Retransplantation (re-LT) of patients with recurrent hepatitis C virus (HCV) carries significant morbidity and mortality, negatively impacting on an already scarce donor allograft pool. In this study, we investigated the outcome of allografts and patients after re-LT due to recurrent HCV. Between 1989 and 2002, 47 patients were retransplanted at our institution due to HCV-related graft failure. Clinical HCV recurrence after re-LT was diagnosed when patients had acute liver enzyme elevation correlated with histological recurrence. The independent influence of these variables on survival was tested using Cox regression model. Chi-squared tests were used to examine the influence of individual demographic and pre/perioperative variables on recurrence. Thirty-one (66%) patients died after re-LT (median 2.2 months). Donor age >60, clinical HCV recurrence, and graft failure due to cirrhosis were significant risk factors for mortality (risk ratios of 3.6, 3.3, and 2.4, respectively). Pre-LT MELD score was lower among survivors (22± 5 vs. 27± 8). Following re-LT, 38 patients had at least one biopsy due to acute liver dysfunction; 19 of them (50%) had recurrence within the first 3 months. High-dose solumedrol was correlated with early recurrence. No association was found between time of recurrence after the first LT and time of recurrence after re-LT. In conclusion, patients with cirrhosis due to recurrent HCV undergoing re-LT have an extremely high mortality rate; older allografts should be avoided in retransplanting these patients. The timing of clinical recurrence after initial liver transplantation is not predictive of the timing of recurrence after re-LT. Patients experiencing early graft failure due to accelerated forms of HCV should not be denied re-LT with the expectation that a similar disease course will occur after re-LT. (Liver Transpl 2005;11:1567–1573.)
Cirrhosis secondary to hepatitis C viral (HCV) infection is the most common indication for liver transplantation (LT) in the United States and Europe.1, 2 Virological recurrence of HCV is almost universal after LT,3, 4 with 50–90% of allografts demonstrating histological evidence of recurrence within 12 months post-LT.3, 5, 6 Several studies have shown that progression to cirrhosis and graft failure may occur in up to 10–15% of these patients within 5 yr.3, 7 Earlier time to histological recurrence has been associated with higher morbidity and mortality related to graft failure.8, 9 Prolonged warm ischemic time, higher viral loads at the time of LT, use of OKT3, and the use of high-dose corticosteroids in the treatment of acute cellular rejection have all been shown to contribute to early histological recurrence.9–15
Recurrent HCV post-LT may progress to cirrhosis or may take a more aggressive and rapid course as recurrent cholestatic hepatitis (RCH) or advanced fibrosis (AF) with severe necroinflammatory activity, as defined at the recent International Liver Transplantation Society consensus conference.16 The former is manifested by hyperbilirubinemia and profound cholestasis in the absence of biliary ductal abnormalities.17, 18 These conditions may cause early graft failure1 and the need for re-LT within several months. Recent data demonstrate that older donor age may negatively impact the histological progression and clinical outcome of recurrent HCV after LT.19 Re-LT due to recurrent HCV is becoming an increasingly common problem as time goes on, as well as a controversial issue in that re-LT due to recurrent HCV appears to carry significant morbidity and mortality.9, 19–25 It is becoming increasingly important to prognosticate survival in these patients so as to optimize more judicious use of liver allografts in light of the critical organ donor shortage. The course of recurrent HCV after re-LT is poorly defined; anecdotal evidence has suggested that the pattern of HCV reinfection of a second allograft may be similar to that of the initial one.22, 23 If true, this would provide compelling evidence not to retransplant some patients who required retransplantation for HCV recurrence, especially if graft failure occurred soon after transplantation. In this study, we examined the rate of clinical HCV recurrence as reflected by elevated liver enzymes together with histological recurrence in patients undergoing re-LT due to HCV recurrence. Another aim was to identify clinical parameters that may be associated with recurrence and to examine graft and patient survival.
