Christian Moench

Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection

BACKGROUND & AIMS Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. METHODS Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C. RESULTS Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected toward the adverse genotypes rs12979860 CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860 CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No association was observed between ALT/HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR, and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively). CONCLUSIONS We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.

Posthepatectomy liver failure.

Background: Posthepatectomy liver failure (PHLF) is one of the most serious complications after liver resection and is still reported in up to 8% after liver resection. Aims: To provide an overview about the current status of risk analysis and definition of PHLF. Prevention and treatment is also discussed. Methods: A literature review was carried out on PubMed using the terms ‘liver failure’, ‘posthepatectomy’ and ‘liver surgery’ to search relevant papers. Discussion: PHLF remains a serious problem in patients undergoing major liver resection. Adequate preoperative risk assessment and an optimal postoperative treatment are essential for PHLF prevention.

Long‐term follow‐up of endoscopic therapy for stenosis of the biliobiliary anastomosis associated with orthotopic liver transplantation

Endoscopic treatment for stenosis of an anastomotic biliary stricture (ABS) after orthotopic liver transplantation (OLT) has been proven to be effective and safe, but the long‐term outcomes and the risk factors for recurrence are unknown. All 374 patients who underwent OLT at Frankfurt University Hospital were screened for the occurrence of ABSs. ABSs were treated via the endoscopic insertion of a plastic endoprosthesis (29.8%), balloon dilation (12.8%), or a combination of the two (57.4%). The mean follow‐up time was 151 weeks, and the mean survival time was 3.4 years. ABSs were observed in 47 patients (12.6%). The mean time from OLT to an ABS was 16.25 months (median = 3.25 months). The cumulative incidence rates for ABSs were 0.09 after 12 months, 0.10/24 m. and 0.11/36 m. In 12 cases (25.5%), ABSs were observed more than 12 months after OLT. ABSs recurred in 16 of the 47 patients (34%). The occurrence of an ABS 6 weeks or more after OLT was a significant predictor of ABS recurrence [P = 0.04, hazard ratio (HR) = 0.235]. There was a trend of hepatitis C virus (HCV) infections being predominant in patients experiencing ABS recurrence (30% for HCV etiology versus 4% for non‐HCV etiology) in comparison with patients not experiencing recurrence (36% for HCV etiology versus 30% for non‐HCV etiology, P > 0.05). The severity of the initial stricture predicted ABS recurrence (P = 0.046, HR = 2.78), but it did not influence overall survival. The long‐term resolution of ABSs was observed in 45 of the 47 patients (95.7%), and ABS recurrence was treated with another attempt (n = 16 or 34%) or 2 more attempts (n = 1) at endoscopic treatment. In conclusion, the long‐term success of the endoscopic treatment of ABSs is highly probable if recurrent strictures are again treated endoscopically. ABSs might occur late (>36 months) after OLT, and lifelong follow‐up is essential for identifying OLT patients with ABSs. Liver Transpl 19:586–593, 2013.

Daily dosing of tacrolimus in patients treated with HIV-1 therapy containing a ritonavir-boosted protease inhibitor or raltegravir

OBJECTIVES The number of HIV-infected patients receiving orthotopic liver transplantation (OLTX) is increasing. One major challenge is the severe drug-drug interactions between immunosuppressive drugs such as tacrolimus and ritonavir-boosted HIV-1 protease inhibitors (PIs). The introduction of raltegravir, which is not metabolized by the cytochrome system, may allow concomitant treatment without dose adaptation. PATIENTS AND METHODS We conducted a retrospective analysis of HIV-1-infected patients receiving tacrolimus concomitantly with different HIV therapies, including 12 h pharmacokinetic assessment of drug levels. RESULTS Three OLTX patients received a ritonavir-boosted PI therapy when tacrolimus was added at very low doses of 0.06, 0.03 and 0.08 mg daily. Median tacrolimus blood levels were 6.6, 3.0 and 7.9 ng/mL over a follow-up period of 8, 22 and 33 months, respectively. In two other patients (one after OLTX and one with Crohns disease), a raltegravir-based HIV therapy was started while patients received 1 or 2 mg of tacrolimus twice daily. No tacrolimus dose adjustment was necessary and drug levels remained unchanged. CONCLUSIONS Decreasing the dose of tacrolimus to 0.03-0.08 mg daily in patients with concomitant boosted PI therapy resulted in stable tacrolimus blood levels without alteration of PI drug levels. Concomitant use of raltegravir and tacrolimus revealed no clinically relevant drug interaction.

