Christopher R. Shackleton

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.

Long-term results of pediatric liver transplantation: an analysis of 569 transplants.

OBJECTIVE To analyze a single centers 13-year experience with 569 pediatric orthotopic liver transplants for end-stage liver disease. SUMMARY BACKGROUND DATA Despite advances in medical therapy, liver replacement continues to be the only definitive mode of therapy for children with end-stage liver disease. Innovative surgical techniques and improved immunosuppression have broadened the application of liver replacement for affected children. However, liver transplantation in the child remains challenging because of the scarcity of donor organs, complex surgical technical demands, and the necessity to prevent long-term complications. METHODS The medical records of 440 consecutive patients younger than 18 years of age undergoing orthotopic liver transplantation for end-stage liver disease from March 20, 1984, to November 15, 1997, were reviewed. Results were analyzed using Cox multivariate regression analysis to determine the statistical strength of independent associations between pretransplant covariates and patient and graft survival. Actuarial patient and graft survival rates were determined at 1, 3, 5, and 10 years. The type and incidence of posttransplant complications were determined, as was the quality of long-term allograft function. The median follow-up period was 4.1 years. RESULTS Biliary atresia was the most common cause (50.4%) of endstage liver disease in this patient population. The median recipient age was 2.4 years; 239 patients (54%) were younger than 3 years of age and 1 11 patients (25%) were younger than 1 year of age. There were 471 whole organs, 29 were ex vivo reduced size, 33 were living-related donor, and 36 were in situ split-liver allografts. Three hundred forty-three (78%) patients underwent a single allograft, whereas 97 patients required retransplantation; hepatic artery thrombosis was the most common indication for retransplantation (55 patients). The 1-, 3-, 5-, and 10-year actuarial patient survival rates were 82%, 80%, 78%, and 76%, respectively; allograft survival rates were 68%, 63%, 60%, and 54%. Long-term liver function remains excellent: current median follow-up values for total bilirubin and aspartate aminotransferase were 0.5 mg/dl and 54 IU/L, respectively. Cox multivariate regression analysis demonstrated that pretransplant patient age, the era of transplantation, and the number of allografts performed significantly and independently predicted patient survival rates, whereas allograft type and pretransplant diagnosis did not. CONCLUSIONS Liver transplantation in the pediatric patient is a durable procedure that provides excellent long-term survival. Although there have been overall improvements in patient outcome with increased experience, the effect is most pronounced for patients younger than 1 year of age. Retransplantation, although effective in a meaningful number of patients, continues to carry a progressive decrement in survival with the number of allografts performed. Use of living-related and in situ split-liver allografts has dramatically reduced waiting times for small children and has improved patient survival.

Indocyanine green clearance as a predictor of successful hepatic resection in cirrhotic patients.

Twenty-two cirrhotic patients who underwent hepatic resection from July 1989 to March 1991 at Vancouver General Hospital were analyzed prospectively in order to determine whether there was any preoperative evaluation of liver function that would help identify those patients who would not survive hepatic resection. Patients were analyzed on the basis of age, type of resection, and a variety of so-called standard liver function tests. In addition, all patients were evaluated preoperatively with an indocyanine green (ICG) clearance test, a relatively new test that we attempted to evaluate in terms of its role in hepatic resection in cirrhotic patients. Parametric statistical evaluation used included Students t-test and multivariate regression, as well as discriminate analysis. The nonparametric evaluation used was the Wilcoxon rank sum test. Overall, the 30-day mortality rate was 18%, with those patients who did not survive resection having a significantly lower ICG clearance than those who underwent successful resection (p less than 0.0001). No other liver function test was useful in determining the outcome of resection. Similarly, neither age nor type of resection appeared to influence outcome. Use of discriminate analysis (p = 0.0029) allowed the identification of a cutoff point for ICG clearance below which hepatic resection should not be attempted.

