Pretransplant MELD Score As a Predictor of Outcome After Liver Transplantation for Chronic Hepatitis C
Part of the material was presented at The American Transplant Congress held April 26th – May 1st in Washington, D.C.
* Corresponding author: Goran B. Klintmalm, A. N. Author, email@example.com
The Model of End-Stage Liver Disease (MELD) score, an accurate predictor of mortality in patients awaiting liver transplantation (OLTX), did not predict graft or patient survival in the post-transplant setting. Our aim was to test the model in patients who underwent OLTX for chronic hepatitis C. Two hundred and eighty-seven adult patients who underwent primary OLTX for chronic hepatitis C between December 1993 and September 1999 were studied from a prospectively maintained database. The group was stratified by MELD scores of less than 15, 15–24, and greater than 24. Patient survival, graft survival, and interval liver biopsy pathology were reviewed. Both patient and graft survival at 3, 6, and 12 months were significantly lower in the higher MELD score groups, as was patient survival at 24 months (p-values, 0.01–0.05). The difference in survival between the low, medium, and high MELD score groups increases in time. The survival without bridging fibrosis in the allograft at 1 year post-transplant was significantly lower with higher MELD scores (p = 0.037). The decrease in survival seen in hepatitis C patients with MELD scores greater than 24 raises questions of transplant suitability for these patients. Therapeutic modalities to decrease post-transplant graft injury in these patients should be explored.
The Model of End-Stage Liver Disease (MELD) score has been introduced by the United Network of Organ Sharing as the main criteria for allocation of cadaveric donor livers in patients with chronic end-stage liver disease awaiting liver transplantation. The score was validated in the pretransplant setting as an accurate predictor of mortality (1–7). When used in relation to the post-transplant outcome, the MELD score was felt to be less accurate (1,8). The studies performed so far were carried out in the general liver transplant population while investigating the short-term outcome (1,8).
The aim of our study was to determine if there is a correlation between the pretransplant MELD score and the outcome of a group of patients with chronic hepatitis C during the first 2 years after liver transplantation.
Materials and Methods
Seven hundred and sixty-two adult patients underwent liver transplantation from cadaveric donors at the Baylor University Medical Center between December 1993 and September 1999. Of them, 711 patients underwent primary liver transplantation, including 287 patients with end-stage liver disease secondary to chronic hepatitis C who were selected for the study. Clinical data obtained on the patients were entered in the Liver Transplant Database in a prospective fashion. The data was analyzed retrospectively for this study.
The MELD score was calculated using the immediate preoperative data (i.e. from laboratory tests obtained 2–6 h before the surgery) according to the formula:
The study group was then split into three separate groups according to the pretransplant MELD score (Table 1): patients with a MELD score less than 15 (n = 165), 15–24 (n = 86), and 25 and greater (n = 36).
Table 1. Patient characteristics
|Number of patients||165||86||36||287|
|Mean age||49.8 ± 8||49.7 ± 9.16||50.6 ± 11||49.9 ± 8.73|
|Sex (M:F ratio)||1.32:1||2.44:1||2:1||179:108|
|Past alcohol consumption||23%||31.4%||16.7%||15.7%|
|Donor age||38.4 ± 16.6||34.3 ± 16.8||38.9 ± 16.3||37.5 ± 16.7|
|Acute cellular rejection||61.8%||58.1%||50%||59.2%|
The MELD score stratification correlates to some approximation with the previous UNOS status in the patients in our Organ Procurement Organization (OPO). Most patients who were transplanted being UNOS status 3 had a MELD score less than 15; a MELD score of 15–24 included most status 2B patients, while very sick status 2B and status 2A patients had a MELD score of 25 and greater.
Immunosuppression was achieved using a double- or triple-drug regimen including steroids and cyclosporine or tacrolimus in most cases. Regimen included cyclosporine and steroids (n = 144), cyclosporine-azathioprine-steroids (n = 57), cyclosporine, mycophenolate and steroids (n = 25), tacrolimus and steroids (n = 17), cyclosporine monotherapy (n = 12), tacrolimus-azathioprine-steroids (n = 9), azathioprine and steroids (n = 6), steroids only (n = 5), tacrolimus, mycophenolate and steroids (n = 3), rapamycin, cyclosporine and steroids (n = 3), rapamycin and cyclosporine (n = 3), azathioprine and cyclosporine (n = 2), and tacrolimus and mycophenolate (n = 1).
OKT3 was used for induction therapy in 10 patients with acute renal failure at the time of transplant.