Comparison of Cyclosporine Microemulsion and Tacrolimus in 39 Recipients of Living Donor Liver Transplantation

New immunosuppressive agents and regimens should be evaluated specifically in living donor liver transplant patients due to potential clinical and pharmacokinetic differences between deceased donor and living donor transplant recipients. The analysis presented here is the first direct comparison of clinical outcomes using cyclosporine microemulsion (CsA‐ME) with monitoring of blood concentration at 2 hours postdose (C2) and tacrolimus‐based immunosuppression in living donor liver transplantation. The analysis was conducted on the data provided by the 39 recipients of a living donor transplant out of the 495 patients enrolled in a 6‐month, randomized, prospective, multicenter, open‐label study (LIS2T). Patients were randomized to CsA‐ME (C2 monitoring) or tacrolimus (monitoring of predose trough drug blood level [C0)]) and were administered corticosteroids with or without azathioprine. Twenty‐three living‐donor patients received CsA‐ME and 16 received tacrolimus. By month 6, 9% of patients receiving CsA‐ME and 19% of those receiving tacrolimus had lost their graft or died (not significant [NS]). Nine episodes of biopsy‐proven acute rejection were reported: 4 in the CsA‐ME group (17%) and 5 in the tacrolimus cohort (31%, NS). There were no significant differences in any safety parameter between groups. The most frequently reported serious adverse events were infections, which occurred in 14 patients in the CsA‐ME group (61%) and 13 patients in the tacrolimus arm (81%, NS). Twelve patients in the CsA‐ME arm (52%) and 5 in the tacrolimus arm (31%, NS) discontinued the study prematurely. In conclusion, CsA‐ME C2 monitoring or tacrolimus both offer effective protection against rejection in living donor liver transplants while maintaining a good safety profile. (Liver Transpl 2005;11:1395–1402.)

A possible role of microRNAs as predictive markers for the recurrence of hepatocellular carcinoma after liver transplantation

With favourable 5‐year survival rates up to 75%, liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). Nonetheless, tumour recurrence after LT remains a challenge. The aim of this retrospective study was to develop a predictive score for tumour recurrence after LT by combining clinical parameters with HCC biomarkers (microRNA). A microRNA (miRNA) microarray analysis was used to compare miRNA expression patterns in tissue samples of 40 patients with and without HCC recurrence after LT. In a screening cohort (n = 18), the miRNA analysis identified significant differences in the expression of 13 miRNAs in patients with tumour recurrence. Using the most significant miRNAs in this screening cohort, we could develop a predictive score, which combined the expression levels of miR‐214, miR‐3187 and the Milan criteria, and we could define low‐ and high‐risk groups for tumour recurrence and death. The above score was evaluated in a second and independent cohort (n = 22). In contrast to the Milan criteria alone, this score was significantly associated with tumour recurrence. Our analysis indicated that the use of a specific miRNA expression pattern in combination with a limited tumour burden as defined by the Milan criteria may lead to a more accurate prediction of tumour recurrence.

Effects of mycophenolate mofetil introduction in liver transplant patients: results from an observational, non-interventional, multicenter study (LOBSTER)

The benefits of calcineurin inhibitor (CNI)‐sparing regimens on renal function following liver transplantation (LT) have been demonstrated in clinical studies. This observational study assessed the real‐life effects of mycophenolate mofetil (MMF) introduction in LT patients. Four hundred and ninety‐seven patients in whom MMF was introduced according to local standards or clinical considerations were entered. Patients were grouped by time between transplantation and start of MMF (start of study): Group A (n = 263): ≤6 d; Group B (n = 64): >6 d to ≤1 month; Group C (n = 74): >1 month to ≤1 yr; and Group D (n = 96): >1 yr. CNI sparing occurred in all groups, particularly in Groups C and D. Mean MMF doses at 12 months were 1202.7, 1363.5, 1504.7, and 1578.1 mg/d, respectively, in Groups A–D. At introduction of MMF, median glomerular filtration rate was 73.3, 81.7, 62.7, and 53.7 mL/min/1.73 m2 in Groups A–D. At 12 months, this decreased to 66 mL/min/1.73 m2 in Groups A and B, remained stable in Group C, and increased in Group D (64.8 mL/min/1.73 m2). Serious adverse drug reactions were lowest in Group D. In conclusion, MMF with a subsequent decrease in CNI was well tolerated and improved renal function even years after transplantation. A more forceful MMF dosing strategy with greater CNI sparing may further improve renal function.

