Sirolimus reduces the risk of significant hepatic fibrosis after liver transplantation for hepatitis C virus: a single-center experience.

INTRODUCTION: Hepatitis C virus (HCV) recurrence following orthotopic liver transplantation is an expected outcome in all patients transplanted for a primary diagnosis of HCV. HCV recurrence has been shown to be associated with graft fibrosis and graft loss. Recent studies suggest that sirolimus (SRL) therapy may slow or inhibit hepatic fibrosis following liver transplant in patients positive for HCV at the time of transplant. METHODS: Among 313 patients who underwent orthotopic liver transplantation for HCV between 2000 and 2009, 251 qualified for inclusion in the study. Per protocol liver biopsies were performed on all patients at 1 year following liver transplantation and/or at the time of a clinical diagnosis of HCV recurrence. Biopsies were scored for fibrosis using the Batts-Ludwig staging system (0-4); significant fibrosis was defined as fibrosis ≥ stage 2. RESULTS: Overall, there was no difference in overall survival or graft loss in the SRL compared with the control group. Multivariate analysis revealed SRL therapy to be associated with decreased odds of significant hepatic fibrosis at year 1 postoperatively and over the study duration. CONCLUSIONS: This retrospective, single-center study showed sirolimus-based immunosuppression to be associated with a lower risk of significant graft fibrosis, both at year 1 and throughout the study period, following liver transplantation in HCV-infected recipients.

Biological implications of extracellular adenosine in hepatic ischemia and reperfusion injury.

The purine nucleoside adenosine is clinically employed in the treatment of supraventricular tachycardia. In addition, it has direct coronary vasodilatory effects, and may influence platelet aggregation. Experimental observations mechanistically link extracellular adenosine to cellular adaptation to hypoxia. Adenosine generation has been implicated in several pathophysiologic processes including angiogenesis, tumor defenses and neurodegeneration. In solid organ transplantation, prolonged tissue ischemia and subsequent reperfusion injury may lead to profound graft dysfunction. Importantly, conditions of limited oxygen availability are associated with increased production of extracellular adenosine and subsequent tissue protection. Within the rapidly expanding field of adenosine biology, several enzymatic steps in adenosine production have been characterized and multiple receptor subtypes have been identified. In this review, we briefly examine the biologic steps involved in adenosine generation and chronicle the current state of adenosine signaling in hepatic ischemia and reperfusion injury.

Complications of living donor hepatic lobectomy--a comprehensive report.

A wider application of living donor liver transplantation is limited by donor morbidity concerns. An observational cohort of 760 living donors accepted for surgery and enrolled in the Adult-to-Adult Living Donor Liver Transplantation cohort study provides a comprehensive assessment of incidence, severity and natural history of living liver donation (LLD) complications. Donor morbidity (assessed by 29 specific complications), predictors, time from donation to complications and time from complication onset to resolution were measured outcomes over a 12-year period. Out of the 760 donor procedures, 20 were aborted and 740 were completed. Forty percent of donors had complications (557 complications among 296 donors), mostly Clavien grades 1 and 2. Most severe counted by complication category; grade 1 (minor, n = 232); grade 2 (possibly life-threatening, n = 269); grade 3 (residual disability, n = 5) and grade 4 (leading to death, n = 3). Hernias (7%) and psychological complications (3%) occurred >1 year postdonation. Complications risk increased with transfusion requirement, intraoperative hypotension and predonation serum bilirubin, but did not decline with the increased center experience with LLD. The probability of complication resolution within 1 year was overall 95%, but only 75% for hernias and 42% for psychological complications. This report comprehensively quantifies LLD complication risk and should inform decision making by potential donors and their caregivers.

Liver transplantation for primary biliary cirrhosis: results of aggressive corticosteroid withdrawal.

