Early γGT and bilirubin levels as biomarkers for regeneration and outcomes in damaged bile ducts after liver transplantation.

BACKGROUND: Early patient and allograft survival after liver transplantation (LT) depend primarily on parenchymal function, but long-term allograft success relies often on biliary-tree function. We examined parameters related to cholangiocyte damage that predict poor long-term LT outcomes after donation after brain death (DBD). METHODS: Sixty bile ducts (BD) were assessed by a BD damage-score and divided into groups with "major" BD-damage (n = 33) and "no relevant" damage (n = 27) during static cold storage. Patients with "major" BD damage were further investigated by measuring biliary excretion parameters in the first 14 days post-LT (followed-up for 60-months). RESULTS: Patients who received LT showing "major" BD damage had significantly worse long-term patient survival, versus grafts with "no relevant" damage (p = .03). When "major" BD damage developed, low bilirubin levels (p = .012) and high gamma-glutamyl transferase (GGT)/bilirubin ratio (p = .0003) were evident in the early post-LT phase (7-14 days) in patients who survived (> 60 months), compared to those who did not. "High risk" patients with bile duct damage and low GGT/bilirubin ratio had significantly shorter overall survival (p < .0001). CONCLUSIONS: Once "major" BD damage occurs, a high GGT/bilirubin ratio in the early post-operative phase is likely indicator of liver and cholangiocyte regeneration, and thus a harbinger of good overall outcomes. "Major" BD damage without markers of regeneration identifies LT patients that could benefit from future repair therapies.

Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: A retrospective multicenter analysis.

Liver transplantation (LT) is the only definitive treatment for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow-up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow-up for 98.8 months. The 1-, 5-, and 10-year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient-donor constellation.

[Organ replacement therapy - extracorporeal liver assist devices]. / Organersatzverfahren - Leberunterstützungsverfahren.

Liver failure is a disease with a high mortality rate. Often liver transplantation is the sole therapeutic option. On the one hand, liver support systems probably support the liver to allow regeneration, on the other hand they are an option to bridge for transplantation. This article gives an overview on the clinically used liver assist devices (molecular adsorbent recirculating system [MARS], Prometheus system, single-pass albumin dialysis [SPAD], plasmapheresis) and discusses the applications in liver failure.

Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis.

BACKGROUND & AIMS: ASP9831 is a phosphodiesterase-4 inhibitor developed to treat nonalcoholic steatohepatitis (NASH); it showed potent anti-inflammatory and antifibrotic effects in preclinical studies. We evaluated the efficacy and safety of ASP9831 in patients with NASH. METHODS: In a phase 1 trial, we determined the optimal therapeutic window of ASP9831 in healthy volunteers and evaluated 2 doses (50 and 100 mg) in patients with NASH. Based on the positive outcomes of the phase 1 study, we performed a phase 2 trial to compare the biochemical effects of ASP9831 vs placebo. Patients with NASH were assigned randomly to groups given either 50 mg (n = 33) or 100 mg (n = 33) ASP9831 twice daily, or placebo (n = 30), for 12 weeks. The primary end point was the mean percentage change, from baseline to the end of ASP9831 administration, in serum level of alanine aminotransferase (ALT); secondary outcomes included changes in aspartate aminotransferase (AST) levels, ratio of AST:ALT, and various biomarkers of NASH. RESULTS: After 12 weeks of administration, there was no significant change in mean serum levels of ALT (P = .42) or AST (P = .20) or other biomarkers in any group, and no significant differences were observed among groups. Most adverse events were mild; gastrointestinal disorders occurred more frequently in the ASP9831 groups than the placebo group. CONCLUSIONS: Despite a relevant mechanism of action, ASP9831 did not significantly alter the biochemical markers of NASH, compared with placebo, in a clinical trial. This highlights the difficulties of developing therapeutics for NASH and the need for more extensive preclinical testing of mechanisms of potential drug candidates. Clinicaltrialsregister.eu: 2005-001687-31; EudraCT numbers: 2007-002114-19.

Bile duct damage after cold storage of deceased donor livers predicts biliary complications after liver transplantation.