Patients and Methods
This study concerns survival of 47 patients who underwent re-LT due to graft failure from recurrent HCV following an initial transplant for a primary diagnosis of HCV cirrhosis. These patients were identified from 62 HCV patients in the Mount Sinai Medical Center's Liver Transplantation database who underwent re-LT between December 1989 and March 2002 (15 patients undergoing re-orthotopic LT for other reasons such as biliary structuring, chronic rejection, etc., were excluded from data analysis). The 47 re-LTs occurred at least 1 month after the initial transplant and thus do not include patients undergoing early re-LT for primary nonfunction or acute vascular or biliary complications. Patients with at least one liver biopsy after re-LT are included in the analyses concerning recurrence of HCV. At our center, liver biopsies are performed only when clinically indicated, not as per protocol. Thirty-eight of the 47 patients had at least one follow-up liver biopsy. The remaining nine patients died within 2 months of their re-LT. Patient and liver biopsy information were obtained from the databases of the Recanati/Miller Transplantation Institute and the Department of Pathology, The Mount Sinai Medical Center. Patient data included demographics, time interval between transplants, donor age, ischemia time, and immunosuppressive regimen. The model for end-stage liver disease (MELD) score was calculated according to the international normalized ratio, creatinine, and bilirubin levels prior to re-LT. Donor age was divided into two groups, <60 and >60 yr. Total ischemia time longer than 10 hr and warm ischemia longer than 1 hr were considered prolonged. Solumedrol (SMD) was used after re-LT to treat acute cellular rejection. The total dose given prior to recurrence was calculated as ≤2 or >2 g (low and high dose, respectively), while the use of OKT3 with either dosage was considered to be the third category for immunosuppression. Mild acute cellular rejection was not treated with SMD.
Histological Diagnosis of Recurrent HCV
A constellation of histological findings consisting of lobular disarray, individual hepatocyte necrosis, and activation of sinusoidal lining cells denoted early recurrent HCV. To determine chronic recurrent HCV, lymphocytic aggregates in portal areas, interface hepatitis, and different stages of fibrosis in addition to lobular necroinflammation were assessed. The modified Knodell histological activity index was used to score grade of inflammation and stage of fibrosis.26 RCH was diagnosed if there were characteristic features present such as hepatocyte and canalicular cholestasis, hepatocyte swelling, and a prominent ductular reaction. AF with severe necroinflammatory activity consisted of areas of multiacinar collapse replaced by fibrosis and no well-defined cirrhotic nodules. The areas of fibrosis were heavily infiltrated by chronic inflammatory cells. Acute cellular rejection was diagnosed histologically using the Banff criteria.27 All explanted liver allografts and liver biopsy specimens were reviewed by a single liver pathologist (M.I.F.) in a blinded fashion.
Diagnosis of Clinical and Histological Recurrence
Patients with elevated liver enzymes and normal imaging studies underwent liver biopsy. Elevated liver enzymes in the presence of histological hepatitis C was defined as acute liver dysfunction related to recurrent HCV.
All data were entered into an Excel database (Microsoft Redmond, WA) and converted to an SAS file for statistical analysis (SAS/STAT software, version 80z, SAS Institute, Inc., Cary, NC). The independent influence of various patient and disease features on patient survival was tested using the Cox regression model. Influences of the different variables on the frequency of histological evidence of recurrent HCV were tested one at a time using the chi-squared test separately for two time periods, for recurrence within the first 3 months and then 3–12 months after re-orthotopic LT. Since there were early deaths in some patients, which precludes the chance of documenting HCV recurrence, both early death and recurrence are shown together. For the first time period, patients were assigned to one of three categories: histological recurrence of HCV within 3 months, early death without recurrence, and survivors without recurrence at 3 months. The analysis for the later time period (3–12 months) was applied to patients who survived the first 3 months without clinical and histological HCV recurrence.
Sixty-two patients initially transplanted with HCV underwent re-LT due to graft failure between December 1989 and March 2002. Forty-seven patients were retransplanted for HCV-related reasons. The median age at the time of the first LT was 47 yr (range 20–61), and the median interval between LT and re-LT was 2.0 yr (range 3.6 months–9.1 yr) (see Table 1). The interval between transplants was the longest among patients who lost their allografts due to cirrhosis, median 3 yr (range 4.2 months–9.1 yr) compared with 1.4 yr (range 3.6 months–3.2 yr) in patients who underwent re-LT due to RCH or AF. All patients were assessed as Child's class C at the time of re-LT. MELD score at the time of re-LT was calculated for 39 patients (data missing for five patients who expired and three survivors). The average MELD score was 26 ± 7.5 (range 15–44) (Table 2).