INTRODUCTION: A subset of patients with primary biliary cirrhosis (PBC) may require long-term corticosteroid (CS) therapy following liver transplantation (OLT) due to concern over the possibility of recurrence. Our center has attempted to minimize CS use in all of our OLT recipients. In this study, we review our experience in this cohort to determine (1) patient outcome including PBC recurrence following transplantation and (2) the long-term requirement for CS use in PBC patients. METHODS: From 1988 to 2006, 1102 OLTs were performed in 1032 adults at the University of Colorado, of which 70 patients (6.8%) with PBC received 74 allografts. Bivariate and multivariate analyses were used to evaluate predictors of CS withdrawal. Thirteen potential predictors of CS discontinuation were considered: age, gender, body mass index (BMI), race, type of graft (cadaveric or living donor [LD]), recurrence of PBC, warm ischemia time, and immunosuppressant. RESULTS: Overall survival at 5 years was 85%. The 1-, 5-, and 10-year recurrence-free survivals were 90%, 72%, and 54%, respectively. PBC recurred in 18 patients (25.7%). Of these, none received a second transplant due to disease recurrence. At the time of last follow-up, 73% of recipients were steroid free. Independent predictors of CS discontinuation are age (>54; P = .0059) and LD graft type (P = .0008). Conversely, cyclosporine (P = .0007), female gender (P = .0216), and BMI > 31 (P = .0306) were negatively associated with CS withdraw. Importantly, steroid discontinuation did not influence PBC recurrence. CONCLUSIONS: While long-term outcomes in PBC patients are favorable, disease recurrence can generally be managed medically without the need for a second transplant. Using an aggressive CS minimization approach, nearly three-quarters of the patients were CS free at the time of last follow-up. Increasing age and LD grafts were associated with successful CS withdraw. Conversely, cyclosporine use, female gender, and increasing BMI were associated with unsuccessful steroid discontinuation.

Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation.

We examined mortality and recurrence of hepatocellular carcinoma (HCC) among 106 transplant candidates with cirrhosis and HCC who had a potential living donor evaluated between January 1998 and February 2003 at the nine centers participating in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Cox regression models were fitted to compare time from donor evaluation and time from transplant to death or HCC recurrence between 58 living donor liver transplant (LDLT) and 34 deceased donor liver transplant (DDLT) recipients. Mean age and calculated Model for End-Stage Liver Disease (MELD) scores at transplant were similar between LDLT and DDLT recipients (age: 55 vs. 52 years, p = 0.21; MELD: 13 vs. 15, p = 0.08). Relative to DDLT recipients, LDLT recipients had a shorter time from listing to transplant (mean 160 vs. 469 days, p < 0.0001) and a higher rate of HCC recurrence within 3 years than DDLT recipients (29% vs. 0%, p = 0.002), but there was no difference in mortality or the combined outcome of mortality or recurrence. LDLT recipients had lower relative mortality risk than patients who did not undergo LDLT after the center had more experience (p = 0.03). Enthusiasm for LDLT as HCC treatment is dampened by higher HCC recurrence compared to DDLT.

Outcomes of donor evaluations for adult-to-adult right hepatic lobe living donor liver transplantation.

The purpose of this study is to determine the role of liver biopsy and outcome of patients undergoing donor evaluation for adult-to-adult right hepatic lobe living donor liver transplantation (LDLT). Records of patients presenting for a comprehensive donor evaluation between 1997 and February 2005 were reviewed. Liver biopsy was performed only in patients with risk factors for abnormal histology. Two hundred and sixty patients underwent a comprehensive donor evaluation and 116 of 260 (45%) were suitable for donation, 14 of 260 (5.4%) did not complete evaluation and 130 of 260 (50%) were rejected. Four patients underwent unsuccessful hepatectomy surgery due to discovery of intraoperative abnormalities. Between 1997 and 2001, the acceptance rate of donor candidates (63%) was higher than 2002-2005 (36%), p < 0.0001. Sixty-six of the 150 eligible patients (44%) fulfilled criteria for liver biopsy and 28 of 66 (42%) had an abnormal finding. Less than half of the patients undergoing donor evaluation were suitable donors and the donor acceptance rate has declined over time. A large proportion of the patients undergoing liver biopsy have abnormal findings. Our evaluation process failed to identify 4 of 103 who had aborted donor surgeries.

