Leonard I. Goldstein

Analysis of long-term outcomes of 3200 liver transplantations over two decades: A single-center experience

Objective:Few studies have evaluated long-term outcomes after orthotopic liver transplantation (OLT). This work analyzes the experience of nearly 2 decades by the same team in a single center. Outcomes of OLT and factors affecting survival were analyzed. Methods:Retrospective analysis of 3200 consecutive OLTs that were performed at our institution, between February 1984 and December 31, 2001. Results:Of 2662 recipients, 578 (21.7%) and 659 (24.7%) were pediatric and urgent patients, respectively. Overall 1-, 5-, 10-, and 15-year patient and graft survival estimates were 81%, 72%, 68%, 64% and 73%, 64%, 59%, 55%, respectively. Patient survival significantly improved in the second (1992–2001) versus the era I (1984–1991) of transplantation (P < 0.001). Similarly, graft survival was better in the era II of transplantation (P < 0.02). However, biliary and infectious complications increased in era II. When OLT indications were considered, best recipient survival was obtained in children with biliary atresia (82%, 79%, and 78% at 1, 5, and 10 years, respectively), while malignant disease in adult patients resulted in the worst outcomes of 68% and 43% at 1 and 5 years, post-OLT. Further, patients <18 years and nonurgent recipients exhibited superior survival when compared with recipients >18 years (P < 0.001) or urgent patients (P < 0.001). Of 13 donor and recipient variables, era of OLT, recipient age, urgent status, donor age, donor length of hospital stay, etiology of liver disease, retransplantation, warm and cold ischemia, but not graft type (whole, split, living-donor), significantly impacted patient survival. Conclusions:Long-term benefits of OLT are greatest in pediatric and nonurgent patients. Multiple factors involving the recipient, etiology of liver disease, donor characteristics, operative variables, and surgical experience influence long-term survival outcomes. By balancing and matching these factors with a given recipient, optimum results can be achieved.

Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience.

OBJECTIVE The purpose of this study was to analyze a single centers 12-year experience with 127 orthotopic liver transplantations (OLT) for primary sclerosing cholangitis (PSC). SUMMARY BACKGROUND DATA Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown origin that occurs most commonly in young men and is associated frequently (70-80%) with inflammatory bowel disease (IBD). Patients with PSC also are at risk for the development of cholangiocarcinoma (CCA) and those with IBD for colon carcinoma. Although the course of PSC is variable, it frequently is progressive, leading to cirrhosis and requirement for OLT. METHODS The medical records of 127 consecutive patients undergoing OLT for PSC from July 1, 1984, to May 30, 1996, were reviewed. Actuarial patient and graft survival was determined at 1,2, and 5 years. The incidence and outcome of patients with CCA, recurrent sclerosing cholangitis, and post-transplant colon carcinoma was determined. Results were analyzed by way of stepwise Cox regression to determine the statistical strength of independent associations between pretransplant covariates and patient survival. The median follow-up period was 3.01 years. Incidental cholangiocarcinoma (ICCA) was defined as a tumor < 1 cm in size that was discovered at the time of pathologic sectioning of the explanted liver. RESULTS Ninety-two patients (72%) had associated IBD. Seventy-nine (62%) had undergone previous biliary tract surgery. One hundred seven patients (84%) received a single graft, whereas 20 patients (16%) required 22 retransplants. Patients received either cyclosporine- (n = 76) or tacrolimus- (n = 51) based immunosuppression. The 1-, 2-, and 5-year actuarial patient survivals were 90%, 86%, and 85%, respectively, whereas graft survival was 82%, 77%, and 72%, respectively. The presence of previous biliary surgery had no effect on patient survival. Ten patients (8%) had ICCA and their survival was not significantly different from patients without ICCA (100%, 83%, and 83% at 1, 2, and 5 years, respectively). Four patients were known to have CCA at the time of OLT, all recurred within 6 months, and had a significantly worse outcome (p < 0.0001). Recurrent sclerosing cholangitis developed in 11 patients (8.6%). The patient and graft survival in this group was not different from those in whom recurrence did not develop (patient; 100%, 90%, and 90%; graft: 80%, 70%, and 52%). Thirty patients (23%) underwent colectomy after liver transplantation for dysplasia-carcinoma or symptomatic colitis. Of the nine covariates entered into the Cox multivariate regression analysis, only common bile duct frozen section biopsy specimen showing CCA was predictive of a survival disadvantage. CONCLUSIONS Liver transplantation provides excellent patient and graft survival rates for patients affected with PSC independent of pretransplant biliary tract surgery. Incidental cholangiocarcinoma does not affect patient survival significantly. However, known CCA or common duct frozen section biopsy specimen or both showing CCA are associated with poor recipient survival, and OLT should be proscribed in these cases. Recurrent PSC occurs in approximately 9% of cases but does not affect patient survival. Post-transplant colectomy does not affect patient survival adversely.