The patients were followed up as outpatients with annual follow-up visits including liver biopsies. Liver biopsies were also obtained when indicated for clinical reasons, mainly for elevated liver enzymes. All patients included in the study completed at least 2 years of follow up, unless death or retransplantation occurred.
The liver biopsies were reviewed by a dedicated pathologist and assessed for recurrence of hepatitis C. When recurrence was present, grading and staging of the inflammation and fibrosis were made according to Desmet et al. (9).
The endpoints of the study were death, retransplantation, and histological outcome of the liver allograft according to protocol biopsies. Significant fibrosis in the allograft was defined as stage 3 or 4 (i.e. bridging fibrosis or nodules on microscopy).
The data obtained were included in a separate database. A univariate analysis was performed using the Chi-square test for nonparametric data, and the patient outcome was assessed at 1, 3, 6, 12, 18 and 24 months. This was followed by a logistic regression analysis. The parameters for the logistic regression analysis included the MELD score (grouped as previously described), age and gender of the donor and the recipient, immunosuppression regimen, acute cellular rejection episodes and steroid resistant rejection, cytomegalovirus (CMV) infection, and hepatocellular carcinoma (HCC) in the recipient. The outcome parameters used were patient and graft survival at 3 months, 1 year and 2 years and severe fibrosis (stage 3–4) at 2 years after transplant.
The study group included 287 patients, 179 male (62.4%) and 108 female (37.6%), who underwent primary liver transplantation. The follow-up period ranged between 2 and 7 years.
The immediate pretransplant MELD score was less than 15 in 165 cases (57.5%), 15–24 in 86 cases (30%), and 25 and greater in 36 cases (12.5%).
Seventy out of 287 patients died in the first 2 years after the liver transplant in the study group, with an overall 2-year survival rate of 75.61%. The 2-year patient survival was 80.6% for patients with MELD scores less than 15, 72.1% for patients with scores between 15 and 24, and 61.1% for patients with MELD scores of 25 and greater (Table 2). The difference in survival was 12.8% at 3 months, 14.3% at 6 months, 21.6% at 1 year, 19.1% at 18 months, and 19.5% at 2 years. The difference was statistically significant (p-value range, 0.01–0.032). The 30-day survival rate was lowest in the patient group, with MELD scores between 15 and 24.
Table 2. Absolute patient survival at different intervals within 2 years after liver transplantation in different Model of End-Stage Liver Disease score groups (minimum follow up of 2 years)
|MELD less than 15||165||95.76%||93.33%||92.12%||85.45%||83.03%||80.61%|
|MELD 25 and greater||36||94.44%||80.56%||77.78%||63.89%||63.89%||61.11%|
| || ||p = 0.65||p = 0.026||p = 0.017||p = 0.01||p = 0.022||p = 0.032|
The causes of death were infectious in 17 patients (septicemia in 13 cases, pneumonia with respiratory failure in two cases, CMV infection, urosepsis), graft-related in 12 cases (hepatic artery thrombosis in three cases, rejection in eight cases, primary nonfunction in one case), cardiovascular in nine cases (congestive heart failure in four cases, arrhythmias in three cases, myocardial infarction in one case and intractable pulmonary hypertension in one case), recurrent hepatitis C in nine cases, malignancy in nine cases (recurrent HCC in eight cases and disseminated squamous cell carcinoma in one case), neurological in eight patients (hemorrhagic stroke in four cases, embolic stroke, central pontine myelinolysis, not clearing preexisting hepatic encephalopathy, anoxic brain injury with necrosis: one case each), graft vs. host disease in three patients, ruptured aneurysms (mycotic: 2, splenic artery: 1), ischemic bowel in two patients, and drug toxicity in one case.
Two hundred and ten patients were alive and had a functioning liver allograft at 2 years after transplant, with an overall graft survival rate of 73.2% (Table 3). The survival rate at different intervals (1, 3, 6, 12, 18, 24 months) was higher for patients with a MELD score less than 15 and worst for patients with MELD scores of 25 and greater at 3 months and beyond. The 30-day survival rate was lowest (90.7%) in patients with a MELD score between 15 and 24. The difference in graft survival rates between the patients with the lower MELD scores and the higher MELD scores was 12.8% at 3 months, 12.5% at 6 months, 19.1% at 1 year, 16.7% at 18 months, and 17.1% at 2 years after transplant (Figure 2). This difference was significant at all intervals (p-value range, 0.012–0.041) except of the 2-year survival rate (p = 0.059).