Adult-to-adult living donor liver transplantation using right-lobe grafts: results and lessons learned from a single-center experience.

Living donor liver transplantation (LDLT) for adults is now a practical alternative to cadaveric liver transplantation. Use of right-lobe grafts has become the preferred donor procedure. Because of the complexity of this operation, a learning curve is to be expected. We report the outcome of our first 41 LDLTs at the University of Colorado Health Sciences Center (Denver, CO). We also discuss the lessons learned and the resultant modifications in the procedure that evolved during our series. Patient records were retrospectively reviewed between August 1997 and February 2001 for the following end points: recipient survival, graft survival, and donor and recipient complications. Thirty-eight of 41 living donor liver transplant recipients (93%) are alive and well postoperatively with a mean follow-up of 9.6 months. Four patients required retransplantation secondary to technical problems (9.8%); all 4 patients were in our initial 11 cases. Modification of the donor liver plane of transection resulted in venous outflow improvement. Also, biliary management was modified during the series. Donor complications are listed; all 41 donors have returned to normal pretransplantation activity. Our results indicate that LDLT can be performed safely with excellent donor and recipient outcomes. Dissemination of our experience can help shorten the learning curve for other institutions.

Right hepatic lobe donation for living donor liver transplantation: impact on donor quality of life.

Adult right hepatic lobe living donor liver transplantation (LDLT) has rapidly gained widespread acceptance as an effective procedure for selected patients with end-stage liver disease. However, there are currently no published data on the effect of this procedure on the quality of life of donors. We report the results of a survey of our living liver transplant donors to determine the effect of right hepatic lobe donation on quality of life. We have performed 30 LDLTs since 1997; 24 of these have a follow-up of 4 months or longer. In August 2000, these patients were sent a questionnaire (including a Medical Outcomes Study 36-Item Short-Form Survey) regarding psychosocial outcomes and symptoms after surgery. Major complications occurred in 4 of 24 patients (16%), and minor complications, in 4 of 24 patients (16%). Complete recovery occurred in 75% of patients at a mean time of 3.4 months. Ninety-six percent of patients returned to the same predonation job after a mean time of 2.4 months, and 66% of patients required a period of light-duty work for a mean of 2.8 months before returning to full-duty work. A change in body image was reported in 42% of patients, and 71% reported mild ongoing symptoms (primarily abdominal discomfort) that they related to the donor surgery for which 29% sought evaluation by a physician. The donor's relationship with the recipient was the same or better in 96% of donors, and the relationship with the donor's significant other was the same or better in 88% of donors. Mean out-of-pocket expenses incurred by donors were $3,660. Sixty-three percent of donors reported experiencing more pain than anticipated. All patients would donate again if necessary, and 96% benefited from the donor experience. In conclusion, (1) all our donors are alive and well after donation; (2) almost all donors were able to return to predonation employment status within a few months; (3) most donors have mild persistent abdominal symptoms, and some donors had a change in body image that they attribute to the donor surgery; and (4) this information should be provided to potential donors so they may better understand the impact of donor surgery.

Dyslipidemia during sirolimus therapy in liver transplant recipients occurs with concomitant cyclosporine but not tacrolimus.