Xenon Anesthesia for Liver Transplant Surgery: A Report of Four Cases

It is well established that patients presenting for orthotopic liver transplantation pose challenging surgical and anesthesiological problems. Intraoperatively, severe hemodynamic instability due to profuse bleeding and acute cardiomyopathy during reperfusion are major concerns. In addition, ischemia-reperfusion injury can compromise postoperative graft function. Xenon, with its potential to maintain hemodynamic stability, preserve cardiac function, and protect the liver graft of the recipient, seems to be a promising anesthetic agent for liver transplant surgery. To date, xenon has not been used as an anesthetic in liver transplantations. We therefore have reported our initial experience with four patients who underwent orthotopic deceased donor liver transplantation under xenon anesthesia. Although all patients had advanced liver disease and experienced significant intraoperative bleeding, their intraoperative courses, including reperfusion, under xenon anesthesia were remarkably stable. The patients required only moderate, temporary catecholamine support, which was withdrawn at the end of the surgery. Xenon anesthesia for liver transplant procedures proved to be feasible. Immediate postoperative organ function was satisfactory in all patients.

The right to refuse

The clinical success of organ transplantation started with live donor kidney transplantation more than half a century ago. Living donation was originally limited to kidney donation – a paired organ whose removal is usually tolerated by the donor with certain risk that is rarely life threatening. Partial liver transplantation was originally developed for pediatric liver transplantation, where a parent would donate part of the liver to his or her sick child. In many countries, especially in Asia, cultural traditions have hindered the development of recovery of organs from deceased donors. In these regions, living liver donation among adults has become the de facto standard of care. In contrast to kidney donation adult-to-adult liver transplantation (mostly utilizing the right liver lobe) carries with it considerable risks to the donor including a mortality of 0.2–0.5% – which may even seem to be an underestimation, and a morbidity risk of around 50% in the immediate perioperative period. In the early days, and in part ascribable to limitations of immunosuppression, living donation was limited to family members and blood relatives. While blood relation is not a prerequisite for donation any more, donation between individuals who have some sort of personal relation is the rule. In many countries this relationship between potential donor and recipient is scrutinized by specially designated, usually multiprofessional committees to rule out commercial donation. In comes so-called ‘‘Samaritan donation’’ where a healthy person donates part of his or her body anonymously into the pool of waiting recipients and the organ is allocated following standard allocation rules to a patient unknown to the donor. Today the term ‘‘Samaritan donation’’ is widely used but perhaps misleading: according to the scriptures the good Samaritan, ‘‘moved by compassion’’ took care of a road side robbery trauma victim by providing him oil, wine, wound dressings, transportation, and prepayment for in-patient treatment – only time and valuables, but not part of his body (Luke 10:30–37). Against this complex background Hilhorst et al. describe the case of an individual who had previously donated a kidney anonymously and now wishes to donate another part of his body i.e part of his liver [1]. The question whether or not ‘‘we’’ can turn down this wish starts with the definition of ‘‘we’’ – it may imply we as physicians, we as hospital employees in a transplant center, we as a professional society or we as a society of the whole. The easiest answer is: yes, of course we can turn down this offer individually as a physician – however, we Correspondence Prof. Dr. Wolf O. Bechstein, Department of General and Visceral Surgery, TheodorStern-Kai 7, 60590 Frankfurt am Main, Germany. Tel.: +49 69 6301 5251; fax: +49 69 6301 7452; e-mail: wolf.bechstein@kgu.de

Early echocardiographic detection of a massive intracardiac thrombus in a patient scheduled for orthotopic liver transplantation

Transesophageal echocardiography (TEE) in cases of orthotopic liver transplantation is gaining acceptance for intraoperative hemodynamic monitoring. The timepoint of TEE probe insertion varies and is based on the fear of bleeding complications in the setting of portal hypertension with esophageal varices. In this case, early insertion of the TEE probe and examination resulted in the early detection of a large intracardiac thrombus, and thus the cancellation of the planned procedure. This case highlights the potential value of early TEE examination in orthotopic liver transplantation.