A 10-year Experience of Liver Transplantation for Hepatitis C: Analysis of Factors Determining Outcome in Over 500 Patients

ObjectiveTo determine the factors affecting the outcome of orthotopic liver transplantation (OLT) for end-stage liver disease caused by hepatitis C virus (HCV) and to identify models that predict patient and graft survival. Summary Background DataThe national epidemic of HCV infection has become the leading cause of hepatic failure that requires OLT. Rapidly increasing demands for OLT and depleted donor organ pools mandate appropriate selection of patients and donors. Such selection should be guided by a better understanding of the factors that influence the outcome of OLT. MethodsThe authors conducted a retrospective review of 510 patients who underwent OLT for HCV during the past decade. Seven donor, 10 recipient, and 2 operative variables that may affect outcome were dichotomized at the median for univariate screening. Factors that achieved a probability value less than 0.2 or that were thought to be relevant were entered into a stepdown Cox proportional hazard regression model. ResultsOverall patient and graft survival rates at 1, 5, and 10 years were 84%, 68%, and 60% and 73%, 56%, and 49%, respectively. Overall median time to HCV recurrence was 34 months after transplantation. Neither HCV recurrence nor HCV-positive donor status significantly decreased patient and graft survival rates by Kaplan-Meier analysis. However, use of HCV-positive donors reduced the median time of recurrence to 22.9 months compared with 35.7 months after transplantation of HCV-negative livers. Stratification of patients into five subgroups, based on time of recurrence, revealed that early HCV recurrence was associated with significantly increased rates of patient death and graft loss. Donor, recipient, and operative variables that may affect OLT outcome were analyzed. On univariate analysis, recipient age, serum creatinine, donor length of hospital stay, donor female gender, United Network for Organ Sharing (UNOS) status of recipient, and presence of hepatocellular cancer affected the outcome of OLT. Elevation of pretransplant HCV RNA was associated with an increased risk of graft loss. Of 15 variables considered by multivariate Cox regression analysis, recipient age, UNOS status, donor gender, and log creatinine were simultaneous significant predictors for patient survival. Simultaneously significant factors for graft failure included log creatinine, log alanine transaminase, log aspartate transaminase, UNOS status, donor gender, and warm ischemia time. These variables were therefore entered into prognostic models for patient and graft survival. ConclusionThe earlier the recurrence of HCV, the greater the impact on patient and graft survival. The use of HCV-positive donors may accelerate HCV recurrence, and they should be used judiciously. Patient survival at the time of transplantation is predicted by donor gender, UNOS status, serum creatinine, and recipient age. Graft survival is affected by donor gender, warm ischemia time, and pretransplant patient condition. The authors’ current survival prognostic models require further multicenter validation.

Biliary strictures complicating liver transplantation. Incidence, pathogenesis, management, and outcome.

Six hundred sixty-six patients received 792 liver transplants between February 1, 1984 and September 30, 1991. Biliary reconstruction was by choledochocholedochostomy (CDCD) with T-tube (n = 509) or Roux-en-Y choledochojejunostomy (CDJ) (n = 283). Twenty-five patients (4%) developed biliary strictures. Anastomotic strictures were more common after CDJ (n = 10, 3.5%) than for CDCD (n = 3, 0.6%). Intrahepatic strictures developed in 12 patients. Six patients had occult hepatic artery thrombosis (HAT). The other six patients received grafts in which cold ischemia time exceeded 12 hours. Anastomotic strictures were successfully managed by percutaneous dilation (PD) in five patients (n = 10), operation in three (n = 6), with retransplantation required in two patients. Intrahepatic strictures were managed by PD in seven, retransplantation in one, and expectantly in four patients. Of 25 patients, 19 (76%) are alive with good graft function. In three of six deaths, the biliary stricture was a significant factor to the development of sepsis and allograft failure. The authors conclude that (1) anastomotic strictures are rare after LT; (2) the development of biliary strictures may signify occult HAT; (3) PD is effective for most strictures; and (4) extended cold graft ischemia (less than 12 hours) may be injurious to the biliary epithelium, resulting in intrahepatic stricture formation.

