Endoscopic ultrasound: valuable tool for diagnosis of biliary complications in liver transplant recipients?

BACKGROUND: Biliary complications after liver transplantation (LT) are still common and are an important cause of mortality and morbidity. Until now, endoscopic retrograde cholangiopancreatography (ERCP) has been considered the gold standard for diagnosing such complications. The aim of this study was to evaluate the diagnostic yield and therapeutic impact of endoscopic ultrasound (EUS) in the management of biliary complications after LT. METHODS: Thirty-seven liver transplant patients who presented with clinical, biochemical, sonographic, and/or histological evidence of biliary complications, and who first received EUS followed by ERCP, were enrolled into this prospective observational study. Subsequently, we evaluated the value of EUS in detecting and classifying biliary complications after LT. RESULTS: Thirty-seven biliary complications were detected in 32 patients. Endoscopic ultrasound showed an overall sensitivity and accuracy of 94.6 % each. In cases of biliary cast and ischemic cholangiopathy, EUS was found to be diagnostically superior to ERCP and has had, in these cases, a significant impact on clinical decision-making. However, EUS was less reliable when diagnosing anastomotic strictures. CONCLUSION: EUS can complement ERCP to improve diagnosis of biliary complications after LT and help guide treatment strategies to address these complications.

Hepatitis C in Special Patient Cohorts: New Opportunities in Decompensated Liver Cirrhosis, End-Stage Renal Disease and Transplant Medicine.

Worldwide, hepatitis C virus (HCV) is a common infection. Due to new antiviral approaches and the approval of direct-acting antiviral agents (DAA), HCV therapy has become more comfortable. Nevertheless, there are special patient groups, in whom treatment of HCV is still challenging. Due to only few data available, tolerability and efficacy of DAAs in special patient cohorts still remain unclear. Such special patient cohorts comprise HCV in patients with decompensated liver disease (Child-Pugh Class B or C), patients with chronic kidney disease, and patients on waiting lists to renal/liver transplantation or those with HCV recurrence after liver transplantation. HCV infection in these patient cohorts has been shown to be associated with increased morbidity and mortality and may lead to reduced graft survival after transplantation. Successful eradication of HCV results in a better outcome concerning liver-related complications and in a better clinical outcome of these patients. In this review, we analyze available data and results from recently published literature and provide an overview of current recommendations of HCV-therapy regimen in these special patient cohorts.

Preoperative prediction of curative surgery of perihilar cholangiocarcinoma by combination of endoscopic ultrasound and computed tomography.

BACKGROUND: Perihilar cholangiocarcinomas are often considered incurable. Late diagnosis is common. Advanced disease therefore frequently causes questioning of curative surgical outcome. AIM: This study aimed to develop a prediction model of curative surgery in patients suffering from perihilar cholangiocarcinomas based on preoperative endosonography and computer tomography. METHODS: A cohort of 81 patients (median age 67 (54-75) years, 62% male) with perihilar cholangiocarcinoma was retrospectively analyzed. Multivariate logistic regression analysis of staging variables taken from the European Staging System was performed and applied to ROC analysis. RESULTS: The correlation of predicted rates of eligibility for surgery with actual rates reached AUC values between 0.652 and 0.758 for endosonography and computer tomography (p < 0.05 each). Best prediction for curative surgical option was achieved by combining endosonography and computer tomography (AUC: 0.787; 95% CI 0.680-0.893, p < 0.0001). A predictive model (pSurg) was developed using multivariate analysis. CONCLUSIONS: Our predictive web-based model pSurg with inclusion of T, N, M, B, PV, HA and V stage of the recently published European Staging System for perihilar cholangiocarcinoma results in highly significant predictability for curative surgery when combining preoperative endosonography and computer tomography, thus allowing for better patient selection in terms of possibility of curative surgery.

Lipids in liver transplant recipients.

Hyperlipidemia is very common after liver transplantation and can be observed in up to 71% of patients. The etiology of lipid disorders in these patients is multifactorial, with different lipid profiles observed depending on the immunosuppressive agents administered and the presence of additional risk factors, such as obesity, diabetes mellitus and nutrition. Due to recent improvements in survival of liver transplant recipients, the prevention of cardiovascular events has become more important, especially as approximately 64% of liver transplant recipients present with an increased risk of cardiovascular events. Management of dyslipidemia and of other modifiable cardiovascular risk factors, such as hypertension, diabetes and smoking, has therefore become essential in these patients. Treatment of hyperlipidemia after liver transplantation consists of life style modification, modifying the dose or type of immunosuppressive agents and use of lipid lowering agents. At the start of administration of lipid lowering medications, it is important to monitor drug-drug interactions, especially between lipid lowering agents and immunosuppressive drugs. Furthermore, as combinations of various lipid lowering drugs can lead to severe side effects, such as myopathies and rhabdomyolysis, these combinations should therefore be avoided. To our knowledge, there are no current guidelines targeting the management of lipid metabolism disorders in liver transplant recipients. This paper therefore recommends an approach of managing lipid abnormalities occurring after liver transplantation.