Table 3. Absolute graft survival at different intervals within 2 years after liver transplantation in different Model of End-Stage Liver Disease score groups (minimum follow up of 2 years)
|MELD less than 15||165||95.76%||93.33%||90.3%||83.03%||80.61%||78.18%|
|MELD 25 and greater||36||94.44%||80.56%||77.78%||63.89%||63.89%||61.11%|
| || ||p = 0.272||p = 0.012||p = 0.034||p = 0.027||p = 0.041||p = 0.059|
Seven patients (2.4%) underwent retransplantation within 2 years from the initial liver transplant. The causes of retransplantation were hepatic artery thrombosis in three cases, ischemic biliary strictures in two cases, and chronic allograft rejection in two cases. The MELD scores before the initial transplant were 6, 7, 11, 13, 17 (two cases) and 20.
Out of the 210 patients who were alive at 2 years after transplant with a functioning graft, 31 (14.76%) developed significant fibrosis according to liver biopsies (bridging fibrosis and/or cirrhotic nodules), 21 out of 129 patients (16.3%) with MELD scores less than 15, six out of 59 (10.2%) patients with MELD scores between 15 and 24, and four out of 22 patients (18.2%) with MELD scores of 25 and greater. There was no statistically significant difference in the incidence of fibrosis in the MELD subgroups (p = 0.49).
The cirrhosis-free survival, defined as survival with a functioning liver allograft and without bridging fibrosis in the allograft, was 65.45% at 2 years for patients with MELD scores less than 15, 61.63% for patients with scores between 15 and 24, and 50% for patients with MELD scores of 25 and greater. We considered stage 3 and 4 fibrosis on liver biopsies as significant fibrosis for this purpose. The difference in the cirrhosis-free survival (Table 4, Figure 3) was 20.46% at 1 year (p = 0.037), 14.4% at 18 months (p = 0.195), and 14.55% at 2 years (p = 0.22). The relatively small size of the subgroups probably accounts for the lack of statistical significance. The negative outcome described was induced by mortality and graft loss in 63.1% of cases in patients with MELD scores less than 15 and 77.7–82.8% in these with scores of 15 and more and the remainder was represented by the development of bridging fibrosis or cirrhosis in the allograft.
Table 4. Absolute bridging fibrosis-free graft survival (stage 3–4 fibrosis in liver biopsy) at different intervals within 2 years after liver transplantation in different Model of End-Stage Liver Disease score groups (minimum follow up of 2 years)
|MELD less than 15||165||95.76%||93.33%||90.3%||78.89%||72.73%||65.45%|
|MELD 25 and greater||36||94.44%||80.56%||77.78%||58.33%||58.33%||50%|
| || ||p = 0.272||p = 0.012||p = 0.034||p = 0.037||p = 0.195||p = 0.22|
Out of the 210 patients who were alive at 2 years after transplant and did not undergo retransplantation, 120 patients (57.1%) had previously developed at least one episode of acute cellular rejection in the liver allograft; all treated with high-dose steroids. Three of these patients (2.5%) had steroid-resistant rejection and received further treatment with OKT3. Patients with allograft fibrosis at 2 years post-transplant had a significantly higher incidence of acute cellular rejection earlier in the course: 25 out of 31 in the course (80.6%) as opposed to only 95 of the 179 patients (53.1%) who did not have significant fibrosis (p < 0.001).
The rejection rate was 61.81% for patients with a MELD score less than 15, 57.47% for those with MELD scores between 15 and 24, and 50% for those with MELD scores of 25 and greater, which was not statistically significant (p = 0.401).
Ten patients in the study group received OKT3 for induction while avoiding the initial use of calcineurin inhibitors because of grade 3 encephalopathy (three patients), hepatorenal syndrome (five patients) or both (two patients). All these patients had a MELD score above 25, except a patient with a score of 24. Seven out of 10 patients were alive at 2 years after transplantation, similar to the rest of the group.
A logistic regression analysis was performed. Parameters found as independent factors influencing both patient and graft survival were the HCC and MELD scores. Odds ratio for mortality with HCC were 1.743 at 1 year and 2.774 at 2 years post-transplant (p = 0.0053 for the latter).
Odds ratio for graft loss in patients with HCC were 2.098 at 1 year (p = 0.15) and 3.329 at 2 years (p = 0.0055). The graft loss was not related to recurrent carcinoma.