BACKGROUND & AIMS: The aim of this study was to examine the development of biliary epithelial damage between organ retrieval and transplantation and its clinical relevance for patients. METHODS: Common bile duct samples during donor hepatectomy, after cold storage, and after reperfusion were compared to healthy controls by hematoxylin and eosin (H&E) staining and immunofluorescence for tight junction protein 1 and Claudin-1. A bile duct damage score to quantify biliary epithelial injury was developed and correlated with recipient and donor data and patient outcome. RESULTS: Control (N=16) and donor hepatectomy bile ducts (N=10) showed regular epithelial morphology and tight junction architecture. After cold storage (N=37; p=0.0119), and even more after reperfusion (N=62; p=0.0002), epithelial damage, as quantified by the bile duct damage score, was markedly increased, and both tight junction proteins were detected with inappropriate morphology. Patients with major bile duct damage after cold storage had a significantly increased risk of biliary complications (relative risk 18.75; p<0.0001) and graft loss (p=0.0004). CONCLUSIONS: In many cases, the common bile duct epithelium shows considerable damage after cold ischemia with further damage occurring after reperfusion. The extent of epithelial damage can be quantified by our newly developed bile duct damage score and is a prognostic parameter for biliary complications and graft loss. Possibly, in an intraoperative histological examination, this bile duct damage score may influence decision-making in transplantation surgery.

Esophageal tissue injury following pulmonary vein isolation using the PVAC: assessment by endoscopy and magnetic resonance imaging.

BACKGROUND: We investigate the frequency of esophageal tissue injury (ETI) following ablation of atrial fibrillation (AF) using the pulmonary vein ablation catheter (PVAC) ascertained by esophageal endoscopy (ESE) and corresponding magnetic resonance imaging (MRI). METHODS: A total of 41 patients with symptomatic AF presenting for pulmonary vein isolation (PVI) were included consecutively in two observational groups. Group A received MRI the day before and ESE plus MRI within 3-4 weeks following the ablation procedure using the PVAC. Group B received MRI the day before and ESE plus MRI within 2 days after PVI. MRI included T2-weighted and T1-weighted postcontrast with fat suppression (fs) and late-enhancement scans to demonstrate postprocedural edema and contrast enhancement of the esophageal wall. RESULTS: A total of 13 (32%) patients were enrolled in Group A (26 ± 11 days post-PVI), and 28 (68%) patients in Group B (2 ± 0.6 days post-PVI). ETI was found by ESE in one (2%) patient (Group B) and resolved under conservative therapy. Corresponding MRI showed a false negative result with no alterations of esophageal structures using T1-weighted, T2-weighted, and late enhancement scans. In addition, false positive results were demonstrated by late-enhancement MRI in five (12%) patients (three patients in Group A and two patients in Group B), which could not be verified by corresponding ESE. CONCLUSIONS: Endoluminal ETI is a rare but possible complication, which should be considered following PVAC procedures. MRI of the esophagus is currently not a reliable screening method due to false positive and negative findings compared to ESE.

Serum ferritin concentration and transferrin saturation before liver transplantation predict decreased long-term recipient survival.

UNLABELLED: Serum ferritin (SF) concentration is a widely available parameter used to assess iron homeostasis. It has been described as a marker to identify high-risk patients awaiting liver transplantation (LT) but is also elevated in systemic immune-mediated diseases, metabolic syndrome, and in hemodialysis where it is associated with an inferior prognosis. This study analyzed whether SF is not only a predictor of liver-related mortality prior to LT but also an independent marker of survival following LT. In a dual-center, retrospective study, a cohort of 328 consecutive first-LT patients from Hannover Medical School, Germany (2003-2008, follow-up 1260 days), and 82 consecutive LT patients from Regensburg University Hospital, Germany (2003-2007, follow-up 1355 days) as validation cohort were analyzed. In patients exhibiting SF ≥365 µg/L versus <365 µg/L prior to LT, 1-, 3-, and 5-year post-LT survival was 73.3% versus 81.1%, 64.4% versus 77.3%, and 61.1% versus 74.4%, respectively (overall survival P = 0.0097), which was confirmed in the validation cohort (overall survival of 55% versus 83.3%, P = 0.005). Multivariate analyses identified SF ≥365 µg/L combined with transferrin saturation (TFS) <55%, hepatocellular carcinoma, and the survival after LT (SALT) score as independent risk factors for death. In patients with SF concentrations ≥365 µg/L and TFS <55%, overall survival was 54% versus 74.8% in the remaining group (P = 0.003). In the validation cohort, it was 28.6% versus 72% (P = 0.017), respectively. CONCLUSION: SF concentration ≥365 µg/L in combination with TFS <55% before LT is an independent risk factor for mortality following LT. Lower TFS combined with elevated SF concentrations indicate that acute phase mechanisms beyond iron overload may play a prognostic role. SF concentration therefore not only predicts pre-LT mortality but also death following LT.