[Ultrasound of livertransplants]. / Sonografie der transplantierten Leber.

The overall long-term survival rate of liver transplant patients is 70-75 %. During the early stages, the complications are vascular in nature, and in the later stages, biliary complications are major causes of morbidity. With the help of sonography, in particular with the addition of contrast enhanced ultrasound, a reliable diagnosis is possible. Despite this, in individual cases, other additional imaging methods should still be employed. The therapy should be used exclusively by interventional gastroentologists, radiologists or surgeons.

Successful Anti-HCV Therapy of a Former Intravenous Drug User with Sofosbuvir and Daclatasvir in a Peritranspant Setting: A Case Report.

BACKGROUND Direct-acting antivirals (DAAs) represent a new hallmark in antiviral therapy of hepatitis C virus (HCV). DAAs have been shown to be safe and effective after liver transplantation (LT), but there is little information about their use in peritransplant settings. Former intravenous drug users represent an increasing group seeking HCV treatment. This case report demonstrates the successful peritransplant antiviral treatment of a former intravenous drug user who had been treated in a methadone maintenance program. CASE REPORT The patient was diagnosed with Child B cirrhosis for the first time in 2009. He had a Model for End-stage Liver Disease (MELD) score of 21 and started antiviral therapy with sofosbuvir (SOF) and daclatasvir (DCV) in March 2014. Due to hepatic decompensation, he received a LT in April 2014. Immunosuppression was performed with tacrolimus (TAC) and mycophenolate-mofetil (MMF), and boosted with prednisolone in the initial stage. Four weeks after his LT, the patient presented with an acute renal injury. The patient was discharged one week later after sufficient hydration, discontinuation of non-steroidal anti-phlogistics therapy, and adjustments to his immunosuppressive regimen. At the beginning of his therapy, the number of RNA copies was 13,000 IU/mL. He received 24 weeks of anti-HCV treatment with SOF and DCV; the antiviral treatment was successful and his LT was well tolerated.  CONCLUSIONS Treatment of HCV is feasible in a peritransplant setting. The antiviral regimen we used did not seem to have any relevant interactions with the patient's immunosuppressive regimens. Still, the peritransplant setting is a very demanding environment for anti-HCV therapy, and further studies are needed.

[Long-term-management of organ transplant recipients]. / Langzeitbetreuung nach Organtransplantation.

Due to advances in immunosuppressive therapy and surgical techniques, survival rates after solid organ transplantation have constantly improved over the last decades. In long-term care after transplantation, physicians need to focus as much on diagnosis and treatment of allograft-related complications as they should consider comorbidities and evaluate risk-factors and adverse events of immunosuppressive agents to prevent secondary diseases. In particular, cardiovascular and metabolic diseases, malignancy and infection play a major role in long-term survival. Therefore, screening of organ transplant recipients in regard to these complications and adverse events is a crucial part of follow up in these patients.

Influence of tacrolimus metabolism rate on BKV infection after kidney transplantation.

Immunosuppression is the major risk factor for BK virus nephropathy (BKVN) after renal transplantation (RTx). As the individual tacrolimus (Tac) metabolism rate correlates with Tac side effects, we hypothesized that Tac metabolism might also influence the BKV infection risk. In this case-control study RTx patients with BK viremia within 4 years after RTx (BKV group) were compared with a BKV negative control group. The Tac metabolism rate expressed as the blood concentration normalized by the daily dose (C/D ratio) was applied to assess the Tac metabolism rate. BK viremia was detected in 86 patients after a median time of 6 (0-36) months after RTx. BKV positive patients showed lower Tac C/D ratios at 1, 3 and 6 months after RTx and were classified as fast Tac metabolizers. 8 of 86 patients with BK viremia had histologically proven BKN and a higher median maximum viral load than BKV patients without BKN (441,000 vs. 18,572 copies/mL). We conclude from our data that fast Tac metabolism (C/D ratio <1.05) is associated with BK viremia after RTx. Calculation of the Tac C/D ratio early after RTx, may assist transplant clinicians to identify patients at risk and to choose the optimal immunosuppressive regimen.

Tacrolimus Concentration/Dose Ratio is Associated with Renal Function After Liver Transplantation.