The influence of the MELD score was addressed at 3 months, 1 year and 2 years after transplant. At 3 months post-transplant, the odds ratio of mortality for patients with scores of 25 and greater compared to those with scores less than 15 was 3.435 (p = 0.0251) and compared to those with scores of 15–24 was 1.29 (p = 0.0584).
At 1 year post-transplant, the odds ratio for mortality with MELD scores of 24 and greater were 2.652 when compared with patients with scores less than 15 (p = 0.0239) and 1.733 when compared to patients with MELD scores between 15 and 24 (p = 0.2255).
At 2 years post-transplant, the odds ratio comparing MELD scores of 25 and greater with those with scores less than 15 was 2.057 (p = NS). The odds ratio between scores of 25 and greater and 15–24 was 1.37 (p = NS). Odds ratio with MELD scores of 15 and greater compared with those of less than 15 was 1.801 (p = 0.0363).
Age and gender of the donor and the recipient, immunosuppression regimen, acute cellular rejection episodes and steroid resistant rejection, and CMV infection were not found to be independent factors associated with mortality.
Acute cellular rejection episodes were found to have a negative influence in graft survival with odds ratios of 2.074 at 1 year (p = 0.0492) and 2.15 at 2 years (p = 0.08).
Fibrosis in the liver allograft (stage 3–4 by liver biopsy) was found to be associated with steroid resistant rejection, with an odds ratio of 3.244 (p = 0.0026). All other parameters, MELD score, age and gender of the donor and the recipient, immunosuppression regimen, and CMV infection, were not independently associated with fibrosis.
The main finding of this study is that hepatitis C patients with severe end-stage liver disease (reflected by higher MELD scores) immediately pretransplant have a significantly diminished survival rate in the first 2 years after liver transplantation as compared with the survival of patients with relatively mild disease. Probably the most startling finding is that the difference in survival is significant starting 3 months after the transplantation, and the survival gap between the patients with the higher and lower MELD scores gradually increases with time and reaches almost 20 percent at 1 year after transplantation. This difference is maintained throughout the second year after transplant as well. This is contrary to the belief that disease severity before liver transplantation affects the outcome only in the early postoperative course, namely in the first month after liver transplantation (1,8). Our perception is that advances in intensive care management are able to postpone mortality in certain cases while not necessarily improving the outcome. This might explain the shift in mortality past the classic 30-day landmark. Graft survival is also significantly lower in the group of patients with higher MELD scores. The MELD scores were an independent factor associated with higher mortality in a logistic regression analysis.
Sepsis was the leading cause of death (10,11) followed by cardiovascular and neurologic complications.
Patients with higher MELD scores tend not to develop more severe recurrent hepatitis C in the allograft earlier than the patients with low MELD scores. The only significant factor associated with early severe recurrent hepatitis C in our study was acute cellular rejection, especially if steroid resistant, probably related to the inevitable increase in immunosuppression associated with it, as described by us and others (12–15). Patients with the higher MELD scores had less rejection episodes, but it is unclear if this alone can explain the above observation. Acute cellular rejection also influenced graft survival in our study.
The impact of introducing the MELD score as the determinant in the allocation of donor livers for transplantation has not been completely assessed. The effect largely depends on the previous pattern of organ allocation in different centers. In most transplant centers hepatitis C is the main disease of the liver transplant recipients (16). A shift towards transplant of the patients with higher MELD scores avoids mortality of patients on the waiting list but may result in a significant decline in post-transplant survival as well as increased in-hospital costs (17). It has been felt that the pretransplant medical condition may influence the short-term survival post-transplant (1). Our study indicates that there is a survival disadvantage for the sick hepatitis C patients that increases with time throughout the year after transplantation and is maintained throughout the second year. This difference in survival is concerning, as it is unknown whether this difference will increase with time.
Only half of the liver transplant patients with MELD scores of 25 or above survive 2 years without significant fibrosis (bridging fibrosis) in the liver allograft, and although bridging fibrosis in the liver allograft does not necessarily correlate with a low quality of life, it might impact the long-term outcome (13,18–20). In this population, 4/5 of the adverse outcome is induced by mortality and the remainder by recurrent hepatitis C.
Is the implementation of the MELD score going to affect the long-term outcome of the patient population in the new allocation system and their healthcare expenses? Would the MELD score of these patients need a correction factor? Should some of the hepatitis C patients with MELD scores above 25 be inactivated, as the benefit or appropriateness of transplantation in these circumstances is questionable? Is there another cutting point? A large-scale study may be able to answer these questions.