Colonic bowel wall thickening: is there a need for endoscopic evaluation?

PURPOSE: Clinical relevance of colonic bowel wall thickening seen on abdominal CT scans is unknown. Recommendations for further diagnostic procedures are lacking. The aim of this retrospective study was to evaluate detecting of bowel wall thickening on CT scan and findings that were seen in case of endoscopical evaluation. METHODS: The radiological database was retrospectively reviewed for all reports of CT scans from 2003 to 2009 at the University Hospital Regensburg, Germany. Patients with underlying diseases for suspected bowel wall thickening were excluded. RESULTS: Sixty-two patients with bowel wall thickening were detected. Twenty-one percent (13/62) had generalized bowel wall thickening. In 58%, bowel wall thickening was limited to one segment of the colon (36/62), mostly left sided (25/62). Forty-four percent of patients (27/62) were sent to endoscopy. In 15% (4/27), malignancy was suspected, and it could be histologically confirmed in two patients. Nineteen percent (5/27) had normal endoscopy, and 67% (18/62) showed benign findings. CONCLUSION: Colonic bowel wall thickening is not a common finding on CT scan in this study. Consequential endoscopic evaluation was performed in less than 50% of patients. Pathological findings were detected in 80% of these patients. We recommend endoscopical evaluation if bowel wall thickening is reported on CT scan.

Strong predictors for alcohol recidivism after liver transplantation: non-acceptance of the alcohol problem and abstinence of <3 months.

OBJECTIVE: Alcohol-toxic liver cirrhosis (ALC) is one of the main indications for liver transplantation (LT). The aim of the study is to define predictors for alcohol recidivism and to identify the outcome and quality of life of such patients. MATERIAL AND METHODS: From March 2003 to July 2009, 226 patients underwent LT in our centre. In 53% liver cirrhosis was caused by alcohol abuse (sole/cofactor). Outcome and alcohol recidivism were assessed using patients' records, laboratory tests and interviews (patient, family members and family doctor). Furthermore, patients received an SF-36 quality of life and a self-designed questionnaire anonymously. RESULTS: Mean follow-up after LT was 31 + 23 months. The 5-year survival rate after LT in patients with ALC was significantly better compared to patients with other indications (78 vs. 64%; p = 0.016). Quality of life of both patient groups was comparable. After LT, alcohol recidivism rate was 16%. Patients with an alcohol abstinence of <3 months before LT had a significantly higher (p = 0.012) rate of alcohol recidivism in comparison to those with an abstinence of >3 months. Another predictor for alcohol recidivism was the patients' non-acceptance of having an alcohol problem before LT (p = 0.001). CONCLUSIONS: ALC is a good indication for LT. An alcohol abstinence of <3 months before LT and a non-acceptance of having an alcohol problem are strong predictors for alcohol recidivism after LT.

Causes of bolus impaction in the esophagus.

BACKGROUND: Bolus impaction in the esophagus is a common indication for emergency endoscopy. The aim of this study was to determine the most common causes of esophageal bolus impaction. METHODS: In this retrospective study, data of 54 patients (41 male, 13 female) with bolus impaction in the esophagus were analyzed. Type and localization of the bolus and the endoscopic extraction tool used were evaluated. In 48 of 54 patients (89%), biopsy samples were taken of the esophagus for histological examination. RESULTS: Mean age of the patients was 53 ± 20 years. Fourteen of 54 patients (26%) had experienced bolus impaction previously. Meat bolus (n = 35, 65%) was the most common cause of esophageal obstruction. In most cases, boluses were found in either the distal (n = 31) or the proximal (n = 18) esophagus. In 22 patients (41%), the bolus was pushed into the stomach by the endoscope. In most other cases the bolus, including foreign bodies, could be removed with the 5-arm polyp grasper or alligator forceps. Main causes of bolus impaction were eosinophilic esophagitis (n = 10) or reflux disease with or without peptic stenosis (n = 10), respectively. CONCLUSION: Bolus impaction is frequently correlated with eosinophilic esophagitis and reflux esophagitis; therefore, diagnostic workup should include esophageal biopsy sampling.