Table 1. Characteristics of Patients with HCV Undergoing re-LT
|Men||27||47 (32–60)||2.4 (0.3–8)||17 (63%)||19 (70)||5 (18.5)||3 (11)|
|Women||20||49 (20.5–61)||1.8 (0.79–9)||14 (70%)||13 (65)||4 (20)||3 (15)|
|Total||47||47 (20.5–61)||2.0 (0.3–9)||31 (66%)||32 (68)||9 (19)||6 (13)|
Table 2. Pre-re-LT MELD Score of 38/47 Patients
|MELD score||22 ± 5||27 ± 8||25 ± 8||27 ± 6||26 ± 7.5|
Thirty one patients (66%) died after re-LT during a median time to death of 2.2 months (range 1 day–57 months); 23 of them died within the first yr, 17 of the deaths occurring during the first 3 months (14 of those 17 without documented histological recurrence). The median follow-up of the 16 survivors was 3 yr (range 0.7 months–9.4 yr). MELD score among survivors was lower compared to nonsurvivors (22 ± 5 vs. 27 ± 8, P = 0.03, respectively) (Table 2). Independent influences of the following parameters on the rate of mortality were tested one at a time: donor age >60, indication for re-LT defined by cirrhosis in the explanted liver vs. AF and RCH, recipient gender, recipient age, interval between transplants, time to histological recurrence after the first transplant, ischemia time, and immunosuppressive regimen. The impact of clinical and histological recurrence of HCV after re-LT and the time of recurrence after re-LT on the mortality rate were tested as time-changing covariates. Donor age >60, indication for re-LT, and recurrence of HCV were found to be significant and entered in a multiple regression (Table 3). The use of donor allografts >60 yr old increased the death rate about 3.6 times compared to allografts from those <60 yr old at any point during follow-up (P = 0.002). Patients being retransplanted due to cirrhosis had a 2.4 times higher rate of mortality compared to patients being retransplanted due to AF and RCH (P = 0.05). MELD score was not significantly different between these two groups (25 ± 8 vs. 27 ± 6, respectively) (Table 2). Patients with clinical and histological recurrence of HCV had a 3.3 times higher rate of death than patients without a clinical and histological recurrence (P = 0.02). The timing of acute liver dysfunction due to HCV recurrence did not add any independent influence to the mortality rate.
Table 3. Independent Risk Factors of Mortality in HCV Patients after re-LT
|Donor age ≥60 yr||3.58||0.0018|
|Histology of explanted allograft (cirrhosis vs. RCH/AF)||2.35||0.051|
Indication for re-LT
All explanted allografts were reviewed histologically. The indication for re-LT was diagnosed according to the explant's histology. Thirty-eight of the 47 patients who underwent re-LT due to recurrent HCV had at least one follow-up biopsy (Table 1): 32/47 (68%) had HCV cirrhosis demonstrated on explant, nine (19%) had RCH, and six (13%) had AF due to recurrent HCV.
All patients received SMD for primary immunosuppressive therapy posttransplantation and during the first days after re-orthotopic LT and were later converted to prednisone. Cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil was started during the first days after the operation according to standardized dosing. Pulses of SMD were given to treat acute cellular rejection. The use of OKT3 was reserved for cases of severe steroid-resistant acute cellular rejection. Twenty-eight (60%) patients were treated with low cumulative dosages of SMD <2 g. For rejection, 10 (21%) patients were treated with high-dose SMD (>2 g) and nine (19%) required OKT3.
Clinical Recurrence of Hepatitis C
Thirty-eight patients had a liver biopsy due to elevated liver enzymes, and their allograft biopsies were reviewed for recurrence, acute cellular rejection, or other causes of liver dysfunction. One patient was not included in the 3-month analyses since her follow-up was shorter than 3 months. Early-recurrence HCV was found in 19 of the 37 remaining patients (51%). Eleven out of these 19 patients (55%) had also experienced an early recurrence after their primary LT. The rate of early recurrence was higher among women compared to men (12/1,614 [86%] women compared to 7/23 [30%] men), while more men died early without a recurrence compared to women (6/23 [26%] men and 0% of women, P = 0.003) (Table 4). Twelve patients (32%) survived the first 3 months without histological recurrence, and all were followed until the end of the year. There were no deaths without a recurrence during the 3–12 months, so a patient was classified as either having a recurrence or being alive without a recurrence. Forty-two percent (5/12) of the patients who survived the first 3 months without clinical and histological recurrence had a recurrence by the end of the first year (Table 4). Only seven patients completed 1 yr follow-up without clinical hepatitis related to recurrent HCV. No significant difference in recurrence rate was found between the genders after 3 months (Table 4).
