[The German Guideline on Liver Transplantation by DGVS and DGAV]. / Lebertransplantation ­ Die deutschsprachige Leitlinie der DGVS und DGAV.

The S2k guideline "Liver Transplantation", jointly developed by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and the German Society of General and Visceral Surgery (DGAV), represents the first German-language guideline for the care of adult patients before and after liver transplantation. This guideline has been crafted through a collaborative, consensus-based approach, involving experts from various disciplines. It integrates current scientific insights and clinical experience to ensure optimal care for patients undergoing liver transplantation. Targeting health care professionals in diagnostics and therapy, patient advocates, affected individuals, and their families, the guideline aims to establish a framework for common decisions in clinical practice.

Body fat composition determines outcomes before and after liver transplantation in patients with cirrhosis.

Cachexia occurs in late stages of liver cirrhosis, and a low-fat mass is potentially associated with poor outcome. This study compared different computed tomography (CT)-derived fat parameters with respect to its prognostic impact on the development of complications and death before and after liver transplantation. Between 2001 and 2014, 612 patients with liver cirrhosis without hepatocellular carcinoma listed for liver transplantation met the inclusion criteria, including abdominal CT scan (±200 days to listing). A total of 109 patients without cirrhosis served as controls. The subcutaneous fat index (SCFI), the paraspinal muscle fat index, and the visceral fat index were assessed at L3/L4 level and normalized to the height (cm2 /m2 ). Data were collected and analyzed retrospectively. Low SCFI was associated with a higher rate of ascites and increased C-reactive protein levels (p < 0.001). In addition, multivariate Cox regression analysis adjusting for sex, age, body mass index (BMI), and Model for End-Stage Liver Disease showed that decreasing SCFI was also associated with an increased risk of cirrhosis-related complications (p = 0.003) and death on the transplant wait list (p = 0.013). Increased paraspinal and visceral fat were not only positively correlated with creatinine levels (p < 0.001), BMI, and metabolic comorbidities (all p < 0.001) before transplantation, but also predictive for 1-year mortality after transplantation. Conclusion: The distribution of body fat is a major determinant for complications and outcome in cirrhosis before and after liver transplantation.

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study).

BACKGROUND & AIMS: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. METHODS: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 µg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. RESULTS: Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. CONCLUSIONS: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. GOV NUMBER: NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

Current State and Future Possibilities in Liver Transplantation.

Due to medical and surgical progress, liver transplantation (LT) is is nowadays a routine treatment for terminal liver failure and hepatic malignancies. However, in recent years there has been a change in the indications for LT. Especially in western industrialized countries, the use of LT for chronic hepatis B and hepatitis C cirrhosis is continuously decreasing since the introduction of effective antiviral drugs. Liver cirrhosis due to non-alcoholic steatohepatitis (NASH), alcoholic liver disease and hepatocellular carcinoma (HCC) in cirrhosis are now among the leading indications for LT. Due to tremendous progress in oncology, immunology, and technical aspects, multidisciplinary cancer treatment increasingly includes LT for non-HCC hepatobiliary malignancies. Excellent 5-year survival rates of 75 to 80% can now be achieved after LT. However, in patients with liver cirrhosis, the implementation of a 'sickest first' principle for liver allocation has led to an increasing number of critically ill patients undergoing liver transplantation. This results in an increased morbidity and mortality after liver transplantation. Moreover, donor characteristics have markedly shifted to less ideal grafts due to an increasing shortage of donor organs in many countries. In this context, normothermic machine perfusion with oxygenated blood components using pulsatile flow has been shown to reduce liver damage despite a prolonged preservation time and might be able to provide viability testing for otherwise discarded organs. With favorable donor and recipient conditions, excellent long-term results can be obtained with a 10-year survival rate of close to 70%. However, in patients with a high MELD score (>30), survival rates markedly decrease by 12-18%. Future research should focus on optimization of organ allocation, optimization of immunosuppression including tolerance induction, and on increasing the donor organ pool to further improve and the numbers of successful LT.

