J. L. Lazaro

Indications and management of everolimus after liver transplantation.

OBJECTIVEnOur aim was to assess our experience with the use and management of everolimus after orthotopic liver transplantation (OLT).nnnMATERIALS AND METHODSnAmong the 759 patients who underwent transplantation from 1988 to 2008, 25 (3.2%) received immunosuppression with everolimus. Their mean age was 55.6 years. We analyzed indications for use, time between transplantation and introduction of everolimus, as well as its efficacy, side effects, and patient survival.nnnRESULTSnThe indications for everolimus treatment were: extended hepatocellular carcinoma (HCC) in the explanted liver (n = 6; 24%); HCC recurrence during follow-up (n = 4; 16%); de novo tumor (n = 6; 24%); refractory rejection (n = 3; 12%); side effects of calcineurin inhibitors (CNI; n = 3; 12%); and other causes (n = 3; 12%). Mean time between OLT and everolimus treatment was 40 +/- 33 months (range, 10 days-178 months). Mean follow-up after conversion was 10 +/- 9 months (range, 1.5-25 months). More than half of the patients resolved the event for which the drug was indicated: 75% of patients with refractory rejection; 60% of those with renal insufficiency; and 100% of those converted for neurotoxicity or hepatotoxicity. Two patients with recurrent HCC and 1 with extended HCC died at a mean time of 10.5 months. The 6 cases of de novo tumors were operated and are healthy. Side effects were dyslipidemia in 8 and infection in 2. Five patients (20%) discontinued the drug.nnnCONCLUSIONSnIn the early posttransplantation period, everolimus is indicated for refractory rejection or as prophylaxis for recurrence of extended tumors. In any time but especially in the late period, everolimus is indicated for patients with serious side effects due to a CNI or to a de novo tumor.

Severe Rhabdomyolysis and Acute Renal Failure Secondary to Concomitant Use of Simvastatin With Rapamycin Plus Tacrolimus in Liver Transplant Patient

OBJECTIVEnTo report a severe interaction between simvastatin and rapamycin resulting in rhabdomyolysis and acute renal failure in a liver transplant patient.nnnBACKGROUNDnA 56-year-old man with hepatitis C virus cirrhosis (Child B) was diagnosed with hepatocellular carcinoma and underwent liver transplantation in April 2007. He was immunosuppressed with tacrolimus (FK) and mycophenolate mofetil (MMF). Postoperative complications were arterial hypertension and renal insufficiency. In June 2007, liver dysfunction was detected and acute rejection was diagnosed by biopsy. He received three 500-mg boluses of methylprednisolone and FK levels were maintained between 10 and 12 ng/mL. Laboratory values revealed persistent rejection and MMF was stopped with initiation of rapamicin. One month later, hyperlipidemia appeared as a consequence of rapamicin therapy; simvastatin was administered. In August 2007, the patient was readmitted due to severe muscule pain and the inability to ambulate. Laboratory values were: total bilirubin 16 mg/dL, serum creatinine 4.3 mg/dL, and total creatine kinase (CK) 42,124 U/L. With the suspicion of rhabdomyolysis, leading to worsening of his basal renal insufficiency, rapamycin and tacrolimus were stopped. Hemodialysis was initiated owing to renal failure and hyperkalemia. Some hours later, the patient developed ventricular fibrillation and respiratory failure and succumbed.nnnDISCUSSIONnCalcineurin inhibitors (CNI), corticosteroids, and mammalian target of rapamycin (m-TOR) inhibitors are associated with adverse dyslipidemic effects. To reduce the overall cardiovascular risk in these patients, lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been widely used. CNI and m-TOR inhibitors, as well as most statins, are metabolized by cytochrome P450 (CYP)3A4; thus, pharmacokinetic interactions between these drugs are possible. Previous reports have indicated an increased risk of rhabdomyolysis in the presence of concomitant drugs that inhibit simvastatin metabolism.nnnCONCLUSIONSnConcomitant administration of statin therapy and drugs that inhibit cytochrome P450 (CYP)3A4 increased the risk of rhabdomyolysis in a patient suffering liver and renal dysfunction.