Table 4. Factors Impacting on HCV Recurrence after re-LT
|Men (%)||6 (26%)||7 (30%)||10 (43%)||23||4 (40%)||6 (60%)||10|
|Women (%)||0 (0%)||12 (86%)||2 (14%)||14||1 (50%)||1 (50%)||2|
| || || || ||P = 0.003|| || ||NS|
|Total HCV-related re-LT (%)||6 (16.2%)||19 (51.4%)||12 (32.4%)||37||5 (42%)||7 (58%)||12|
|Low-dose SMD||4 (20%)||10 (50%)||6 (30%)||20||1 (17%)||5 (83%)||6|
|High-dose SMD||0 (0%)||8 (89%)||1 (11%)||9||1 (100%)||0||1|
|SMD + OKT3||2 (25%)||1 (12.5%)||5 (62.5%)||8||3 (60%)||2 (40%)||5|
| || || || ||P = 0.033|| || ||NS|
The frequency of early recurrence was higher among patients who were treated with high doses of SMD (8/9, 89%) compared to patients treated with low-dose SMD (10/20, 50%) or OKT3 (1/8, 12.5%) (P = 0.03), while the incidence of death without recurrence was higher in patients receiving low-dose SMD and OKT3 compared to the high-dose group (Table 4). This trend of worse outcome continued for the next 9 months with recurrence in 1/1 (100%) patients treated with >2 g SMD, while recurrence was found in only 60% (3/5 patients) of patients receiving OKT3 and 17% (1/6 patients) of patients treated with <2 g SMD.
None of the factors, such as recipient age, time interval between transplants, donor age, and ischemia time, was associated with the rate of recurrent HCV after re-LT. No association was found between the timing of recurrence after the first LT and the timing of recurrence after re-LT; no patients were diagnosed with RCH or AF after re-LT.
It is now estimated that 10–15% of HCV patients will require re-LT within 5–10 yr because of recurrent HCV.2, 7 Recent data have shown that re-LT for recurrent HCV carries significant mortality and morbidity.25 It is perceived that patients requiring re-LT due to RCH or AF shortly after LT are not good candidates for re-LT as they are presumed to be at risk for developing a similar pattern of aggressive recurrence after re-LT. Scant data exist regarding predictive factors for survival after re-LT for recurrent HCV and the histological progression of re-recurrent HCV infection after re-LT.
The current study, looking at outcomes of HCV patients after re-LT due to recurrent HCV, found similar results to previous reports,9, 19–25 in that the rate of early mortality among these patients is extremely high. Thirty-one patients (66%) died after re-LT, 17/31 (55%) of them within the first 3 months (Table 1). As expected, MELD score among all nonsurvivors was higher. High mortality rates early after re-LT in HCV patients have been shown by several groups.21–25 We found that cirrhosis, as a pre-re-LT diagnosis, was associated with an increased rate of mortality after re-LT (risk ratio = 2.4) compared to the mortality rate of patients retransplanted due to AF or RCH. A possible explanation for this is that patients with a more slowly progressing disease may eventually suffer more complications related to portal hypertension, cirrhosis itself, side effects of immunosuppressive therapy, significant muscle wasting, and a higher incidence of renal failure compared to those patients requiring re-LT more acutely for AF or RCH.17 We observed that the median time interval between primary LT to re-LT in cirrhotic patients was longer, 3.0 yr, compared to patients with AF or RCH, 1.4 yr. Interestingly, MELD score was similar in cirrhotic and AF/RCH patients. Some of these factors may not be directly reflected by the MELD score; therefore, alternate ways of prioritizing HCV re-LT candidates should be considered.
In addition, there was a high rate of HCV histological recurrence in the early postoperative period; 51% of patients experienced HCV recurrence during the first 3 months after re-LT. Early recurrence after initial LT previously has been shown to play a significant role in predicting patient outcome. Testa and colleagues demonstrated that 76% of patients who had progressed to cirrhosis after their first LT had experienced recurrence within the first 12 months.8 Although we failed to show an association between the initial time of recurrence and patient outcome, we showed that recurrence alone is a powerful independent risk factor for increasing the chance of mortality, 3.3-fold compared to patients without recurrence following re-LT. It is possible that with a longer period of follow-up, early histological recurrence will be shown to result in a higher rate of allograft failure. Therefore, we cannot ignore the significant role of recurrence in determining the prognosis after re-LT. Not performing protocol liver biopsies for detecting histological recurrence was a limitation in our study. However, the majority of the study patients indeed experienced early recurrence after re-LT (biochemical and histological), which makes it unlikely that many cases of earlier subclinical histological recurrence were missed.