The Current Status of Granulocyte-Colony Stimulating Factor to Treat Acute-on-Chronic Liver Failure.

Patients with acute-on-chronic liver failure (ACLF) have a devastating prognosis and therapeutic options are limited. Granulocyte-colony stimulating factor (G-CSF) mobilizes immune and stem cells and possess immune-modulatory and proregenerative capacities. In this review, we aim to define the current evidence for the treatment with G-CSF in end-stage liver disease. Several smaller clinical trials in patients with different severity grades of end-stage liver disease have shown that G-CSF improves survival and reduces the rate of complications. Adequately powered multicenter European trials could not confirm these beneficial effects. In mouse models of ACLF, G-CSF increased the toll-like receptor (TLR)-mediated inflammatory response which led to an increase in mortality. Adding a TLR4 signaling inhibitor allowed G-CSF to unfold its proregenerative properties in these ACLF models. These data suggest that G-CSF requires a noninflammatory environment to exert its protective properties.

Safety and efficacy of direct oral anticoagulants under long-term immunosuppressive therapy after liver, kidney and pancreas transplantation.

The safety of direct oral anticoagulants (DOACs) in patients after solid organ transplantation (SOT) is not well defined. This study aimed at describing the safety and efficacy of DOACs in patients after SOT. Patients after kidney and/or liver transplantation under maintenance immunosuppression treated with rivaroxaban (n = 26), apixaban (n = 20) and edoxaban (n = 1) were included. Clinical data were collected retrospectively and using a questionnaire. DOAC plasma levels and thrombin generation (TG) were measured in patients after SOT and compared with nontransplanted controls receiving DOACs. DOACs were administered for 84.6 patient-years. Mean immunosuppressive trough levels after DOAC initiation increased from baseline by 18.8 ± 29.6% compared to 3.0 ± 16.5% in matched controls (P = 0.004), without significant differences in dose adjustments. No transplant rejection or significant change in liver or renal function was observed. There was one major bleeding after the observation period but no thromboembolic complication. DOAC plasma levels reached the expected range in all patients. The intrinsic hemostatic activity in transplanted patients was higher compared to nontransplant controls. Treatment with DOACs after SOT is safe and effective. Immunosuppressive trough levels should be monitored after DOAC initiation, particularly in the early phase after SOT. These data should be confirmed in a prospective study.

[Liver transplantation - current trends]. / Aktuelle Entwicklungen bei der Lebertransplantation ­ Wo stehen wir?

INDICATION OF TRANSPLANTATION: There is an ongoing change in the indications of orthotopic liver transplantation (OLT) with non-alcoholic and alcoholic liver disease and hepatocellular carcinoma (HCC) becoming the main indications whereas the numbers of cirrhosis due to chronic viral hepatitis are declining. 6-MONTH ABSTINENCE RULE: : The directive of the German Federal Medical Association requires absolute abstinence from alcohol for at least 6 months. New data show that patients with severe alcoholic hepatitis for the first time who do not show a response to medical treatment may benefit from OLT. For these patients an individual exception for OLT listing can be requested. HCC BEYOND MILAN CRITERIA: New data show that patients with HCC outside the Milan criteria may have a favorable prognosis, which can be comparable to patients with HCC within the Milan criteria, if effective pre-transplant "down-staging" therapies but also alfa fetoprotein levels are taken into consideration. TOO SICK TO TRANSPLANT?: Even patients with decompensated cirrhosis and multi-organ dysfunction, defined as acute-on-chronic liver failure, may undergo OLT successfully with a beneficial long-term prognosis. However, the timeframe to realize OLT is short. ORGAN SHORTAGE: OLT using organs from HBV- or HCV-infected patients represents a relevant strategy to mitigate organ shortage and can be safely and effectively be performed due to the excellent therapeutic options against these infections which are available now. In addition, machine perfusion, a novel tool for organ conservation and conditioning, may help preserving organs for transplantation that formerly could not be used.

