Thomas G. Heffron

Improved results of living-related liver transplantation with routine application in a pediatric program

Living related liver transplantation (LRT) was introduced as a response to the shortage of donor organs that has existed for small children. Results were promising in the initial experience, with a one-year patient survival of 80% and a graft survival of 75%. Since the completion of the protocol, LRT has been considered routinely in the management of children in our center. We present here our experience with 45 consecutive transplants in which LRT accounts for 40% of grafts with an overall patient survival of 90%. Between 4/91 and 4/92, 45 OLT were performed in 41 children. Median age was 2.7 years (3 months to 13 years) and weight was 10.4 kg (3.5-60 kg). Thirty-five were primary grafts, 10 were retransplants. One patient received 2 grafts in the orthotopic auxiliary position. Cholestatic disorders including biliary atresia accounted for 60%, metabolic diseases for 15%. Grafts were obtained from cadaver donors in 27/45 (60%) cases; reduction was required in 12/27 (44%). LRT was performed in 18 cases. Fifty-two percent of recipients of cadaver grafts were UNOS status 4, while 16% of LRT recipients met these criteria. Actual patient survival for cadaver grafts is 21/24 (88%) and graft survival is 20/27 (74%). Patient survival in 18 LRT was 94%. Two grafts were lost to arterial thrombosis for a graft survival of 83%. All donors have been discharged and are well. One patient, a teenager with fulminant hepatitis, was successfully transplanted with a left lobe from his father. This experience demonstrates the programmatic flexibility accorded by use of LRT. Since 40% of grafts were LRT, more livers were available for urgent use for patients who did not have a donor available, as reflected in the 73% incidence of cadaver recipients on status 3 or 4. Therefore, patients are more likely to receive a transplant at the optimal time. We are now prepared to offer LRT for fulminant hepatic failure since the benefit of graft availability appears to outweigh concerns about coerced donation. The successful treatment of a teenaged patient may herald extension of LRT to adults. We conclude that the use of LRT should be expanded.

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

Hepatic artery thrombosis in infants : a comparison of whole livers, reduced-size grafts, and grafts from living-related donors

Hepatic artery thrombosis (HAT) is a major cause of patient morbidity and graft loss in pediatric liver transplantation (OLT). Although some grafts may be salvaged by arterial thrombectomy and reconstruction, many patients require retransplantation. Patient survival is reduced by HAT. It has been suggested that the incidence of HAT may be altered by the use of reduced-size grafts (RSG). We analyzed our series of infants receiving OLT to determine the frequency of HAT in full-size OLT, cadaveric RSG, and living-related RSG. The role of arterial anastomotic technique in the development of HAT was also examined. Between 10/1/84 and 12/7/90 433 liver transplants were performed. During this period 100 patients between 3 months and 2 years of age (mean 13 months) received 134 liver grafts. The mean weight at the time of transplant was 7.9 kg. (range: 1.9-15 kg). Of the 134 grafts, 60 were whole livers, 61 were cadaveric RSGs, and 13 were living-related RSGs. The cadaveric RSGs were 9 right lobe grafts, 21 left lobe grafts, and 31 left lateral segment grafts. Twenty-seven of the cadaveric RSGs were from split livers, while the other 34 were simple reductions. All 13 living-related RSGs were left lateral segments. HAT occurred in 15 of 60 (25%) whole livers, 9 of 61 (15%) cadaveric RSGs, and 3 of 13 (23%) of the living-related-donor RSGs (P = NS). Subdividing the cadaveric RSGs revealed that HAT occurred in 3 of 9 (33%) right lobe grafts, 3 of 21 (14%) left lobe grafts, and 3 of 31 (10%) left lateral segment grafts (P = NS). The site of the arterial anastomosis in the recipient correlated with the incidence of HAT (hepatic artery 21/86 [24%], celiac axis 1/9 [11%], aorta 2/32 [6%], P = 0.06). In conclusion, it appears that use of a cadaveric left lobe or left lateral segment graft and an aortic arterial anastomosis reduces the risk of hepatic artery thrombosis in liver transplant recipients less than 2 years of age.

