[Expert recommendations: Hepatitis C and transplantation]. / Empfehlungen zur antiviralen Therapie der chronischen Hepatitis C bei Patienten auf der Warteliste und nach Transplantation.

With the approval of new direct acting antiviral agents (DAA), therapeutic options for patients with chronic hepatitis C virus (HCV) infection are now generally available before and after liver transplantation (LT). Interferon-free DAA regimens are highly effective therapies and provide a good safety profile. However, the body of clinical evidence in this patient population is limited and the best treatment strategies for patients on the waiting list with (de)compensated cirrhosis and after LT are not well defined. The following recommendations for antiviral therapy in the context of LT are based on the currently available literature and clinical experience of experts in the field, and have been discussed in an expert meeting. The aim of this article is to guide clinicians in the decision making when treating patients before and after LT with DAAs.

Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Use of paclitaxel-eluting balloons for endotherapy of anastomotic strictures following liver transplantation.

Biliary anastomotic strictures after liver transplantation are a major source of morbidity and graft failure; however, repeated endoscopic therapy has shown variable long-term success rates. Thus the aim of this prospective case series was to evaluate the safety and efficacy of using paclitaxel-eluting balloons in 13 patients requiring treatment for symptomatic anastomotic strictures following liver transplantation. Sustained clinical success-defined as no need for further endoscopic intervention for at least 6 months - was achieved in 12 /13 patients (92 %). One, two, and three interventions were required in 9 (69 %), 1, and 2 patients, respectively (mean number of sessions was 1.46). Mean (± SD) bilirubin level dropped from 6.8 (± 4.1) mg/dL to 1.4 (± 0.9) mg/dL. These promising results justify carrying out a randomized comparative trial to confirm this innovative approach.

Claudin-7 expression in hepatocellular carcinoma.

BACKGROUND: The importance of adhesion molecules for local invasion by neoplastic cells and development of metastasis has been confirmed by numerous studies over the past decade. Claudins are integral parts of tight junctions. The aim of the present study was to examine the significance of the expression of claudin-7 messenger RNA (mRNA) as a prognostic factor for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We examined liver tumor and nontumor tissues from 20 HCC patients who underwent resection or liver transplantation. RESULTS: A significant increase in the expression of claudin-7 was observed in tumor versus nontumor tissues. There was no significant correlation between the expression profile of claudin-7 mRNA and patient demographic data, the presence of cirrhosis, or the histological stage of tumor differentiation or vascular invasion. Survival analysis showed a trend toward a better prognosis among patients with overexpression of claudin-7 in tumor tissues.

Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Orthotopic liver transplantation in human-immunodeficiency-virus-positive patients in Germany.

Objectives. This summary evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-positive patients in Germany. Methods. Retrospective chart analysis of HIV-positive patients, who had been liver-transplanted in Germany between July 1997 and July 2011. Results. 38 transplantations were performed in 32 patients at 9 German transplant centres. The reasons for OLT were end-stage liver disease (ESLD) and/or liver failure due to hepatitis C (HCV) (n = 19), hepatitis B (HBV) (n = 10), multiple viral infections of the liver (n = 2) and Budd-Chiari-Syndrome. In July 2011 19/32 (60%) of the transplanted patients were still alive with a median survival of 61 months (IQR (interquartile range): 41-86 months). 6 patients had died in the early post-transplantation period from septicaemia (n = 4), primary graft dysfunction (n = 1), and intrathoracal hemorrhage (n = 1). Later on 7 patients had died from septicaemia (n = 2), delayed graft failure (n = 2), recurrent HCC (n = 2), and renal failure (n = 1). Recurrent HBV infection was efficiently prevented in 11/12 patients; HCV reinfection occurred in all patients and contributed considerably to the overall mortality. Conclusions. Overall OLT is a feasible approach in HIV-infected patients with acceptable survival rates in Germany. Reinfection with HCV still remains a major clinical challenge in HIV/HCV coinfection after OLT.