The first 100 liver transplants at UCLA

A clinical program in liver transplantation was begun at UCLA in 1984 after a period of laboratory investigation. The first 100 orthotopic liver transplants (OLT) were performed in 83 patients (43 adults and 40 children) between February 1, 1984 and November 1, 1986. Donors and recipients were matched only for size and ABO blood group compatibility, with OLT performed across blood groups in 28 patients. Standard operative techniques were used, including venous-venous bypass in adults. Arterial reconstruction was performed using an aortic Carrel patch or “branch patch” in 65% of cases and by end-to-end or aortic conduit techniques in the remainder. The hepatic artery thrombosis rate was 5%. Biliary reconstruction was choledochocholedochostomy in 67 OLT and Roux-en-Y choledochojejunostomy in 33 (complication rate of 24% and 24%, respectively). Average lengths and ranges of donor liver ischemia, operating time, and blood replacement were 4 hours (range: 1–10 hours), 7.6 hours (range: 4–15 hours), and 17 units packed cells (range: 2–220 units). Immunosuppressive regimen was cyclosporine-steroid combination, with monoclonal anti-T-cell antibody (OKT3) used for refractory rejection. All patients had one or more complications: pulmonary (78%), infectious (51%), renal dialysis (25%), neurologic (22%). All patients had at least one episode of acute rejection, and 3.6% had chronic rejection. Retransplantation was needed in nine patients once and in four patients twice. The overall retransplant survival rate was 54%, and two of four patients who received a second retransplant are alive. Sixty-three of the 83 patients (76%) are alive (adults 72%, children 80%). The 1-and 2-year actuarial survival rate is 73% (adults 68%, children 78%). Thirty-eight of 43 patients (88%) who had transplantation in the past year are alive. Of 14 perioperative variables assessed as predictors of early mortality, only postoperative dialysis (p < 0.0005) and presence of severe rejection (p < 0.01) had statistical significance. Seventy per cent of adults returned to work, and 84% of children had normal or accelerated growth. A new program in liver transplantation provides a dramatic option in patient care and an academic stimulus to the entire medical center.

Orthotopic liver transplantation for hepatitis C : Outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center experience