Since its approval as an immunosuppressive agent in renal transplantation, sirolimus (RAPA) recently has been used in the primary immunosuppression regimen at several liver transplant centers. One of the major side effects of RAPA is hypercholesterolemia, which is reported in up to 44% of patients. We describe our experience in 57 primary liver transplant recipients treated with RAPA and either cyclosporine A (CSA) or tacrolimus (TAC). We report the incidence and severity of hypercholesterolemia using a prednisone-free immunosuppressive regimen. Between January 2000 and September 2000, a total of 57 patients underwent transplantation at the University of Colorado Health Sciences Center (Denver, CO) with RAPA and either CSA or TAC. The initial 10 patients who underwent transplantation under this protocol were not administered corticosteroids, and the subsequent 47 patients were administered only 3 doses of methylprednisolone days 0, 1, and 2 postoperatively (1, 0.5, and 0.5 g, respectively). Total fasting cholesterol, high-density cholesterol, low-density cholesterol, and triglyceride levels were measured at monthly intervals. Mean serum cholesterol level was significantly greater in CSA patients (200 mg/dL) compared with TAC patients (158 mg/dL; P =.0003). Serum triglyceride levels were more than 2-fold greater with CSA (292 mg/dL) compared with TAC (134 mg/dL; P =.002). Hypercholesterolemia (cholesterol > 240 mg/dL) was present in 10 of 57 patients (18%) and was significantly more common in CSA-treated patients (8 of 27 patients; 30%) compared with TAC-treated patients (2 of 30 patients; 6%; P <.05). Hypertriglyceridemia (serum triglyceride > 300 mg/dL) was present in 10 of 57 patients (18%) and was significantly more common in CSA-treated patients (9 of 27 patients; 33%) compared with TAC-treated patients (1 of 30 patients; 3%; P <.05). We conclude that (1) concomitant use of TAC with RAPA reduces the prevalence and severity of posttransplantation dyslipidemia, and (2) these findings have important implications in the prevention of complications of hypercholesterolemia in liver transplant recipients.

Liver transplantation using sirolimus and minimal corticosteroids (3-day taper).

At our center, we have performed liver transplantation since 1995 with a rapid-taper steroid protocol (weaning steroids by day 14 posttransplantation). Beginning in 2000, we further reduced the use of corticosteroids to 3 days and added sirolimus to our immunosuppressive regimen. We report our experience with 39 patients who underwent liver transplantation with either tacrolimus or cyclosporin A (Neoral; Novartis Pharmaceuticals Corp., Summit, NJ) and sirolimus, with a 3-day tapered dose of corticosteroids. Thirty-two patients received a cadaveric graft and 7 patients received a right hepatic lobe from a living donor. All patients initially were administered either tacrolimus (0.1 mg/kg/d) or cyclosporin A (10 mg/kg/d) and sirolimus (6 mg/d for 1 day, followed by 2 mg/d), in addition to methylprednisolone on the first 3 days (1, 0.5, and 0.5 g/d) after transplantation. Patients were administered corticosteroids for presumptive or biopsy-proven evidence of acute cellular rejection (methylprednisolone, 1, 0.5, and 0.5 g on 3 successive days). Seventeen patients were administered tacrolimus and 22 patients were administered cyclosporin A. Six patients were excluded from analysis because they were administered sirolimus for less than 2 weeks. Mean duration of follow-up was 124 days. Patient survival was 36 of 39 patients (92%), and graft survival was 35 of 39 grafts (89%). Ten of 33 patients (30%) experienced 12 episodes of rejection (7 biopsy proven, 5 presumptive) compared with 70% in historical controls (P <.01). OKT3 was required in 1 of 33 patients (3%) compared with 37% in controls (P <.01). Twenty-six of 33 patients (79%) were not administered prednisone, and 7 of 33 patients (21%) were administered prednisone for reasons other than rejection. Posttransplantation, there was no significant change in values for creatinine, glucose, aspartate aminotransferase, bilirubin, cholesterol, and white blood cell counts. Platelet counts were significantly reduced, and hematocrits were significantly elevated (P <.05). Liver transplantation may be successfully performed with minimal use of corticosteroids by using sirolimus and either tacrolimus or cyclosporin A. Despite the absence of prednisone from our immunosuppressive protocol, the incidence of rejection and OKT3 use was lower than in historical controls. Patient and graft survival rates were identical to those of historical controls. The findings in this report will serve as the basis for a formal trial evaluating the efficacy of sirolimus in liver transplantation.

Combined liver-pancreas transplantation in a patient with primary sclerosing cholangitis and insulin-dependent diabetes mellitus.

Combined liver-pancreas transplantation is a relatively uncommon procedure. We report successful combined liver-pancreas transplantation in a patient with primary sclerosing cholangitis and insulin-dependent diabetes mellitus and review the literature on this topic.