Biliary complications in pediatric liver transplantation: A comparison of reduced-size and whole grafts

One of the major changes in liver transplantation has been the application of reduced-size liver transplants(RLT). RLT has the great advantage of expanding the donor pool up to ten times the weight of the recipient, thereby decreasing pretransplant mortality in the pediatric age group. It has been suggested that RLT is a risk factor for biliary complications. To analyze the role of RLT and biliary complications, the results of 213 consecutive liver transplants in 164 pediatric patients over a 6-year period will were reviewed. These included 113 whole-liver transplants and 100 reduced-size liver transplants (49 reduced cadaveric liver transplants (RCLT), 38 split-liver transplants (SLT) and 13 living-related liver transplants (LRLT). The average weight and age were significantly higher in recipients receiving whole-size grafts (average weight 18.4 mg, average age 4.9 years) than in those receiving reduced size grafts (average age 2.3 years, average weight 11.1 kg). Biliary reconstruction consisted of Roux-en-Y, cholangiojejunostomy (n = 203) or choledochocholedochostomy (n = 10). There were 29 total biliary complications, (13.6%) with no significant difference in the complication rate between the whole (n = 13, 11.5%) or reduced livers (n = 16, 16%). Biliary leakage was the most common complication (n = 20), and it occurred at the biliary enteric anastomoses (n = 10), the roux limb (n = 7), or at the cut edge (n = 3). Of the leaks occurring at the biliary enteric anastomoses, 50% were caused by hepatic artery thrombosis. Biliary obstruction accounted for their remaining complications (n = 9) or 4.2%. Actuarial survival from 6 years to a minimum of two months of follow-up was 73% in the whole-size and 70% in reduced-size liver transplants. This series demonstrates that the incidence of biliary complications is similar in reduced-size and full-size grafts. No grafts were lost to biliary complications in the absence of hepatic artery thrombosis.

Corticosteroid‐free immunosuppression with daclizumab in HCV+ liver transplant recipients: 1‐year interim results of the HCV‐3 study

This work is a 1‐yr interim analysis of a prospective, randomized, multicenter trial evaluating the effect of corticosteroid‐free immunosuppression on hepatitis C virus–positive (HCV+) liver transplant recipients following liver transplantation (LT). Patients received tacrolimus and corticosteroids (Arm 1; n = 80); tacrolimus, corticosteroids, and mycophenolate mofetil (MMF) (Arm 2; n = 79); or daclizumab induction, tacrolimus, and MMF (Arm 3; n = 153). At 1 yr, 64.1%, 63.4%, and 69.4% of patients achieved the composite primary endpoint of freedom from rejection, freedom from HCV recurrence, and freedom from treatment failure, respectively. Excellent patient and graft survival did not differ significantly among treatment arms. Freedom from HCV recurrence at 1 yr was 61.8 ± 6.2%, 60.1 ± 6.1%, and 67.0 ± 4.3% in Arms 1, 2, and 3, respectively (P = not significant). Freedom from rejection was significantly higher in Arm 3 compared to Arm 1 (93.0 ± 2.2% vs. 81.9 ± 4.4%; P = 0.011). Multivariate analysis identified acute rejection (hazard ratio = 2.692; P = 0.001) and donor age (hazard ratio = 1.015; P = 0.001) as significant risk factors for HCV recurrence. HCV recurrence was not influenced by recipient demographics, HCV genotype, or immunosuppression. In conclusion, these results suggest that a corticosteroid‐free regimen of tacrolimus and MMF following daclizumab induction is safe and effective in HCV+ liver transplant recipients. Liver Transpl 13:1521–1531, 2007.

Orthotopic auxiliary liver transplantation for Crigler-Najjar syndrome type 1

Some diseases that result from inborn errors of critical metabolic or synthetic processes mainly involving the liver do not cause structural liver damage. These disorders can be treated by the addition of liver tissue (auxiliary liver transplantation) rather than liver replacement. We report correction of the metabolic error in a 13-year-old girl with Crigler-Najjar syndrome type 1 by auxiliary (left lateral segment) transplantation. The first graft failed and was replaced successfully. The second graft shows features of chronic rejection, but at 2 years postoperatively bilirubin conjugating ability has not been impaired. Another graft may become necessary in due course.

