patients who died, and the sample size was small; the median MELD scores for the 59 living patients and the 3 patients who died were 13 and 15, respectively. Recently, Terrault et al.29 and Uchida et al.30 reported that a high pretransplant MELD score was associated with poor long-term survival by multivariate analysis. However, the other important predictor of graft loss was the experience of transplant centers in Western countries.29 In addition, the Japanese experience30 was based on pediatric recipients; 417 of 464 patients were pediatric recipients.
However, in Korea we do not exclude very ill patients with high MELD scores or acutely ill patients that are UNOS status 1 or 2A from ALDLT. This is because there is little chance for these patients to undergo DDLT. Fortunately, recent advances in surgical techniques and perioperative care have resulted in excellent outcomes for ALDLT even in cases with an SFSG.15, 31, 32 The outcome of LDLT is dependent on the year of transplant, that is, the center's experience.29, 33–35 The center's experience was also an important prognostic predictor in this study. In our center, the ALDLT program began in 1999,21, 36 and there have been no operative mortalities with ALDLT even in very ill patients with a small graft during the last 2 years.22, 23, 25, 31 LDLT has advantages compared to DDLT; the waiting time for the transplant and ischemic time are short, a scheduled operation is possible, and the mean donor age is about 30 years (usually <50 years in ALDLT). In addition, the major indication for liver transplantation (80% of the total number of adult recipients) in Korea is HBV-related liver disease, which has a better outcome after liver transplantation than hepatitis C–related liver disease. However, critical care is required in high-risk patients, that is, patients with a high MELD score and an SFSG; in this study, the 6-month patient survival rate in group Hs (73%) was lower than that in the other groups (more than 83%). Reconstruction of the MHV or its major branches to maintain the functional graft volume might aid in the reduction of the incidence of graft failure in an SFSG. For this reason, we aggressively reconstructed the branches of the MHV in order to maintain the functional graft volume in those cases with an SFSG; the proportion of reconstruction of the MHV or its branches was higher in groups Hs (81.8%) and Ls (88.9%), which used SFSGs, than in groups Hn (37.3%) and Ln (49.4%), which used normal-size grafts (P = 0.026).
On the other hand, one of the predictors of the 1-YSR was the pretransplant diagnosis of HCC by multivariate analysis. According to the American Association for the Study of Liver Diseases practice guidelines for the management of HCC,37 liver transplantation is an effective option in HCC patients who fit the Milan criteria. LDLT can be offered to patients with HCC if the waiting time is not long enough to allow tumor progression, which would lead to exclusion from the waiting list.38 However, patients who could benefit from liver transplantation but do not fit the Milan criteria have been excluded from any potentially curative strategy,38–40 although a graft from a live donor is considered a private gift. In our center, the pretransplant minimal listing criteria for HCC patients considered for ALDLT include no gross vascular invasion and no extrahepatic metastasis, including lymph nodes. According to the minimal listing criteria, the overall 3-year survival rate and recurrence-free survival rate of the HCC patients at our center were 67% and 70% after ALDLT.38 There were 3 patients who died of HCC recurrence within 1 year after transplantation in this study. They did not fit the Milan criteria and had more than 1 risk factor for HCC recurrence, including a high pretransplant alpha-fetoprotein level (>1000 ng/mL), capsular invasion, microvascular invasion, and an (18)F-fluoro-2-deoxy-D-glucose positron emission tomography–positive lesion.38–40 Therefore, if the selection criteria38, 40 are aligned with the prediction for HCC recurrence, the outcome of ALDLT may improve.
In fact, the pretransplant factors of recipients were not perfectly comparable between the 2 groups because this is a retrospective review and the disease severity of the 2 groups was very different. In Korea, the MELD score has not been used for organ allocation. In addition, MELD exception points have not been allotted on the basis of HCC. In this study, the MELD score was also calculated purely on the basis of liver disease severity. Therefore, there has been an increase in the number of recipients with HCC on the waiting list; these patients typically have had multiple interventions such as transarterial chemoembolization and do not have the severe complications associated with cirrhosis, that is, a low MELD score. For this reason, HCC was more prevalent in group L than group H. Therefore, we analyzed the data after exclusion of the HCC patients. As noted in the Results section, the overall 1-YSR was similar in comparisons of groups H (91.6%) and L (90.2%; P = 0.847).
On the other hand, although there was no statistical difference in the 1-YSR without the patients accompanying HCC, the patients' groups with an SFSG (group Hs, 80.8%, and group Ls, 72.7%) showed lower survival rates than those with a normal-size graft (group Hn, 94.7%, and group Ln, 96.7%). This might be associated with the small sample size and the retrospective nature of its design. In addition, the only factor affecting the poor 1-YSR was GRWR in patients without HCC. Therefore, the physician must be alert in the care of very ill patients with an SFSG.
In conclusion, a high MELD score (> 25) did not predict the 1-YSR of HBV-infected recipients after ALDLT, and it was also not an important predictor of the 1-YSR in cases with an SFSG. Because HCC and the experience of the transplant center were important predictors of the 1-YSR, increased center experience as well as the selection of patients with a low risk of HCC recurrence may improve the 1-YSR after ALDLT, even in very ill patients with an SFSG. However, critical care is required for high-risk patients with a high MELD score and an SFSG because the 6-month patient survival rate in group Hs was lower than that in the other groups.