BACKGROUND: The calcineurin inhibitor (CNI) tacrolimus (Tac) is an effective immunosuppressant used after liver transplantation (LTx), but is often associated with CNI nephrotoxicity. Currently, there is no simple clinical predictor for CNI nephrotoxicity after LTx. We hypothesized that the Tac metabolism rate - defined as the blood concentration normalized by its daily dose (the C/D ratio) - is associated with post-LTx renal impairment. MATERIAL AND METHODS: We analyzed the relationship between the C/D ratio and post-transplant renal function in 179 patients who underwent LTx between 2000 and 2012 and were initially immunosuppressed with Tac, mycophenolate mofetil, and prednisolone. Six months after LTx, 115 patients were categorized into 1 of 2 groups based on their Tac C/D ratio (<1.09 or ≥1.09): fast (n=58) or slow (n=57) metabolizers. The renal function was determined 36 months after LTx using the estimated glomerular filtration rate (eGFR) as described by Cockcroft and Gault. RESULTS: At the time of LTx there was no statistically significant difference between the eGFR of fast and slow metabolizers. Six months (P=0.016), 12 months (P=0.001), and 36 months (P=0.018) after LTx, fast Tac metabolizers had significantly more impaired renal function than slow metabolizers. Because of a presumption of CNI nephrotoxicity, 32.8% of fast metabolizers and 14.0% of slow metabolizers were switched from Tac to other immunosuppressants (P=0.027). CONCLUSIONS: In this study, the Tac metabolism rate appears to influence renal function after LTx, suggesting that a C/D ratio of <1.09 is associated with increased CNI nephrotoxicity in LTx recipients.

[Critically ill patients with decompensated liver cirrhosis - New aspects and intensive care management]. / Dekompensierte Leberzirrhose: intensivmedizinische Aspekte.

The prevalence of liver cirrhosis in the German population is about 1 %. Clinically, compensated liver cirrhosis should be distinguished from decompensated cirrhosis with poor prognosis. Decompensated cirrhosis is defined by the occurrence of complications and consequences of portal hypertension (such as ascites, variceal bleeding, hepatic encephalopathy and hepatorenal syndrome) and progressive liver failure. Optimizing the management of these patients in the intensive care unit could essentially improve their outcome.

Circulating microRNA-200 Family as Diagnostic Marker in Hepatocellular Carcinoma.

GOALS: In this clinical study, we aimed to evaluate the role of circulating microRNA-200 family as a non-invasive tool to identify patients with cirrhosis-associated hepatocellular carcinoma (HCC). BACKGROUND: Prognosis of HCC remains poor with increasing incidence worldwide, mainly related to liver cirrhosis. So far, no reliable molecular targets exist for early detection of HCC at surgically manageable stages. Recently, we identified members of the microRNA-200 family as potential diagnostic markers of cirrhosis-associated HCC in patient tissue samples. Their value as circulating biomarkers for HCC remained undefined. METHODS: Blood samples and clinicopathological data of consecutive patients with liver diseases were collected prospectively. Expression of the microRNA-200 family was investigated by qRT-PCR in blood serum samples of 22 HCC patients with and without cirrhosis. Serum samples of patients with non-cancerous chronic liver cirrhosis (n = 22) and of healthy volunteers (n = 15) served as controls. RESULTS: MicroRNA-141 and microRNA-200a were significantly downregulated in blood serum of patients with HCC compared to liver cirrhosis (p<0.007) and healthy controls (p<0.002). MicroRNA-141 and microRNA-200a could well discriminate patients with cirrhosis-associated HCC from healthy volunteers with area under the receiver-operating characteristic curve (AUC) values of 0.85 and 0.82, respectively. Additionally, both microRNAs could differentiate between HCC and non-cancerous liver cirrhosis with a fair accuracy. CONCLUSIONS: Circulating microRNA-200 family members are significantly deregulated in patients with HCC and liver cirrhosis. Further studies are necessary to confirm the diagnostic value of the microRNA-200 family as accurate serum marker for cirrhosis-associated HCC.

Paclitaxel-eluting balloon dilation of biliary anastomotic stricture after liver transplantation.

AIM: To investigate the safety and effectiveness of endoscopic therapy with a paclitaxel-eluting balloon (PEB) for biliary anastomotic stricture (AS) after liver transplantation (LT). METHODS: This prospective pilot study enrolled 13 consecutive eligible patients treated for symptomatic AS after LT at the University Hospital of Münster between January 2011 and March 2014. The patients were treated by endoscopic therapy with a PEB and followed up every 8 wk by endoscopic retrograde cholangiopancreatography (ERCP). In cases of re-stenosis, further balloon dilation with a PEB was performed. Follow-up was continued until 24 mo after the last intervention. RESULTS: Initial technical feasibility, defined as successful balloon dilation with a PEB during the initial ERCP procedure, was achieved in 100% of cases. Long-term clinical success (LTCS), defined as no need for further endoscopic intervention for at least 24 mo, was achieved in 12 of the 13 patients (92.3%). The mean number of endoscopic interventions required to achieve LTCS was only 1.7 ± 1.1. Treatment failure, defined as the need for definitive alternative treatment, occurred in only one patient, who developed recurrent stenosis with increasing bile duct dilatation that required stent placement. CONCLUSION: Endoscopic therapy with a PEB is very effective for the treatment of AS after LT, and seems to significantly shorten the overall duration of endoscopic treatment by reducing the number of interventions needed to achieve LTCS.