Improved outcome after 'bottom-up' immunosuppression in liver transplant recipients with preoperative renal impairment.

BACKGROUND: Most patients with high MELD scores have impaired renal function prior to transplantation. PATIENT AND METHODS: A retrospective case control study was conducted with initial low immunosuppression, which was increased when patients rejected or were clinically stable beyond day 30 ('bottom-up'). RESULTS: Thirty patients with impaired renal function were included. Fifteen were treated with de novo cyclosporine A (CsA; group A), and 15 had 'bottom-up' immunosuppression (group B). Baseline renal function was similar: serum creatinine (SCr) median 1.8 mg/dl (range: 1.5-4.0 mg/dl; group A) versus 2.4 mg/dl (range: 1.5-4.0 mg/dl; group B; p = 0.24). The requirement for renal replacement therapy was significantly lower in group B (p = 0.032). Ten received 'bottom-up' immunosuppression [4 CsA/1 sirolimus (Sir) 'on demand' after rejection, 5 Sir (stable)] beyond day 30. By months 6 and 12 (1.6 mg/dl vs. 1.2 mg/dl), SCr values were significantly better in group B (p = 0.006). Renal function in group B did not differ between patients receiving CsA or Sir. Overall complication rates, survival and biopsy-proven acute rejection were similar, although BANFF scores were higher in group B (p = 0.004). CONCLUSION: Successful implementation of 'bottom-up' immunosuppression in liver transplant recipients with high lab-MELD scores and renal dysfunction at the time of transplantation has the potential to substantially improve short- and long-term outcomes.

Current Challenges in the Post-Transplant Care of Liver Transplant Recipients in Germany.

Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but also on medical factors such as de novo malignancies, metabolic disorders (e.g., new-onset diabetes, osteoporosis), psychiatric conditions (e.g., anxiety, depression), renal failure, and cardiovascular diseases. While a comprehensive post-transplant care at the LT center and the connected regional networks may improve outcome, there is currently no generally accepted standard to the post-transplant management of LT recipients in Germany. We therefore described the structure and standards of post-LT care by conducting a survey at 12 German LT centers including transplant hepatologists and surgeons. Aftercare structures and form of cost reimbursement considerably varied between LT centers across Germany. Further discussions and studies are required to define optimal structure and content of post-LT care systems, aiming at improving the long-term outcomes of LT recipients.

Perihilar lymph nodes in patients with primary sclerosing cholangitis with and without cholangiocellular carcinoma.

OBJECTIVE: Enlarged perihilar lymph nodes have been described in patients with primary sclerosing cholangitis (PSC). The aim of the study was to determine the clinical relevance of perihilar lymph nodes in PSC patients with and without cholangiocellular carcinoma (CCC). MATERIAL AND METHODS: The status of perihilar lymph nodes was investigated in 117 patients with PSC using "high-end" ultrasound. Thirty-five of the 117 PSC patients had histologically proven CCC. Lymph node status was correlated with the presence of CCC and inflammatory bowel disease (IBD). RESULTS: Seventy-three percent of PSC patients without CCC and 86% of patients with CCC had enlarged perihilar lymph nodes (NS). In CCC patients, the width of lymph nodes was significantly larger (12+/-6 mm versus 8+/-4 mm; p=0.0001), and the length:width ratio (2.15+/-0.7:1 versus 2.5+/-0.6:1; p=0.004) of the lymph nodes was significantly lower. Thirty-seven percent of PSC patients without CCC and 57% of patients with PSC and CCC had multiple perihilar lymph nodes (p=0.04). In all patients, the presence versus absence of IBD had no influence on the number (84% versus 74%,) and size of perihilar lymph nodes (length: 21+/-10 mm versus 19+/-7 mm). Lymph node status did not correlate with the number of episodes of cholangitis. CONCLUSIONS: Enlarged perihilar lymph nodes are characteristic of patients with PSC. Since perihilar lymph nodes are not predictive of the presence of complicating CCC, such patients should not be excluded from liver transplantation.