Outcome of hepatitis C virus-associated membranoproliferative glomerulonephritis after liver transplantation.

BACKGROUNDnHepatitis C virus was the most frequent cause of liver failure requiring liver transplantation in our series. Hepatitis C virus infection has been associated with glomerulonephritis and, more frequently, type I membranoproliferative glomerulonephritis. Renal disease in patients with liver failure is often clinically silent and difficult to diagnose; thus, biopsy is required to establish the diagnosis. Our aim was to study the evolution of six patients diagnosed with membranoproliferative glomerulonephritis some months before liver transplantation.nnnMETHODSnLiver transplantation alone was performed in four patients and combined liver-kidney transplantation in the remaining two, who were on hemodialysis for kidney failure. These patients were followed for a mean of 38.3+/-7.8 months. Evolution of proteinuria, renal function, hepatic function, and hepatitis C virus activity was studied.nnnRESULTSnIn the four patients who underwent liver transplantation alone, proteinuria became negative initially and renal function remained stable. Proteinuria reappeared and renal function was altered in two of these patients at 17 and 36 months of follow-up, respectively, coinciding with a recurrence of active chronic hepatitis. In the two patients who received a combined liver-kidney transplant, proteinuria became negative, and their renal grafts currently maintain normal renal function.nnnCONCLUSIONSnMembranoproliferative glomerulonephritis does not constitute an absolute contraindication for liver transplantation alone; combined liver-kidney transplantations are reserved for patients with end-stage kidney failure. Proteinuria is reversed after liver transplantation, and recurrence seems to be associated with severe hepatitis C virus hepatic allograft disease relapse.

Analysis of adult 20-year survivors after liver transplantation

BackgroundLiver transplantation (LT) is the treatment of choice for chronic and acute liver failure; however, the status of long-term survivors and allograft function is not well known.AimTo evaluate the clinical outcome and allograft function of survivors 20xa0years post-LT, cause of death during the same period and risk factors of mortality.MethodsA retrospective study was conducted from prospective, longitudinal data collected at a single center of adult LT recipients surviving 20xa0years. A comparative sub-analysis was made with patients who were not alive 20xa0years post-transplantation to identify the causes of death and risk factors of mortality.ResultsBetween 1988 and 1994, 132 patients received 151 deceased-donors LT and 28 (21xa0%) survived more than 20xa0years. Regarding liver function in this group, medians of AST, ALT and total bilirubin at 20xa0years post-LT were 33xa0IU/L (13–135xa0IU/L), 27 (11–152xa0IU/L) and 0.6xa0mg/dL (0.3–1.1xa0mg/dL). Renal dysfunction was observed in 40xa0% of patients and median eGFR among 20-year survivors was 64xa0mL/min/1.73xa0m2 (6–144xa0mL/min/1.73xa0m2). Sixty-one percent of 20-year survivors had arterial hypertension, 43xa0% dyslipidemia, 25xa0% de novo tumors and 21xa0% diabetes mellitus. Infections were the main cause of death during the 1st year post-transplant (32xa0%) and between the 1st and 5th year post-transplant (25xa0%). After 5thxa0year from transplant, hepatitis C recurrence (22xa0%) became the first cause of death. Factors having an impact on long-term patient survival were HCC indication (pxa0=xa00.049), pre-transplant renal dysfunction (pxa0=xa00.043) and long warm ischemia time (pxa0=xa00.016); furthermore, post-transplant factors were diabetes mellitus (pxa0=xa00.001) and liver dysfunction (pxa0=xa00.05) at 1xa0year.ConclusionOur results showed the effect of immunosuppression used during decades on long-term outcome in our LT patients in terms of morbidity (arterial hypertension, diabetes mellitus, dyslipidemia and renal dysfunction) and mortality (infections and hepatitis C recurrence).