A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation--PROTECT.

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal-sparing alternative. In this randomized 1-year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post-LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft-Gault formula (-2.9 mL/min in favor of EVR, 95%-CI: [-10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (-7.8 mL/min, 95%-CI: [-14.366; -1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy-proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI-based to EVR-based immunosuppression proved to be a safe alternative post-LTx that deserves further investigation in terms of nephroprotection.

Transhilar passage in right graft live donor liver transplantation: intrahilar anatomy and its impact on operative strategy.

The passage through the hilar plate during right graft live donor liver transplantation (LDLT) can have dangerous consequences for both donors and recipients. The purpose of our study was to delineate hilar transection and biliary reconstruction strategies in right graft LDLT, with special consideration of central and peripheral hilar anatomical variants. A total of 71 consecutive donors underwent preoperative three-dimensional (3D) CT reconstructions and virtual 3D hepatectomies. A three-modal hilar passage strategy was applied, and its impact on operative strategy analyzed. In 68.4% of cases, type I and II anatomical configurations allowed for an en block hilar transection with simple anastomotic reconstructions. In 23.6% of cases, donors had "difficult" type II and types III/IV hilar bile duct anatomy that required stepwise hilar transections and complex graft biliary reconstructions. Morbidity rates for our early (A) and recent (B) experience periods were 67% and 39%, respectively. (1) Our two-level classification and 3D imaging technique allowed for donor-individualized transhilar passage. (2) A stepwise transhilar passage was favored in types III and IV inside the right-sided hilar corridor. (3) Reconstruction techniques showed no ameliorating effect on early/late biliary morbidity rates.

Long-term outcomes of liver transplant patients with human immunodeficiency virus infection and end-stage-liver-disease: single center experience.

OBJECTIVE: Orthotopic-liver-transplantation (OLT) in patients with Human-Immunodeficiency-Virus infection (HIV) and end-stage-liver-disease (ESDL) is rarely reported. The purpose of this study is to describe our institutional experience on OLT for HIV positive patients. MATERIAL AND METHODS: This is a retrospective study of all HIV-infected patients who underwent OLT at the University Hospital of Essen, from January 1996 to December 2009. Age, sex, HIV transmission-way, CDC-stage, etiology of ESDL, concomitant liver disease, last CD4cell count and HIV-viral load prior to OLT were collected and analysed. Standard calcineurin-inhibitors-based immunosuppression was applied. All patients received anti-fungal and anti-pneumocystis carinii pneumonia prophylaxis post-OLT. RESULTS: Eight transplanted HIV-infected patients with a median age of 46 years (range 35-61years) were included. OLT indications were HCV (n = 5), HBV (n = 2), HCV/HBV/HDV-related cirrhosis (n = 1) and acute liver-failure (n = 1). At OLT, CD4 cell-counts ranged from 113-621 cells/µl, and HIV viral-loads from <50-175,000 copies/ml. Seven of eight patients were exposed to HAART before OLT. Patients were followed-up between 1-145 months. Five died 1, 3, 10, 31 and 34 months after OLT due to sepsis and graft-failure respectively. Graft-failure causes were recurrent hepatic-artery thrombosis, HCV-associated hepatitis and chemotherapy-induced liver damage due to Hodgkin-disease. One survivor is relisted for OLT due to recurrent chronic HCV-disease but non-progredient HIV-infection 145 months post-OLT. Two other survivors show stable liver function and non-progredient HIV-disease under HAART 21 and 58 months post-OLT. CONCLUSIONS: OLT in HIV-infected patients and ESLD is an acceptable therapeutic option in selected patients. Long-term survival can be achieved without HIV disease-progression under antiretroviral therapy and management of the viral hepatitis co-infection.

[Psychosomatic aspects of living donor liver transplantation]. / Psychosomatische Aspekte der Leberlebendspende.