Hepatitis B Vaccination in Patients with Liver Cirrhosis Evaluated for Liver Transplantation - A Simple Intervention Ensures High Adherence.

BACKGROUND There is an unmet need to improve the HBV vaccination status in patients with chronic liver diseases. Primary care physicians and outpatient hepatologists often fail to vaccinate as recommended. Thus, new strategies to improve the HBV vaccination rate are required. MATERIAL AND METHODS This study was performed in a cohort of patients with chronic liver diseases evaluated for liver transplantation. Vaccination status was taken from the patients' vaccination cards. HBsAg-, anti-HBc-, and anti-HBs-negative individuals were vaccinated against HBV at hospital discharge, and subsequent outpatient completion of the standard vaccination protocol was recommended in detail in the discharge letter. At months 2 and 8, titer controls were performed, and completion of vaccination was evaluated. RESULTS We prospectively recruited 37 patients. At baseline, the vaccination rate against HBV was 24% (N=9/37), and 3/9 HBV vaccinated patients presented with an anti-HBs-titer >10 IU/L. Thus, N=34 were vaccinated with Engerix® or Twinrix®. We evaluated 26/34 patients at month 2 and 10/26 again at month 8. The second vaccine dose was obtained by 21/26 (80%) of the patients seen at month 2, and 9/10 (90%) seen at month 8 obtained the third vaccine dose by primary care physicians or ambulant hepatologists. Only 2 patients presented with an anti-HBs-titer >10 IU/L at month 8. CONCLUSIONS Initiation of HBV vaccination during hospitalization and detailed recommendations on subsequent vaccinations in the discharge letter improve previously inadequate vaccination rates in the outpatient setting. Similar measures should be implemented at earlier time points of chronic liver diseases to achieve higher immune response rates.

Loss of paraspinal muscle mass is a gender-specific consequence of cirrhosis that predicts complications and death.

BACKGROUND: Loss of skeletal muscle mass is a recognised complication with a prognostic impact in patients with cirrhosis. AIM: To explore in a retrospective analysis which muscle compartment most reliably predicts the occurrence of cirrhosis-associated complications and if there are gender-related differences. METHODS: 795 patients with cirrhosis listed for liver transplantation between 2001 and 2014 met the inclusion and exclusion criteria including an abdominal CT scan (±200). Controls were 109 patients who underwent a CT scan after polytrauma. The paraspinal muscles index (PSMI), the abdominal wall muscles index (AWMI) and its combination skeletal muscle index (SMI) were assessed at L3/L4, normalised to the height (cm2 /m2 ). RESULTS: 62.0% of patients with cirrhosis had alcoholic liver disease, and 70.6% were male. As compared to controls, a reduction in PSMI and SMI but not AWMI was associated with high model of end-stage liver disease (MELD) score, high Child-Pugh class, and the presence or history of cirrhosis-associated complications in males but not females. PSMI independently predicted the occurrence of bacterial infections (HR 0.932), spontaneous bacterial peritonitis (HR 0.901), hepatic encephalopathy (HR 0.961), and hepatorenal syndrome (HR 0.946) by multivariate Cox regression analysis in a gender-independent manner. Post-transplant survival was not associated with the PSMI; neither AWMI nor SMI predicted any clinical endpoints. CONCLUSIONS: This study links muscle wasting in patients with cirrhosis predominantly to males. However, the presence of a low PSMI mass is a gender-independent predictor of developing cirrhosis-associated complications and death. Scores combining the MELD with muscle parameters should be re-validated by utilizing the PSMI.

Tacrolimus and Mycophenolate Mofetil as Second-Line Therapies for Pediatric Patients with Autoimmune Hepatitis.

BACKGROUND: We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine). PATIENTS AND METHODS: We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8-182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy. RESULTS: Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.