In situ splitting of the cadaveric liver for transplantation

BACKGROUND The shortage of cadaveric donor livers is the rate-limiting step in clinical liver transplantation. Split liver transplantation provides a means to expand the cadaveric donor pool. However, this concept has not reached its full potential because of inferior patient and graft survival and high complication rates when traditional ex vivo split techniques are used. Therefore we sought to evaluate the safety, applicability, and effectiveness of a new technique for split liver transplantation. METHODS This study consists of 15 in situ split liver procurements, which resulted in 28 liver transplants. In situ splitting of selected livers from hemodynamically stable cadaveric donors was performed at the donor hospital without any additional work-up or equipment being needed. In situ liver splitting is accomplished in a manner identical to the living-donor procurement. This technique for liver splitting results in a left lateral segment graft (segments 2 and 3) and a right trisegmental graft (segments 1 and 4-8). This procedure required the use of the donor hospital operating room for an additional 1.5-2.5 hr and did not interfere with the procurement of 30 kidneys, 12 hearts, 7 lungs, and 9 pancreata from these same donors. RESULTS The 6-month and 1-year actuarial patient survival rates were 92% and 92%, respectively, while the 6-month and 1-year actuarial graft survival rates were 86% and 86%, respectively. The 6-month and 1-year actuarial patient survival rate of patients who received a left lateral segment graft was 100% and 100%, respectively, while those who received a right trisegmental graft had 6-month and 1-year rates of 86% and 86%, respectively. The actuarial death-censored graft survival rates at 6 months and 1 year were 80% and 80%, respectively, for the left lateral segment grafts, and 93% and 93%, respectively, for the right trisegmental grafts. Alograft and patient survival was independent of United Network for Organ Sharing status at the time of liver transplantation. No patient developed a biliary stricture, required re-exploration for intra-abdominal hemorrhage, or suffered from portal vein, hepatic vein, or hepatic artery thrombosis CONCLUSIONS In situ split liver transplantation can be accomplished without complications and provides results that are superior to those obtained previously with ex vivo methods. It abolishes ex vivo benching and prolonged ischemia times and provides two optimal grafts with hemostasis accomplished. This technique decreases pediatric waiting time and allows adult recipients to receive right-sided grafts safely. In situ splitting is the method of choice for expanding the cadaveric liver donor pool.

Correlation between donor age and the pattern of liver graft recovery after transplantation

We have observed an increased rate of delayed non-function (DNF) of liver grafts procured from older donors. The aim of this study was to correlate donor age and the patterns of graft failure after transplantation. Pattern of liver injury, synthetic function, and graft survival in recipients receiving liver grafts from donor older than age 50 (group I, n=95) were compared with matched cohort of recipients transplanted with grafts from donors age 20–30 (group III, n=50). Primary nonfunction (PNF) of the graft was defined as non-recoverable hepatocellular function necessitating emergency retransplantation within 72 hr. DNF was defined as marginal graft function necessitating re-transplantation within one month. Recipient characteristics, including age and preoperative UNOS status, were similar between groups. Ischemic/reperfusion injury, reflected by SGOT and SGPT was more severe in older donors. PNF occurred at similar frequencies for all groups (7%). Normal liver function was regained in 76% of recipients in group I, and in 92% in group II. However, cholestatic pattern was observed in recipient of grafts from group I donors. Rapid rise in bilirubin, despite normalization of prothrombin time and liver transaminases, was the hallmark of DNF. DNF resulted in higher retransplantation rate in group I (24% vs. 8% in group II). Donor age did not affect patient survival. Liberalizing criteria for donor selection, and acceptance of older donors is a calculated risk. Over 75% of the recipients will regain normal liver function. However, a higher number of these grafts will exhibit slow recovery after transplantation, and a significant rate of DNF. Recognition of such

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.

One thousand liver transplants. The lessons learned.

