Experience with sirolimus (SRL)-based immunosuppression following orthotopic liver transplantation (OLT) is rapidly accumulating. In combination with calcineurin inhibitors (CNIs), SRL may reduce the incidence of acute rejection and lower overall required drug levels. This study sought to quantify long-term outcome following OLT in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC) who were treated with an SRL-based regimen as a primary therapy. From January 2000 to June 2007, 97 patients underwent OLT for end-stage liver disease and HCC at the University of Colorado Health Sciences Center. Of those, 45 patients received SRL, in addition to CNIs, as a component of their primary immunosuppression regimen post-OLT. Conversely, 52 patients received the standard immunosuppression regimen including CNIs, mycophenolate mofetil, and corticosteroids. The 2 treatment groups were compared with respect to the following variables: age, gender, tumor stage by explant, grade, size, presence of vascular invasion, focality, Child's class, baseline creatinine, and warm and cold ischemic times. The 2 groups were comparable by all factors save for cold ischemic time, which was significantly longer in the CNI-treated group. Overall survival at 1 and 5 years post-OLT for patients treated with SRL was 95.5% and 78.8%, respectively. Conversely, survival in patients treated with CNIs exclusively at the same time intervals was 83% and 62%. Although there was no difference in the incidence of major complications, the SRL group experienced a modest improvement in renal function. Cumulatively, these data suggest a potential survival benefit with SRL-based therapy in patients undergoing OLT for end-stage liver disease and concomitant malignancy.

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Our center has attempted to minimize corticosteroid (CS) use in all of our orthotopic liver transplantation (OLT) recipients. Because patients with autoimmune hepatitis (AIH) typically require CSs after transplantation, we reviewed our experience in this cohort of patients to determine (1) patient outcomes including recurrent disease and (2) long-term requirements for CS use in AIH patients. From 1988From to 2006From , 1102 OLTs were performed in 1032 adult patients at the University of Colorado, of whom 66 (6%) with AIH received 68 allografts. Recurrence was defined by a clinically worsening examination and histological evidence from biopsy. Bivariate and multivariate analyses were used to evaluate predictors of CS withdrawal. Twelve potential predictors of CS discontinuation were considered: age, gender, presence of inflammatory bowel disease (IBD), type of graft (cadaver or living donor), recurrence of AIH, warm ischemia time, follow-up time (time since transplant), and immunosuppressants (cyclosporine, tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil). Overall survival at 5 years was 91%. The 1-and 5-year recurrence-free survival was 88% and 59%, respectively. Risk (incidence) of recurrent AIH at 1, 3, and 5 years was 12%, 26%, and 36%, respectively. Disease recurred in 23 of 66 patients or 34.8%. Of the 23 patients who developed recurrent disease, none received a second transplant because of recurrent disease. CSs were withdrawn in 50% of patients at the time of review. Only 2 factors on multivariate analysis were strongly associated negatively with CS withdrawal: (1) an increasing dose of the immunosuppressant and (2) the presence of IBD. Controlling for these other factors, we found that recurrent disease did not strongly influence CS withdrawal. In conclusion, outcomes in AIH patients were quite favorable, and none of the patients required retransplantation for recurrent AIH. With a CS minimization approach, one-half of the patients were able to remain CS-free. Liver Transpl 14:1281-1286, 2008. © 2008 AASLD. Received November 7, 2007 accepted February 26, 2008. Orthotopic liver transplantation (OLT) is the treatment of choice for selected patients with end-stage liver disease secondary to autoimmune hepatitis (AIH). 1 AIH is an unresolving inflammation of the liver of unknown etiology that may progress to liver failure. Histologically, the diagnosis requires infiltration of portal tracts by plasma cells, piecemeal necrosis, and bridging necrosis. 2 Recurrence of AIH following OLT is a well-recognized problem. A recent review estimated that 23% of liver transplant recipients with AIH develop recurrent disease. 3 The natural history of AIH after liver transplantation continues to evolve as the number of patients and follow-up interval continue to increase. At present, it is unclear which clinical and/or pathologic variables including immunosuppression may be predictive of disease recurrence after transplant.In the mid 1990s, our center initiated a prednisonewithdrawal protocol for tra...