INTERFERON-?? AND RIBAVIRIN FOR THE TREATMENT OF RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION1

BACKGROUND Initial studies utilizing interferon-alpha and ribavirin for the treatment of recurrent hepatitis C virus (HCV) infection after liver transplantation showed promising results. Here we report our single-center experience using this combination therapy. METHODS Liver transplant recipients with recurrent HCV (elevated serum aminotransferases, positive serum HCV RNA, and biopsy-proven hepatitis without rejection) received interferon-alpha (1.5-3 million units subcutaneously three times a week) and ribavirin (400-1000 mg p.o. daily) for 12 months or more. Serum aminotransferases, HCV RNA, and severity of hepatitis were followed. RESULTS Thirty-two patients have been treated for at least 3 months, including 13 who have been on 12 or more months of therapy. Three died from allograft failure due to recurrent HCV. Dose reductions of interferon-alpha and/or ribavirin occurred in 22 patients. Thirteen had their medications permanently discontinued for severe adverse effects. Twenty-six patients (81%) had a biochemical response (BR; normalization of serum aminotransferases) after 3 months. End-of-treatment and sustained BR were 77% and 71%, respectively. Mean viral loads decreased 68-77%; however, only three patients became serum HCV RNA negative. After 12 months of therapy, no histological improvement was observed in 11 patients who were biopsied. Patients who received mycophenolate mofetil or daclizumab had a less likelihood of achieving a BR. CONCLUSIONS A significant number of patients did not tolerate interferon-alpha or ribavirin. Although BR was excellent and mean viral loads decreased significantly, virological clearance was poor and no histological improvement was noted. A more efficacious treatment with less adverse effects for recurrent HCV after liver transplantation is needed.

A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C

This randomized, prospective, multicenter trial compared the safety and efficacy of steroid‐free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA–positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid‐free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid‐free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS. Liver Transpl, 2011.

Gadolinium-Enhanced MRI for Tumor Surveillance Before Liver Transplantation: Center-Based Experience

OBJECTIVE The purpose of this study was to evaluate prospectively acquired institutional results to determine the accuracy of gadolinium-enhanced MRI in liver tumor surveillance before transplantation. SUBJECTS AND METHODS One hundred fifteen patients underwent MRI of the abdomen within 90 days before liver transplantation. Images were acquired with gadolinium-enhanced 3D gradient-echo sequences in the arterial, venous, and delayed phases. Detection of hepatocellular carcinoma (HCC) was based on the imaging criteria arterial phase enhancement, delayed phase hypointensity, and development of an enhancing outer margin capsule. Imaging findings were compared with findings at histopathologic evaluation of the explanted liver. RESULTS Thirty-six HCCs in 27 patients were detected at histopathologic evaluation. Patient-based analysis showed the sensitivity of MRI was 88.9% (24/27); specificity, 97.7% (false-positive findings in two patients); and accuracy, 95.7%. MRI depicted 28 of 36 HCCs, resulting in a lesion-based sensitivity of 77.8%. Although all 18 HCCs 2 cm or larger were depicted with MRI, only 10 of 18 HCCs smaller than 2 cm were correctly diagnosed. However, two HCCs measuring smaller than 2 cm at pathologic examination were rated as dysplastic nodules on MRI. CONCLUSION Contrast-enhanced MRI can be used as a primary diagnostic method for accurate detection and characterization of HCC 2 cm or larger as required by the criteria of the Model for End-Stage Liver Disease used by the United Network for Organ Sharing. MRI can be considered a standard tool for surveillance before liver transplantation. Reduction in cost and risk may be derived from the diminished need for other diagnostic imaging studies and biopsy and the avoidance of use of iodinated contrast agents in imaging of patients with cirrhosis, many of whom have impaired renal function.

Pediatric liver transplantation with daclizumab induction therapy

Background. A new class of monoclonal antibodies (non-T–cell depleting) has gained favor for induction therapy after transplantation. This study evaluated the non-T–cell depleting antibody to the CD25 cell, daclizumab, as a single-dose induction agent immediately after pediatric liver transplantation to spare the use of the calcineurin inhibitor, tacrolimus, for 7 days in respect to both efficacy and renal function. Methods. From January 1998 to November 2001, 81 pediatric orthotopic liver transplant recipients receiving 89 liver grafts were evaluated. The treatment arm (n=61) received daclizumab 1 mg/kg immediately after liver transplantation along with mycophenolate, steroids, and, on postoperative day 7, tacrolimus. The control group did not receive induction therapy, whereas tacrolimus, mycophenolate, and steroids were started immediately after surgery. Results. The induction group had fewer patients with rejection within the first 30 days after liver transplantation (9 [14.8%] vs. 10 [50%]; P =0.003). The mean time to first rejection was similar between groups (12.1 [±7.8] days vs. 18.5 [±8.1] days; P =not significant). There was a 3.39 increase in relative risk to develop rejection within the first 30 days after orthotopic liver transplantation if the patient did not receive induction therapy (relative risk=3.39; 95% confidence interval [1.61, 7.14]). Two-year actuarial survival for the induction group was 93.2% compared with 85% in the control; graft survival was also similar between groups (87.8% vs. 72.7%) at 2 years. Conclusion. Daclizumab 1 mg/kg given immediately after pediatric liver transplantation and withholding tacrolimus, is safe, efficacious, and reduces rejections within the first 30 days after surgery.