Hemodynamics in human liver transplantation with inferior vena cava preservation

S OME patients do not tolerate inferior vena cava (NC) and portal clamping during the anhepatic phase of orthotopic liver transplantation (OLT), and veno-venous bypass (VVBP) is usually required in order to maintain hemodynamics during this phase.’ Recipient hepatectomy with IVC preservation’ was introduced into our program in 1991 to avoid WBP and complications due to its use. This technique became routine in the majority of cases.3 The aim of this study was to ratify our results by measuring I?C flow and pressure and correlating them with data on patient hemodynamics.

DNA ploidy study of resected hepatocellular carcinoma in cirrhotic liver

BACKGROUND/AIMSnResults of several studies on DNA ploidy as a prognostic indicator in hepatocellular carcinoma are contradictory. The present study analysed the correlations between DNA ploidy of resected hepatocellular carcinoma and tumour characteristics, tumour recurrence, risk factors and survival.nnnMETHODSnTumoural DNA ploidy of hepatocellular carcinomas from 37 patients with cirrhosis who underwent curative tumour resection was studied by flow cytometry.nnnRESULTSnA diploid pattern was found in 23 hepatocellular carcinomas (62.2%) and an aneuploid pattern in 14 (37.8%). The tumour recurrence rate did not differ statistically between diploid (69.6%) and aneuploid (50%) hepatocellular carcinomas. The only prognostic variable with significant difference in DNA pattern was the histologic tumour type; the majority of non-trabecular tumours were aneuploid while most trabecular hepatocellular carcinomas had a diploid DNA pattern. Actuarial survival at 1, 2, 3 and 4 years of patients with diploid and aneuploid tumours was 69.6%, 40.6%, 16.2% and 0%, and 69.3%, 59.4%, 49.5% and 32.9%, respectively (log rank p = 0.1927).nnnCONCLUSIONnThese results indicate that DNA ploidy has no prognostic value in hepatocellular carcinoma.

Evolution of Biliary Complications After Liver Transplantation: A Single European Series

BACKGROUNDnThe aim of this study was to analyze the evolution of biliary complications over 20 years among adult patients undergoing liver transplantation (OLT) at our institution.nnnPATIENTS AND METHODSnBetween 1985 and 2007, we performed 1000 OLT in 789 adults and 211 children. To ascertain the evolution of biliary complications among adult OLT from October 1988 to September 2007, we compared the first 100 to with the last 200 adult OLT.nnnRESULTSnDuct-to-duct was the most common biliary anastomosis performed in both periods (1st; 89% and 2nd; 94%; P = NS). However, a T-tube was used more frequently in the first period (1st; 46% vs 2nd; 6.6%; P < .001). The remaining cases underwent a hepaticojejunostomy (1st; 11% vs 2nd; 7.6%). Biliary complications were more frequent in the first period (1st; 20% vs 2nd; 9%; P < .01). In the first period, the use of a T-tube caused 32% of complications, all of them being bile leaks; but there were none in the second period. Arterial thrombosis or strictures were related to biliary complications in 10% and 33.3% among the first and second periods, respectively. The severity of complications according to the Clavien classification was similar in both periods: IIIa, 15% versus 33.3%; IIIb, 55% versus 55.5%; and IV, 15% versus 11.1%, respectively (P = NS).nnnCONCLUSIONnThe biliary complication rate among adult patients post-OLT decreased over 20 years at our institution, probably owing to the abandonment of the routine use of a T-tube as well as to advances in immunosuppressive protocols, organ preservation, and preoperative patient management.