Fatal transfer of malignant melanoma from multiorgan donor to four allograft recipients.

BACKGROUND: In this report we describe the transfer of malignant melanoma from a single donor to four solid organ transplant recipients, all of whom died from metastatic melanoma. METHODS AND CASE HISTORIES: The donor of a heart, liver, and two kidneys to four separate recipients died of intracerebral hemorrhage. The donor had no history or clinical evidence of melanoma. All four recipients, treated with standard immunosuppression protocols, developed metastatic malignant melanoma within 1 year after transplantation Three patients died within 14 months after transplantation, although the fourth, whose immunosuppressive therapy was discontinued, died of metastatic melanoma 30 months after renal transplantation. FINDINGS: Tumors from all recipients were histologically identical. Donor origin of tumor cells was confirmed by polymerase chain reaction (PCR)-based DNA analysis for polymorphic short tandem tetrameric repeats (Geneprint STR, Promega Corp., Madison, WI). DNAs from nontumorous donor tissue and tumor tissue available from three recipients tested positive for CSF1P0 alleles 10 and 12 and for TH01 alleles 6 and 7, although DNAs from nonneoplastic recipient tissues all exhibited different allelotypes. INTERPRETATION: Transmission of fatal or potentially fatal malignant tumors, notably malignant melanoma, from donor to recipient is an uncommon complication of solid organ transplantation. PCR-based genetic analysis permits definitive assignment of the source of posttransplant tumors.

Evaluation of 100 patients for living donor liver transplantation.

The initial success of living donor liver transplantation (LDLT) in the United States has resulted in a growing interest in this procedure. The impact of LDLT on liver transplantation will depend in part on the proportion of patients considered medically suitable for LDLT and the identification of suitable donors. We report the outcome of our evaluation of the first 100 potential transplant recipients for LDLT at the University of Colorado Health Sciences Center (Denver, CO). All patients considered for LDLT had first been approved for conventional liver transplantation by the Liver Transplant Selection Committee and met the listing criteria of United Network for Organ Sharing status 1, 2A, or 2B. Once listed, those patients deemed suitable for LDLT were given the option to consider LDLT and approach potential donors. Donors were evaluated with a preliminary screening questionnaire, followed by formal evaluation. Of the 100 potential transplant recipients evaluated, 51 were initially rejected based on recipient characteristics that included imminent cadaveric transplantation (8 patients), refusal of evaluation (4 patients), lack of financial approval (6 patients), and medical, psychosocial, or surgical problems (33 patients). Of the remaining 49 patients, considered ideal candidates for LDLT, 24 patients were unable to identify a suitable donor for evaluation. Twenty-six donors were evaluated for the remaining 25 potential transplant recipients. Eleven donors were rejected: 9 donors for medical reasons and 2 donors who refused donation after being medically approved. The remaining 15 donor-recipient pairs underwent LDLT. Using our criteria for the selection of recipients and donors for LDLT gave the following results: (1) 51 of 100 potential transplant recipients (51%) were rejected for recipient issues, (2) only 15 of the remaining 49 potential transplant recipients (30%) were able to identify an acceptable donor, and (3) 15 of 100 potential living donor transplant recipients (15%) were able to identify a suitable donor and undergo LDLT. Recipient characteristics and donor availability may limit the widespread use of LDLT. However, careful application of LDLT to patients at greatest risk for dying on the waiting list may significantly reduce waiting list mortality.

Successful withdrawal of prednisone after adult liver transplantation for autoimmune hepatitis.