ObjectiveTo evaluate the first 1000 liver transplants performed at UCLA Medical Center to determine factors responsible for improved results. Summary Background DataSummary Background Data transplant has evolved impressively since the first case was performed in 1963. The 1980s have highlighted this progress with the development of better organ preservation, standardization of operative procedure, improved immunosuppressive agents, and better understanding of patient selection. MethodsThe first 100 consecutive liver transplants (group 1) performed from February 1984 through October 1986 were compared with the last 200 (group 2) performed between September 1991 and June 1992. An analysis was made of donor use; changes in patient candidacy; patient care variables; morbidity and mortality; survival data; and hospital resource use. ResultsResults group 1,31 % of donors were refused because of medical unsuitability compared with 4% in group 2 (p <0.0001). in group 1, alcoholic patients comprised 1% of liver transplant candidates compared with 20% group 2 (p < 0.0001). High-risk patients (United Network for Organ Sharing criteria 4) only comprised 11 % of patients in group 1 compared with 37% in group 2 (p < 0.0001). Operative time (7.6 hours compared with 5.4 hours), packed cell replacement (17 units compared with 9.5 units), intensive care unit stay (10 days compared with 5 days), and hospital stay (50 days compared with 31 days) were all significantly improved (p < 0.05). In group 1, the 1-year survival rate was 73% and improved to 88% in group 2 (p < 0.0001). ConclusionsConclusions unfavorable donor characteristics (obesity, cause of death, age, hypotension), most organs function well and should not be refused based on history alone. The older and high-risk patient (renal failure, ventilator dependence, portal vein pathology, and so on) is routinely transplanted with good success. Despite liberalization of both donor and recipient criteria patient survival after liver transplant is improved, use of hospital resourances is maximized, and cost reduction is achieved.

Hyperlipidemia after liver transplantation : Natural history and treatment with the hydroxy-methylglutaryl-coenzyme A reductase inhibitor pravastatin

This study was designed to determine the frequency of hyperlipidemia after orthotopic liver transplantation and whether treatment with a hydroxy-methylglutaryl coenzyme A reductase inhibitor was safe and efficacious. Cholesterol levels were assessed in 45 consecutive adult liver transplants (mean +/- SE). Four of 22 patients on cyclosporine (CsA) (18%) and three of 23 patients on FK506 (13%) had levels >225 mg/dl at 12 months (cholesterol levels for patients on CsA [total n=22]: pre-Tx = 140+/-11, 1 month = 183+/-36,3 months = 221+/-12, 6 months = 211+/-11, 12 months = 202+/-14 [P<0.01 vs. pre-Tx]; FK506 [total n=23]: Pre-Tx = 151+/-13, 1 month = 187+/-22, 3 months = 188+/-10, 6 months = 184+/-13, 12 months = 164+/-9 [P=0.02 vs. CsA]). A separate cohort of patients with stable graft function, cholesterol >225 mg/dl, and two additional risk factors for coronary artery disease were started on pravastatin. Ninety-eight patients were enrolled. Sixteen patients (16%) discontinued the drug because of subjective complaints. No episodes of rhabdomyolysis or hepatotoxicity occurred (cholesterol levels for patients on CsA [total n=65]: pretreatment = 251+/-7, 6 months = 220+/-7 [P=0.01 vs. pretreatment], 12 months = 224+/-8 [P=0.01 vs. pretreatment]; FK506 [total n=17]: pretreatment = 251+/-17, 6 months = 219+/-17, 12 months = 208+/-17 [P=0.08 vs. pretreatment]). Natural killer cells isolated from normal volunteers (n=14) exhibited 27+/-9% specific lysis. Patients on FK506 or cyclosporine-based immunosuppression alone (n=11) exhibited 20+/-4% specific lysis. Standard immunosuppression plus pravastatin (n=10) decreased lysis to 0.2+/-10% (P<0.02 vs. controls and standard immunosuppression). We conclude: (1) posttransplant hyperlipidemia occurs less frequently in liver transplant patients than in renal or cardiac transplants; (2) pravastatin is safe and efficacious for cholesterol reduction in liver transplant patients; and (3) pravastatin coadministered with standard immunosuppression reduces natural killer cell-specific lysis in these recipients.