Acute Antibody-Mediated Rejection as Cause of Late Liver Allograft Failure: A Case Report

BACKGROUNDnDespite now being an infrequent complication in liver transplantation (LT) recipients, acute liver failure is still associated with high mortality.nnnCASE REPORTnHere we report a case of acute liver failure 11 months after AB0-compatible LT in a hepatitis C-positive 50-year-old male recipient caused by late antibody-mediated rejection (AMR). De novo donor-specific antibodies appeared later in a previously negative donor-recipient crossmatch, leading to a rapid deterioration of liver function.nnnCONCLUSIONSnWe highlight the importance of an accurate diagnosis and an early therapeutic intervention. The analysis of this case brings novel and generalizable insights to the differential diagnosis of acute liver failure after LT.

Potencial Antifbibrotic Effect of Long-Term Everolimus Based Immunosuppression in HCV Positive Liver Transplant Patients: 817

Introduction: There is in vitro evidence that mTOR proteins protect Hepatitis C(HCV) infected cells and inhibit hepatic fibrosis by attenuating different profibrogenic pathways. Aim.To evaluate the long-term effect of everolimus(EVL) on fibrosis progression in HCV positive liver transplant (LT) recipients. Patients and methods: Retrospective study from a prospectively obtained database which analyzes LT recipients performed in Hospital Vall d ́Hebron from 2005-2010 and minimal follow-up of 2 years. Inclusion criteria: positive HCV RNA PCR, yearly liver biopsies performed at year one and two and no antiviral therapy given during the follow-up or it was stopped after three months of treatment due to adverse events or null response. Patients that received EVL during the first 6 months post-transplant (EVL group) were compared with those who never received EVL (control group) and were on Tacrolimus (TAC)-based immunosuppression. Advanced fibrosis progression (fibrosis stage≥ 4) under Ishak score was evaluated. Results: Eleven patients received EVL compared with 23 who continued on TAC-based immunosuppression.No differences were found between both groups regarding recipient age, HCC indication, HCV genotype, pre-transplant viral load, donor age, graft steatosis and cold ischemia time (p=ns). Reasons for introduction of EVR were calcineurin inbitor side effects (n=4), prevention of HCC recurrence in patients with microvascular invasion (n=4) and severe acute rejection (n=3). The median level and doses of EVL when it was introduced were 1mg (r: 0.5-2mg) and 2.4ng/mL (r:1-2.9ng/mL) respectively. There were no differences between both groups during the follow-up regarding acute rejection rate (36% EVL group vs 35%, p=0.15) and CMV infection (36% EVL group vs 22%, p=0.42). Liver biopsy showed acute hepatitis, fibrosis stage I-III and fibrosis stage≥ IV in 45%, 36% and 0% respectively in EVL group and 61%, 34% and 5% respectively in control group(p=0.27). Advanced fibrosis at two year liver biopsy (fibrosis stage ≥IV) was observed in 27% in EVL group vs 52% in control group (p=0.12). Conclusions: Despite the limits of this study due to reduced number of patients, we observed a tendency to slowly fibrosis progression in liver transplant recipients treated with EVL. Prospective trials are justified to evaluate the anti-fibrotic potential effect of early conversion to EVL in HCV positive LT recipients. 1550

1029 LONG-TERM OUTCOME OF CIRRHOTIC PATIENTS WITH SINGLE HCC ≤ 5CM. DOES LIVER RESECTION HAVE THE SAME RESULTS AS LIVER TRANSPLANTATION?

1027 EARLY ASSESSMENT OF RESPONSE TO SORAFENIB IN ADVANCED HEPATOCELLULAR CARCINOMA USING PERFUSIONAL COMPUTED TOMOGRAPHY: PILOT STUDY R. Sacco, L. Faggioni, A. Romano, I. Bargellini, M. Bertini, B. Ginanni, M. Bertoni, G. Federici, V. Battaglia, S. Metrangolo, G. Parisi, A. Scaramuzzino, E. Tumino, G. Bresci, C. Bartolozzi. Gastroenterology, Cisanello Pisa University Hospital, Pisa, Internal Medicine, University of Foggia, Foggia, Radiology, Cisanello Pisa University Hospital, Pisa, Italy E-mail: r.sacco@ao-pisa.toscana.it