Corticosteroid withdrawal after orthotopic liver transplantation (OLT) represents an attractive therapeutic option for ameliorating post-OLT metabolic complications, although several reports suggest patients who undergo transplantation for autoimmune hepatitis (AIH) may have a greater incidence of acute and chronic rejection when withdrawn from corticosteroid therapy. The aim of this study is to evaluate the success of corticosteroid withdrawal in patients with AIH after OLT. Twenty-six patients underwent successful OLT for AIH. In 21 of these patients, stable maintenance immunosuppression consisted of cyclosporine (CSA) and prednisone (n = 20) or tacrolimus (TAC) and prednisone (n = 1). In this group, a trial of prednisone withdrawal was initiated when patients were 6 months or more post-OLT, with normal liver function, and receiving an average prednisone dosage of 10 mg/d. Five additional patients treated with either TAC (n = 4) or CSA (n = 1) plus mycophenolate mofetil underwent a 14-day taper of prednisone. Overall, 17 of 25 patients (68%) were successfully withdrawn from corticosteroids, with a mean follow-up of 22 months (range, 1 to 34 months). Of the remaining 8 patients, 5 patients received a lower dosage of prednisone or required prednisone to control inflammatory bowel disease. Only 3 patients remained dependent on prednisone to maintain stable liver allograft function. Withdrawal from 10 to 5 mg of prednisone (n = 21) resulted in four episodes of steroid-responsive and two episodes of steroid-resistant rejection in 3 patients, and 18 of 21 patients (86%) were rejection free. Withdrawal from 5 to 0 mg prednisone (n = 17) resulted in eight episodes of steroid-responsive and no episodes of steroid-resistant rejection in 4 patients; 13 of 17 patients (76%) were rejection free. Of the 5 patients in the 14-day prednisone-taper group, 3 patients had steroid-responsive rejection and 1 patient required OKT3. Seventeen of 21 patients (81%) with AIH were successfully withdrawn from corticosteroids. It is notable that corticosteroid withdrawal was associated with a reduction in serum cholesterol levels, decreased use of antihypertensive agents, and reduced need for insulin or oral hypoglycemic agents. We propose corticosteroid withdrawal should be attempted in patients with underlying AIH who undergo OLT because most will benefit without significantly jeopardizing the liver allograft.

Early steroid withdrawal in liver transplantation is safe and beneficial.

This report reviews the literature and discusses steroid withdrawal after hepatic transplantation. Our experience with steroid withdrawal is highlighted. The hypothesis is that steroid withdrawal from liver transplant recipients is safe and beneficial. A review of the English literature yielded 16 reports with a total of 901 patients (749 adults and 152 children). Most reports were nonrandomized and uncontrolled. Only two reports were randomized, controlled trials; three reports featured early steroid withdrawal (

Role of TIPS as a bridge to hepatic transplantation in Budd-Chiari syndrome.

PURPOSE: To investigate the role of transjugular intrahepatic portosystemic shunt (TIPS) as a bridge to transplantation for patients with Budd-Chiari syndrome (BCS). MATERIALS AND METHODS: Eight patients (five women, three men) with a mean age of 49.8 years (range, 20-61 years) were diagnosed with BCS by means of computed tomography, hepatic venography, and liver biopsy. One patient had acute liver failure, with subacute or chronic failure in seven. TIPS placement was attempted in all eight patients. Clinical follow-up and portograms were obtained in all patients until death or transplantation. RESULTS: TIPS placement was completed in seven of eight patients (87.5%). During the follow-up period, TIPS occlusion occurred in four patients. TIPS revision in this patient, although successful, was complicated by hemorrhage and multiorgan failure, and the patient died. Assisted patency rate, excluding the technical failure, was 100%. Mean follow-up in the six survivors with TIPS was 342 days (range, 19-660 days). All six survivors had complete resolution of their ascites. Albumin levels improved an average of 0.43 g/dL (range, 0.3-1.4 g/dL). Bilirubin levels improved in five of six patients (83%), decreasing by an average of 5.6 mg/dL (range, 3.0-15.2 mg/dL). Of the six survivors, three underwent elective liver transplantation, one is awaiting transplantation, and one has been removed from the transplantation list because of clinical improvement. One patient was a candidate for transplantation but declined to be put on the list. CONCLUSION: Hepatic synthetic dysfunction improves markedly after TIPS placement in patients with BCS. Significant improvement in ascites can also occur. TIPS can be an effective bridge to transplantation for patients with BCS.