Living donor liver transplantation (LDLT) offers the option to reduce organ scarcity and thereby waiting list mortality. The crucial ethical problem of LDLT is the fact that the well being of a donor is being jeopardized for the improvement of quality of life of the recipient. To preserve mental health of the donors, psychosomatic evaluation should be conducted including examination of the coping capacity, the mental stability of the donor and the voluntary nature of the donation. Thus a comprehensive disclosure of information to donors is necessary. Realistic outcome expectations, family relationships without extreme conflicts, sufficient autonomy of the donor-recipient relationship and social and familiar support are predictors facilitating a favorable psychosocial outcome for the donor. Before and after LDLT the health-related quality of life of the donors is similar or increased in comparison to the general population. Psychiatric complications following LDLT can occur in 13% of the donors. Female donors, donors who have surgical complications themselves and donors with unrealistic outcome expectations should be given psychotherapeutic support before they are admitted to living liver donation. Urgent indications in the case of acute liver failure and the donation by adult children for their parents are particular stress factors. For the safety of the donor, these combinations should be avoided whenever possible.

Donor/recipient algorithm for management of the middle hepatic vein in right graft live donor liver transplantation.

BACKGROUND: The aim of this study was to delineate an algorithm for donor and recipient criteria and middle hepatic vein (MHV) management in right-graft live-donor liver transplantation (LDLT) on the basis of computerized 3-dimensional computed tomographic image analysis. METHODS: Data on 94 consecutive right-graft LDLTs were prospectively collected. Graft and remnant data for the first 23 cases were retrospectively evaluated by means of 3-dimensional computed tomographic reconstructions, and on the basis of that preliminary series, a graft selection algorithm using 3 parameters-hepatic vein dominance classification, graft and remnant graft volume/body weight ratios, and congestion volumes-was created. It was subsequently applied to the next 71 right-graft LDLTs. RESULTS: Fifty-nine right grafts contained the MHV. Four of the 12 grafts with no MHVs required MHV reconstructions. In 18 cases, small liver grafts were used. The postoperative function of liver grafts and remnants with versus without MHVs was not statistically different. CONCLUSIONS: The proposed algorithm favored the inclusion of the MHV with the right grafts. It also allowed for the procurement of grafts that were potentially small for size without compromising donor or recipient safety.

Established and emerging therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a worldwide increasing incidence. The incidence of HCC is closely related to the epidemiology of the risk factors which are mainly represented by chronic viral hepatitis B and C. Obesity and type II diabetes, often associated with chronic nonalcoholic fatty liver disease, are emerging independent risk factors for HCC development. Although the risk factors for HCC are well characterized, the molecular mechanisms responsible for malignant transformation of hepatocytes are not well understood. HCC diagnosis and therapy follow defined algorithms according to the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases guidelines. Liver transplantation has been shown the best outcome for selected patients with early tumor stage but its application is limited by the shortage of liver grafts. After hepatic resection prognosis remains unsatisfactory due to a high incidence of tumor recurrence. Selective internal radiation therapy is emerging as promising loco-regional treatment for patients with advanced HCC having good performance status and liver reserve but not amenable to surgery. The recently introduced orally active multikinase inhibitor sorafenib has been established as palliative systemic therapy. Further improved understanding of molecular mechanisms underlying HCC development will facilitate the development of new targeted therapeutic strategies.

Combined mycophenolate mofetil and minimal dose calcineurin inhibitor therapy in liver transplant patients: clinical results of a prospective randomized study.