The association between high-dose corticosteroid use and recurrent HCV after LT is well established.8, 13 Berenguer et al. reported that the total number of SMD boluses may be related to a more aggressive form of recurrent HCV post-LT.13 Other authors have reported that multiple rejection episodes and the use of OKT3 for steroid-resistant acute cellular rejection are also associated with early and severe histological HCV recurrence.10, 12 In the current study, however, we looked at the influence of the cumulative dose of SMD or OKT3 on the recurrence rate. We found that patients receiving high intravenous SMD doses (>2 g) had a higher rate of early re-recurrence (89%) compared to patients treated with low doses of SMD (44–50%) and those treated with OKT3 (12.5%) (P = 0.03), given a higher death rate without recurrence for the latter two groups. Five out of eight patients who received OKT3 following severe rejection had no clinical recurrence within the first 3 months, and their outcome during the first year was not different from that of other patients. These data should be interpreted cautiously since the five remaining patients received OKT3 soon before or just after the end of 3-month follow-up and were in relatively good health. Looking at our general population of re-LT HCV patients, 75–100% of them will die and/or experience recurrence within a year, regardless of immunosuppression protocol.
Re-LT in this era of increasing shortage of donor organs is a very controversial issue.20, 28 Although late re-LT for any indication carries increased morbidity and mortality, patients with HCV being retransplanted appear to have an even higher mortality rate.29, 30 Experience from several centers, including our own, shows 6- to 12-month mortality rates of 30–50%.25, 31, 32 More recently, HCV patients have been shown to have a higher rate of mortality after initial LT compared to other groups.6, 18 In the same study, a strong association was found between decreased patient and graft survival with older donor age. Our study confirmed these findings after re-LT by showing that using donor allografts >60 yr old increased the mortality risk 3.6 times compared to allografts <60 yr old, adjusting for other factors (Table 3). Because of the poor overall survival in patients undergoing re-LT for recurrent HCV noted in this and previous studies, our institution no longer utilizes donor allografts age >50 in this specific patient population. This is logistically difficult, however, because these patients are not prioritized via the current MELD allocation system and thus may not be able to receive more favorable donor grafts in a timely fashion.29, 33, 34 As patients developing cirrhosis from HCV recurrence have an extremely rapid rate of decompensation,4 which contributes to their high peri-retransplantation morbidity and mortality, a special variance within the current MELD system should be considered.
An important finding of our analysis is that there was no significant influence of the severity and pattern of HCV infection after primary LT on the course of reinfection after re-LT. Patients with rapid and aggressive forms of HCV recurrence, such as RCH and AF, are often denied re-LT because of the expectation that a similar course will occur after re-LT.22 Our findings differ from those of Berenguer et al.,6 possibly because a large number of the retransplanted patients in our study died within 6 months of surgery and, if they had survived longer, a similar type of re-recurrence may have developed. However, we studied a much larger number of patients than Berenguer et al. (n = 12) and feel that this is a more likely explanation for the disparate results between the two studies. Based on our findings, patients with RCH or AF should not be denied the option of re-LT as it appears they will not develop a similar, rapidly progressive course after re-LT; in fact, these patients appeared to fare better than patients being retransplanted for recurrent cirrhosis.
In conclusion, re-LT for HCV patients with graft failure carries a high rate of mortality, which mainly occurs during the first 3 months. Histological recurrence occurs frequently early after re-LT, and those who experience recurrence have an increased chance of mortality. These data should be considered when evaluating an HCV patient for re-LT. Patients with cirrhosis due to recurrent HCV may need to be considered for re-LT earlier, and the use of older donors should be avoided. Consideration also should be given as to how to prioritize patients with HCV cirrhosis waiting for re-LT. Patients with more accelerated causes of graft failure, such as AF and RCH, do not appear to suffer a similar course after re-LT and actually appear to have a better short-term survival than patients with cirrhosis. Re-LT should not be withheld from these patients under the presumption that they will lose their second allograft as quickly as the first. The timing of HCV recurrence after an initial LT is not predictive of the timing of viral reinfection after re-LT.