Significance of early aminotransferase elevation after liver transplantation

BACKGROUND We retrospectively reviewed 213 consecutive patients who received their first liver allograft between January 1 and December 31, 1993, in order to study the impact of ischemia/preservation/reperfusion injury (IPRI) on patient and graft outcome. METHODS The extent of IPRI was assessed by the peak value of aspartate aminotransferase (ASTmax) observed within the first 72 hr after transplant. For the purpose of univariate analysis, categorical classification of recipients was done based upon ASTmax as follows: group 1, ASTmax<600 U/L (n=46); group 2, ASTmax=600-2000 U/L (n=97); group 3, ASTmax>2000-5000 U/L (n=50), and group 4, ASTmax>5000 U/L (n=17). For multivariate analysis, stepwise Cox regression was performed with age, ASTmax, and United Network for Organ Sharing (UNOS) status as covariates. RESULTS Groups were comparable with respect to age, UNOS status at the time of transplantation, and diagnostic case mix. Median follow-up was 644 days. The overall incidence of primary graft nonfunction (PNF) was 7.6%. PNF incidence was significantly correlated with the severity of IPRI (0%, 4%, 10%, and 41% for groups 1 to 4, respectively, P < 0.0001), but this impact was confined to the respective rates of retransplantation as early patient survival was unaffected. The 1-year survival of patients whose initial grafts manifested extreme IPRI (group 4) was significantly inferior to recipients in the three other groups (77%, 71%, 73%, and 52% for groups 1 to 4, respectively, P=0.03). This increased mortality was confined to patients who never achieved discharge from their initial hospitalization, with no significant differences between groups being detected in the survival of those patients who were discharged (84%, 80%, 85%, and 81% for groups 1 to 4, respectively, P=NS). Although overall 1-year graft survival was strongly correlated with the extent of IPRI (77%, 67%, 62%, and 41% for groups 1 to 4, respectively, P=0.001), this correlation was abolished when survival of grafts not lost to PNF was examined at 1 and 2 years. Stepwise Cox regression analysis confirmed the independent association between ASTmax and patient and graft survival. The long-term quality of allograft function as well as the incidence of chronic rejection and biliary complications were unrelated to the extent of IPRI. CONCLUSIONS We conclude that: (1) patient survival is influenced by IPRI only when it is extreme (ASTmax>5000 U/L), provided parameters of graft function are used in conjunction with aminotransferase values to assess the need for prompt retransplantation; (2) short-term graft survival is proportional to the extent of IPRI, but grafts that are not lost to PNF have equivalent 1- and 2-year survival irrespective of the magnitude of IPRI; (3) 40% of grafts with extreme IPRI are lost to PNF, but the same proportion also provide long-term function; and (4) for surviving grafts, long-term biochemical function as well as the incidence of biliary complications and of chronic rejection are unrelated to the extent of IPRI.

Graft loss following liver transplantation in patients with chronic hepatitis C

Liver disease due to hepatitis C (HCV) is an increasingly frequent indication for orthotopic liver transplantation (OLT). The aim of the current study was to analyze the causes of graft loss following OLT for chronic hepatitis C and the longterm outcome following retransplantation in a large university program. Between January 1990 and December 1995, 1183 patients underwent primary OLT at our center. In 304 patients, HCV was diagnosed by seropositivity and/or polymerase chain reaction. Fifty-six (18.4%) of these patients underwent retransplantation. The 36 patients retransplanted for primary non-function were excluded from further analysis. The other indications for regrafting (>30 days following primary transplant) included hepatic artery thrombosis (5), chronic rejection (4), severe HCV recurrence (5), and other etiologies (6). The cumulative survival rates for the 248 patients who received 1 OLT (group 1) were 84% after one year and 75% after three years. The corresponding rates for the 20 non-PNF patients who were retransplanted (group 2) were 60% and 43%, respectively (P<.0001). Moreover, logistic regression analysis confirmed that patients in group 2 were more than 4 times likely to die than patients in group 1 (P<.0034; risk ratio, 4.2; 95% confidence interval 1.61 to 11.37). Patients undergoing retransplantation had a high incidence of serious infectious complications leading to mortality. Two additional patients with severe recurrent HCV died awaiting liver retransplantation. Eight of the 304 total patients (2.6%) transplanted for chronic HCV developed graft failure secondary to HCV recurrence and 6 of the 8 were retransplanted; 3 of the 6 patients retransplanted are alive without evidence of histologic recurrence (mean follow-up less than 1 year). In summary, despite the high frequency of recurrent histologic evidence of HCV following primary OLT (70% at 3 years), graft loss attributable solely to HCV is an infrequent finding. Retransplantation per se is a risk factor for a fatal outcome, and the indication for reOLT does not appear to impact ultimate outcome. Serious infectious complications were the leading cause of mortality in patients retransplanted. Furthermore, given the indolent natural history of HCV, longer follow-up is necessary to determine the ultimate rate of graft loss due to HCV recurrence.