BACKGROUND: Long-term complications of calcineurin inhibitor (CNI)-based immunosuppression after liver transplantation (LT) have a marked impact on patient morbidity and mortality. METHODS: In this prospective study, LT patients with renal dysfunction were randomized (2:1) to either receive mycophenolate mofetil (MMF) followed by stepwise reduction of CNI with defined minimal CNI trough levels (MMF group) or to continue their maintenance CNI dose (control group). RESULTS: In the MMF group (n = 60), renal function assessed by serum creatinine improved >10% in 67% of patients, was stable in 32%, and deteriorated >10% in 2% after 12 months compared with baseline values. Mean serum creatinine levels (+/-SD) significantly decreased from 1.86 +/- 0.43 to 1.55 +/- 0.38 mg/dL and the corresponding calculated glomerular filtration rate (cGFR) significantly increased from 39.9 +/- 10.1 to 49.2 +/- 11.9 mL/min over a 12-month follow-up period. Blood pressure and levels of liver enzymes significantly decreased, and no allograft rejection occurred. In the control group (n = 30), there were no significant changes in mean serum creatinine and cGFR (1.78 +/- 0.59 mg/dL at baseline vs 1.93 +/- 0.86 mg/dL at month 12, and 41.3 +/- 13.2 mL/min vs 38.7 +/- 11.2 mL/min, respectively), liver enzymes and blood pressure throughout the study. CONCLUSIONS: Combined MMF and minimal dose CNI therapy after LT is safe, and improves kidney function and the cardiovascular risk profile.

Renal function and cardiovascular risk profile after conversion from ciclosporin to tacrolimus: prospective study in 80 liver transplant recipients.

BACKGROUND: Increased risk of cardiovascular and cerebrovascular disease in liver transplant recipients results in particular from the side effects of calcineurin inhibitor-based immunosuppressive therapy. Several studies have demonstrated a more favourable outcome for patients receiving tacrolimus (TAC) as compared with ciclosporin (CS). AIM: To investigate the effects of conversion from CS to TAC on cardiovascular risk factors and renal function in liver transplant recipients. METHODS: In a prospective study, all except two patients had chronic kidney disease stages 2-4 (n = 80), according to estimated glomerular filtration rate using the abbreviated Modification of Diet in Renal Disease equation. RESULTS: Conversion was accompanied with a mean decrease of total cholesterol from 194.6 +/- 54.0 mg/dL to 175.8 +/- 44.2 mg/dL (P < 0.001), low density lipoprotein cholesterol from 106.7 +/- 39.2 mg/dL to 90.9 +/- 28.6 mg/dL (P < 0.001) and mean arterial blood pressure values from 102.2 +/- 13.2 mm Hg to 95.9 +/- 11.7 mm Hg (P < 0.001). Renal function remained stable. No cases of de novo diabetes mellitus were identified. The Framingham risk score was significantly reduced from 5.2 +/- 4.4 at baseline to 4.4 +/- 5.3 after 12 months (P = 0.006). CONCLUSIONS: Conversion from CS to TAC has been shown to improve the cardiovascular risk profile and may retard further decline of renal function after liver transplantation.

When the heart kills the liver: acute liver failure in congestive heart failure.

Congestive heart failure as a cause of acute liver failure is rarely documented with only a few cases. Although the pathophysiology is poorly understood, there is rising evidence, that low cardiac output with consecutive reduction in hepatic blood flow is a main causing factor, rather than hypotension. In the setting of acute liver failure due to congestive heart failure, clinical signs of the latter can be absent, which requires an appropriate diagnostic approach. As a reference center for acute liver failure and liver transplantation we recorded from May 2003 to December 2007 202 admissions with the primary diagnoses acute liver failure. 13/202 was due to congestive heart failure, which was associated with a mortality rate of 54%. Leading cause of death was the underlying heart failure. Asparagine transaminase (AST), bilirubin, and international normalized ratio (INR) did not differ significantly in surviving and deceased patients at admission. Despite both groups had signs of cardiogenic shock, the cardiac index (CI) was significantly higher in the survival group on admission as compared with non-survivors (2.1 L/min/m(2) vs. 1.6 L/min/m(2), p=0.04). Central venous - and pulmonary wedge pressure did not differ significantly. Remarkable improvement of liver function was recorded in the group, who recovered from cardiogenic shock. In conclusion, patients with acute liver failure require an appropriate diagnostic approach. Congestive heart failure should always be considered as a possible cause of acute liver failure.