OBJECTIVE To determine the outcome of orthotopic liver transplantation (OLT) for end-stage liver disease caused by hepatitis C virus (HCV). SUMMARY BACKGROUND DATA HCV has become the leading cause of cirrhosis and hepatic failure leading to OLT. Recurrent HCV after OLT is associated with significant complications and may lead to graft loss that requires retransplantation (re-OLT). The authors studied the outcome of transplantation for HCV, the effect of primary immunotherapy, and causes of retransplantation. METHODS The authors conducted a retrospective review of their experience during an 8-year period (1990-1997), during which 374 patients underwent transplants for HCV (298 [79.6%] received one OLT; 76 [20.4%] required re-OLT). Median follow-up was 2 years (range 0 to 8.3). Immunosuppression was based on cyclosporine in 190 patients and tacrolimus in 132 patients. In a third group of patients, therapy was switched from cyclosporine to tacrolimus or from tacrolimus to cyclosporine (cyclosporine/tacrolimus group). RESULTS Overall, 1-, 2-, and 5-year actuarial patient survival rates were 86%, 82%, and 76%, respectively. The 2-year patient survival rate was 81 % in the cyclosporine group, 85% in the tacrolimus group, and 82% in the cyclosporine/tacrolimus group. In patients receiving one OLT, overall 1-, 2-, and 5-year patient survival rates were 85%, 81%, and 75%, respectively. The 2-year patient survival rate was 79% in the cyclosporine group, 84% in the tacrolimus group, and 80% in the cyclosporine/tacrolimus group. The overall graft survival rates were 70%, 65%, and 60% at 1, 2, and 5 years, respectively. The graft survival rate at 2 years was similar under cyclosporine (68.5%), tacrolimus (64%), or cyclosporine/tacrolimus (60%) therapy. Re-OLT was required in 42 (11.2%) patients for graft dysfunction in the initial 30 days after OLT. Other causes for re-OLT included hepatic artery thrombosis in 10 (2.6%), chronic rejection in 8 (2.1%), and recurrent HCV in 13 (3.4%) patients. The overall survival rates after re-OLT were 63% and 58% at 1 and 2 years. The 1-year survival rate after re-OLT was 61 % for graft dysfunction, 50% for chronic rejection, 60% for hepatic artery thrombosis, and 60% for recurrent HCV. At re-OLT, 85.3% of the patients were critically ill (United Network for Organ Sharing [UNOS] status 1); only 14.7% of the patients were UNOS status 2 and 3. In re-OLT for chronic rejection and recurrent HCV, the 1-year survival rate of UNOS 1 patients was 38.4%, compared with 87.5% for UNOS 2 and 3 patients. In patients requiring re-OLT, there was no difference in the 1-year patient survival rate after re-OLT when cyclosporine (60%), tacrolimus (63%), or cyclosporine/tacrolimus (56%) was used for primary therapy. With cyclosporine, three patients (1.5%) required re-OLT for chronic rejection versus one patient (0.7%) with tacrolimus. Re-OLT for recurrent HCV was required in four (3%) and seven (3.6%) patients with tacrolimus and cyclosporine therapy, respectively. CONCLUSIONS Orthotopic liver transplantation for HCV is performed with excellent results. There are no distinct advantages to the use of cyclosporine versus tacrolimus immunosuppression when patient and graft survival are considered. Re-OLT is an important option in the treatment of recurrent HCV and should be performed early in the course of recurrent disease. Survival after re-OLT is not distinctively affected by cyclosporine or tacrolimus primary immunotherapy. The incidence of re-OLT for recurrent HCV or chronic rejection is low after either tacrolimus or cyclosporine therapy.

Pretransplant Model to Predict Posttransplant Survival in Liver Transplant Patients

ObjectiveTo develop a prognostic model that determines patient survival outcomes after orthotopic liver transplantation (OLT) using readily available pretransplant variables. Summary Background DataThe current liver organ allocation system strongly favors organ distribution to critically ill recipients who exhibit poor survival outcomes following OLT. A severely limited organ resource, increasing waiting list deaths, and rising numbers of critically ill recipients mandate an organ allocation system that balances disease severity with survival outcomes. Such goals can be realized only through the development of prognostic models that predict survival following OLT. MethodsVariables that may affect patient survival following OLT were analyzed in hepatitis C (HCV) recipients at the authors’ center, since HCV is the most common indication for OLT. The resulting patient survival model was examined and refined in HCV and non-HCV patients in the United Network for Organ Sharing (UNOS) database. Kaplan-Meier methods, univariate comparisons, and multivariate Cox proportional hazard regression were employed for analyses. ResultsVariables identified by multivariate analysis as independent predictors for patient survival following primary transplantation of adult HCV recipients in the last 10 years at the authors’ center were entered into a prognostic survival model to predict patient survival. Accordingly, mortality was predicted by 0.0293 (recipient age) + 1.085 (log10 recipient creatinine) + 0.289 (donor female gender) + 0.675 urgent UNOS - 1.612 (log10 recipient creatinine times urgent UNOS). The above variables, in addition to donor age, total bilirubin, prothrombin time (PT), retransplantation, and warm and cold ischemia times, were applied to the UNOS database. Of the 46,942 patients transplanted over the last 10 years, 25,772 patients had complete data sets. An eight-factor model that accurately predicted survival was derived. Accordingly, the mortality index posttransplantation = 0.0084 donor age + 0.019 recipient age + 0.816 log creatinine + 0.0044 warm ischemia (in minutes) + 0.659 (if second transplant) + 0.10 log bilirubin + 0.0087 PT + 0.01 cold ischemia (in hours). Thus, this model is applicable to first or second liver transplants. Patient survival rates based on model-predicted risk scores for death and observed posttransplant survival rates were similar. Additionally, the model accurately predicted survival outcomes for HCV and non-HCV patients. ConclusionsPosttransplant patient survival can be accurately predicted based on eight straightforward factors. The balanced application of a model for liver transplant survival estimate, in addition to disease severity, as estimated by the model for end-stage liver disease, would markedly improve survival outcomes and maximize patients’ benefits following OLT.