For acute liver failure (ALF), living donor liver transplantation (LDLT) may reduce waiting time and provide better timing compared to deceased donor liver transplantation (DDLT). However, there are concerns that a partial graft would result in reduced survival of critically ill LDLT recipients and that the rapid evolution of ALF would lead to selection of inappropriate donors. We report outcomes for ALF patients (and their donors) evaluated for LDLT between 1998 and April 2007 from the Adult-to-Adult Living Donor Liver Transplantation Cohort. Of the 1201 potential LDLT recipients, 14 had ALF, only 6 of whom had an identified cause. The median time from listing to first donor evaluation was 1.5 days, and the median time from evaluation to transplantation was 1 day. One patient recovered without liver transplant, 3 of 10 LDLT recipients died, and 1 of 3 DDLT recipients died. Five of the 10 living donors had a total of 7 posttransplant complications. In conclusion, LDLT is rarely performed for ALF, but in selected patients it may be associated with acceptable recipient mortality and donor morbidity.

Extensive animal work has established mesenteric lymph as the mechanistic link between gut ischemia/reperfusion (I/R) and distant organ injury. Our trauma and transplant services provide a unique opportunity to assess the relevance of our animal data to human mesenteric lymph under conditions that simulate those used in the laboratory. Mesenteric lymph was collected from eleven patients; with lymphatic injuries, during semi-elective spine reconstruction, or immediately before organ donation. The lymph was tested for its ability to activate human neutrophils in vitro, and was analyzed by label-free proteomic analysis. Human mesenteric lymph primed human PMNs in a pattern similar to that observed in previous rodent, swine, and primate studies. A total of 477 proteins were identified from the 11 subject’s lymph samples with greater than 99% confidence. In addition to classical serum proteins, markers of hemolysis, extracellular matrix components, and general tissue damage were identified. Both tissue injury and shock correlate strongly with production of bioactive lymph. Products of red blood cell hemolysis correlate strongly with human lymph bioactivity and immunoglobulins have a negative correlation with the pro-inflammatory lymph. These human data corroborate the current body of research implicating post shock mesenteric lymph in the development of systemic inflammation and multiple organ failure. Further studies will be required to determine if the proteins identified participate in the pathogenesis of multiple organ failure and if they can be used as diagnostic markers.

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Summary Orthotopic liver transplantation (OLT) is increasingly being applied for cure in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC). In recipients with limited tumor burden, OLT achieves reasonable long‐term outcome. This study sought to identify clinical and pathologic variables predictive of long‐term disease‐free survival and the presence of vascular invasion. From 1992 to 2006, 130 patients underwent OLT for cirrhosis and HCC. Malignancy was diagnosed in 107 patients prior to OLT and in 23 patients on pathologic examination of the explant. Nine clinical and pathologic variables were considered including: TNM stage, nodularity, vascular invasion, Milan criteria, incidental lesion, differentiation, tumor size, preOLT transarterial chemoembolization (TACE), and administration of sirolimus‐based immunosuppression. The overall incidence of HCC recurrence was 17% with the majority (82%) being stage III. Cumulatively, tumor recurrence‐free survival (RFS) is 84, 74, and 67% at 1, 3, and 5 years respectively. Independent predictors of RFS included stage III and poorly differentiated lesions (P < 0.05). Furthermore, stage III tumors and those >3.5 cm in size were predictive of vascular invasion. Importantly, preOLT, TACE and postOLT sirolimus had no influence on survival. Pathologic variables including tumor stage and grade have a significant impact on outcome. Importantly, it seems that TACE and sirolimus had no beneficial effect.

Whether a positive crossmatch result has any relevance to liver transplantation (LT) outcomes remains controversial. We assessed the impact of a positive crossmatch result on patient and graft survival and posttransplant complications. During a 20-year period, 2723 LT procedures with crossmatch results were identified: 2479 primary transplants and 244 retransplants. The rates of positive B cell and T cell crossmatches were 10.1% and 7.4%, respectively, for primary transplants and 14.6% and 6.4%, respectively, for retransplants (P = 0.049 for a B cell crossmatch). Across all primary transplants, females (P < 0.001) and patients with autoimmune hepatitis (P < 0.001) had greater frequencies of positive crossmatches. There was no effect from race or age. For both primary transplants and retransplants, patient survival and graft survival were not affected by the presence of a positive crossmatch. With respect to posttransplant complications, there were no differences in rejection episodes (hyperacute, acute, or chronic) or technical complications (biliary and vascular) between negative and positive crossmatch groups. However, there were significant differences in the pathological findings of preservation injury (PI) on liver biopsy samples taken at the time of transplantation and within the first week of transplantation (P = 0.003 for B cells and P = 0.03 for T cells). In summary, a positive crossmatch had no significant impact on patient survival or graft outcomes. However, there was a significantly higher incidence of PI in primary LT recipients with a positive crossmatch. This finding is important for a broader understanding of PI, which may include a significant immunological component.