Suitability of the simplified autoimmune hepatitis score for the diagnosis of autoimmune hepatitis in a German cohort.

BACKGROUND: Several years ago the International Autoimmune Hepatitis Group simplified the previous revised original scoring system for diagnosis of autoimmune hepatitis (AIH) into a scoring system based on only four instead of 13 parameters. OBJECTIVE: We aimed to evaluate the suitability of the simplified AIH score for diagnosis of AIH in a German cohort with chronic liver diseases. METHODS: In this retrospective single-center study, we compared the accuracy of both AIH scores in 70 patients with AIH and 211 patients with chronic liver diseases (PBC (n = 52), PSC (n = 27), NASH (n = 67), DILI (n = 15), CHB/C (n = 50)). Sensitivity, specificity and predictability of each scoring system were calculated. RESULTS: Using the simplified AIH score, the sensitivity and specificity of detecting a probable AIH (scores ≥ 6) were 96% and 97% with a positive and negative predictive value of 92% and 99%, respectively. For diagnosis of definite AIH (scores ≥ 7), the sensitivity and specificity were 43% and 100% with a positive and negative predictive value of 97% and 84%, respectively. The concordance with the revised original criteria was 63%. The specificity for excluding AIH was excellent in both scoring system. CONCLUSION: The simplified diagnostic criteria allow a reliable diagnosis of AIH in a German cohort.

NOD2 gene variants confer risk for secondary sclerosing cholangitis in critically ill patients.

Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease of unknown aetiology characterized by chronic biliary infections. Hence we hypothesized that common NOD2 (nucleotide-binding oligomerisation domain containing 2) gene variants, known risk factors for Crohn's disease and bacterial translocation in liver cirrhosis, increase the odds of developing SC-CIP. Screening of 4,641 endoscopic retrograde cholangiography procedures identified 17 patients with SC-CIP, who were then genotyped for the three common NOD2 mutations (Cohort 1, discovery cohort). To validate the association, we subsequently tested these NOD2 variants in 29 patients from SC-CIP cohorts of three additional medical centers (Cohort 2, replication cohort). In Cohort 1, the NOD2 variants were present in 5 of 17 SC-CIP patients (29.4%), which is twice the frequency of the general population. These results were replicated in Cohort 2 with 8 patients (27.6%) showing NOD2 mutations. In contrast, polymorphisms of hepatocanalicular transporter genes did not have major impact on SC-CIP risk. This first study on genetic susceptibility in SC-CIP patients shows an extraordinary high frequency of NOD2 variation, pointing to a critical role of inherited impaired anti-bacterial defense in the development of this devastating biliary disease.

Update on Sclerosing Cholangitis in Critically Ill Patients.

BACKGROUND: ?Sclerosing cholangitis in critically ill patients' (SC-CIP) is a cholestatic liver disease of unknown etiology and represents the most prevalent form of secondary sclerosing cholangitis. METHODS: This overview is based on a systematic review of the literature searching for 'secondary sclerosing cholangitis', 'SC-CIP', 'cast syndrome', and 'ischemic cholangitis' in the database PubMed. RESULTS: SC-CIP can develop in patients with sepsis and acute respiratory distress syndrome during a long-term intensive care unit (ICU) treatment. It is a rare cholestatic liver disease with a rapid progression to liver cirrhosis and hepatic failure. SC-CIP is initiated by an ischemic injury to the biliary tree with subsequent stenoses of biliary ducts, biliary casts, and infections, often with multi-resistant bacteria. Mechanical ventilation with high positive end-expiratory pressure, prone positioning, and a higher volume of intraperitoneal fat have been proposed as risk factors for developing SC-CIP. Patients with SC-CIP have a poor prognosis, with liver transplantation (LT) being the only curative treatment option. CONCLUSION: In patients with sepsis, long-term ICU therapy and ongoing cholestasis SC-CIP must be excluded by endoscopic retrograde cholangiopancreatography. Due to the poor prognosis, the option of LT should be evaluated in all patients with SC-CIP.

Clinical pharmacokinetics of everolimus.

Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxyethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which has greater polarity than sirolimus, was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase its oral bioavailability. Everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signals in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors ciclosporin and tacrolimus. Everolimus and ciclosporin show synergism in immunosuppression both in vitro and in vivo and therefore the drugs are intended to be given in combination after solid organ transplantation. The synergistic effect allows a dosage reduction that decreases adverse effects. For the quantification of the pharmacokinetics of everolimus, nine different assays using high performance liquid chromatography coupled to an electrospray mass spectrometer, and one enzyme-linked immunosorbent assay, have been developed. Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3-1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children. The interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C8. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system. In patients with hepatic impairment, the apparent clearance of everolimus is significantly lower than in healthy volunteers, and therefore the dosage of everolimus should be reduced by half in these patients. The advantage of everolimus seems to be its lower nephrotoxicity in comparison with the standard immunosuppressants ciclosporin and tacrolimus. Observed adverse effects with everolimus include hypertriglyceridaemia, hypercholesterolaemia, opportunistic infections, thrombocytopenia and leucocytopenia. Because of the variable oral bioavailability and narrow therapeutic index of everolimus, blood concentration monitoring seems to be important. The excellent correlation between steady-state trough concentration and AUC makes the former a simple and reliable index for monitoring everolimus exposure. The target trough concentration of everolimus should range between 3 and 15 microg/L in combination therapy with ciclosporin (trough concentration 100-300 microg/L) and prednisone.

Sirolimus/cyclosporine/tacrolimus interactions on bile flow and biliary excretion of immunosuppressants in a subchronic bile fistula rat model.

The new immunosuppressive agent sirolimus generally is combined in transplant patients with cyclosporine and tacrolimus which both exhibit cholestatic effects. Nothing is known about possible cholestatic effects of these combinations which might be important for biliary excretion of endogenous compounds as well as of immunosuppressants. Rats were daily treated with sirolimus (1 mg kg(-1) p.o.), cyclosporine (10 mg kg(-1) i.p.), tacrolimus (1 mg kg(-1) i.p.), or a combination of sirolimus with cyclosporine or tacrolimus. After 14 days a bile fistula was installed to investigate the effects of the immunosuppressants and their combinations on bile flow and on biliary excretion of bile salts, cholesterol, and immunosuppressants. Cyclosporine as well as tacrolimus reduced bile flow (-22%; -18%), biliary excretion of bile salts (-15%;-36%) and cholesterol (-15%; -47%). Sirolimus decreased bile flow by 10%, but had no effect on cholesterol or bile salt excretion. Combination of sirolimus/cyclosporine decreased bile flow and biliary bile salt excretion to the same extent as cyclosporine alone, but led to a 2 fold increase of biliary cholesterol excretion. Combination of sirolimus/tacrolimus reduced bile flow only by 7.5% and did not change biliary bile salt and cholesterol excretion. Sirolimus enhanced blood concentrations of cyclosporine (+40%) and tacrolimus (+57%). Sirolimus blood concentration was increased by cyclosporine (+400%), but was not affected by tacrolimus. We conclude that a combination of sirolimus/tacrolimus could be the better alternative to the cotreatment of sirolimus/cyclosporine in cholestatic patients and in those facing difficulties in reaching therapeutic ranges of sirolimus blood concentration.

Liver transplantation for malignancy: current treatment strategies and future perspectives.

In 1967, Starzl et al performed the first successful liver transplantation for a patient diagnosed with hepatoblastoma. In the following, liver transplantation was considered ideal for complete tumor resection and potential cure from primary hepatic malignancies. Several reports of liver transplantation for primary and metastatic liver cancer however showed disappointing results and the strategy was soon dismissed. In 1996, Mazzaferro et al introduced the Milan criteria, offering liver transplantation to patients diagnosed with limited hepatocellular carcinoma. Since then, liver transplantation for malignant disease is an ongoing subject of preclinical and clinical research. In this context, several aspects must be considered: (1) Given the shortage of deceased-donor organs, long-term overall and disease free survival should be comparable with results obtained in patients transplanted for non-malignant disease; (2) In this regard, living-donor liver transplantation may in selected patients help to solve the ethical dilemma of optimal individual patient treatment vs organ allocation justice; and (3) Ongoing research focusing on perioperative therapy and anti-proliferative immunosuppressive regimens may further reduce tumor recurrence in patients transplanted for malignant disease and thus improve overall survival. The present review gives an overview of current indications and future perspectives of liver transplantation for malignant disease.