Liver Transplantation for Fulminant Hepatic Failure: Experience With More Than 200 Patients Over a 17-Year Period

ObjectiveTo analyze outcomes after liver transplantation (LT) in patients with fulminant hepatic failure (FHF) with emphasis on pretransplant variables that can potentially help predict posttransplant outcome. Summary Background DataFHF is a formidable clinical problem associated with a high mortality rate. While LT is the treatment of choice for irreversible FHF, few investigations have examined pretransplant variables that can potentially predict outcome after LT. MethodsA retrospective review was undertaken of all patients undergoing LT for FHF at a single transplant center. The median follow-up was 41 months. Thirty-five variables were analyzed by univariate and multivariate analysis to determine their impact on patient and graft survival. ResultsTwo hundred four patients (60% female, median age 20.2 years) required urgent LT for FHF. Before LT, the majority of patients were comatose (76%), on hemodialysis (16%), and ICU-bound. The 1- and 5-year survival rates were 73% and 67% (patient) and 63% and 57% (graft). The primary cause of patient death was sepsis, and the primary cause of graft failure was primary graft nonfunction. Univariate analysis of pre-LT variables revealed that 19 variables predicted survival. From these results, multivariate analysis determined that the serum creatinine was the single most important prognosticator of patient survival. ConclusionsThis study, representing one of the largest published series on LT for FHF, demonstrates a long-term survival of nearly 70% and develops a clinically applicable and readily measurable set of pretransplant factors that determine posttransplant outcome.

Adjuvant chemotherapy improves survival after liver transplantation for hepatocellular carcinoma

ObjectiveThe aim of this study was to evaluate the effect of postoperative adjuvant chemotherapy on the recurrence rate and survival of patients after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). Summary Background DataHistorically, liver transplantation for HCC has yielded poor long-term survival. Multimodality therapy has been initiated in an effort to improve survival statistics. MethodsTwenty-five patients were placed on 6 months of intravenous fluorouracil, doxorubicin, and cisplatin after OLT. Risk factors, recurrence rates, and survival rates were analyzed and compared with historic controls. ResultsOverall long-term survival in the protocol patients was 46% at 3 years, improved over our historic controls of 5.8% at 3 years (p = 0.0001). Overall recurrence rate was 20% (n = 4). Possible risk factors, such as tumor size, vascular invasion, multifocality, capsular invasion, and tumor differentiation, were not found to be significantly predictive of survival. Three patients with long-term, disease-free survival had tumors > 5 cm. Side effects from chemotherapy were common, but rarely severe. ConclusionsThis study suggests that adjuvant chemotherapy after transplantation for HCC can provide long-term cure and may improve survival, even in patients with stage III and IV disease.

Association of primary sclerosing cholangitis with HLA-DRw52a

We sought to determine whether there are specific HLA haplotypes in patients with either primary sclerosing cholangitis or primary biliary cirrhosis. Surprisingly, 100 percent of the 29 patients with primary sclerosing cholangitis had the HLA-DRw52a antigen, which is normally present in 35 percent of the population (relative risk, 109.5; P less than 0.00001). Fifteen of these patients had a single common haplotype: A1,B8,Cw7,DRw17,DQw2,DRw52a. In the remaining 17 patients there was a loss of at least one of these antigens. Of the 15 patients with the common haplotype, 12 also had ulcerative colitis, thereby linking the occurrence of ulcerative colitis in patients with primary sclerosing cholangitis to the presence of this haplotype. Although there was no association in 35 patients between primary biliary cirrhosis and specific HLA haplotypes, there was a significant association of the disease with DRw8 (relative risk, 3.1; P = 0.02). We conclude that the development of primary sclerosing cholangitis involves a strong genetic predisposition. Since the association of primary sclerosing cholangitis with HLA-DRw52a appears to be total, HLA typing should be helpful in differentiating this disease from primary biliary cirrhosis.