Long-Term Renal Function in Liver Transplant Recipients After Conversion From Calcineurin Inhibitors to mTOR Inhibitors.

BACKGROUND: Renal dysfunction often occurs in liver transplant (LT) recipients receiving calcineurin inhibitor (CNI)-based immunosuppressive regimens, increasing morbidity and mortality rates. Replacement of CNIs by mTOR inhibitor-based immunosuppressive protocols may prevent renal impairment in LT recipients. MATERIAL/METHODS: Outcomes in patients who underwent LT between 1996 and 2010 at our center and who were switched from CNI-based to mTOR inhibitor-based immunosuppression were retrospectively analyzed. Renal course, hyperlipidemia, and graft rejection were assessed in patients maintained on this CNI-free regimen for at least 24 months. RESULTS: Of the 85 patients switched from CNI-based to mTOR inhibitor-based, CNI-free immunosuppression, 78 met the inclusion criteria. Within the first 6 weeks after switching, the covariable adjusted estimated glomerular filtration rate (eGFR) increased 5.6 mL/min [95% confidence interval 2.6-8.7 mL/min, p<0.001], but there were no further statistically noticeable changes in eGFR. Concentrations of cholesterol and triglycerides increased statistically, noticeable within the first 12 months after drug conversion. Histologically proven graft rejection was observed in 4 patients (5.1%) after conversion. CONCLUSIONS: Conversion from CNI-based to CNI-free, mTOR inhibitor-based immunosuppression after LT is safe and can result in significant renal recovery. CNI-free, mTOR inhibitor-based immunosuppression is a potential option for patients with contraindications for CNIs and for LT recipients with rapid reduction in kidney function due to CNIs.

Analysis of bile colonization and intestinal flora may improve management in liver transplant recipients undergoing ERCP.

BACKGROUND: Immunosuppression, denervation of biliary tract, and presence of biliary strictures favor colonization of bile with microorganisms after liver transplantation. Little is known about spectrum and antibiotic susceptibility of this colonization. MATERIAL AND METHODS: Bile and feces were collected prospectively from 38 patients who underwent endoscopic retrograde cholangiopancreaticography after liver transplantation. Samples were analyzed for colonization and antibiotic susceptibility. RESULTS: From the 38 tested bile samples, 86.6% tested positive. Of those, 26 (78.8%) were polymicrobial. Of isolated bile samples, 52 (64.2%) were gram-positive, 22.2% were gram-negative, and 13.6% revealed Candida albicans. Most detectable gram-positive bacteria were Enterococcus faecium. Most detectable gram-negative bacteria were E. coli and Klebsiella pneumonia. Our analyses revealed high resistance rates of the isolates. Only 55.6% of isolates were sensitive to ciprofloxacin, 54% were sensitive to piperacillin/tazobactam, and 60.3% were sensitive to imipenem. High susceptibility rates were found for linezolid and vancomycin (72.9% and 72.6%, respectively). We found a high correlation between microorganisms found in bile and those isolated from stool. CONCLUSIONS: Bile of liver transplant recipients is frequently colonized with microorganisms. The starting point of this colonization is usually the intestine. Systematic analysis of bile colonization during endoscopic interventions on biliary tracts of liver transplant recipients might help to select effective prophylactic antibiotic regimes as well as to facilitate the choice of suitable antimicrobial therapy in case of septic complications.

Interferon-Free Sofosbuvir-Based Anti-HCV Therapy After Liver Transplantation.

BACKGROUND: Therapy for HCV-infected patients after orthotopic liver transplantation (OLT) is based on interferon (IFN) as the gold standard, but sustained virologic response (SVR) and safety profiles of the IFN-based therapies are very unsatisfactory. The aim of this continuing analysis is evaluation of the impact of an IFN-free sofosbuvir (SOF)-based therapy in HCV-infected liver transplant recipients. MATERIAL AND METHODS: Post-OLT patients with a proven recurrence of HCV were treated with SOF and ribavirin (RBV) for 24 weeks (n=10). Laboratory parameters and FibroScan® are continuously evaluated at weeks 0, 12, 24, and 36. A retrospectively analyzed HCV patient cohort who received antiviral therapy with pegylated INF and RBV± telaprevir (TLV) were used as a control group. RESULTS: All patients who finished their treatment with SOF/RBV at least 12 weeks ago showed an SVR. The SOF-based therapy showed a significantly higher rate of rapid virologic response (RVR) and sustained virologic response (SVR) compared to the IFN-based therapies (RVR: p=0.007; SVR: p=0.009). According to temporary data on FibroScan® analysis, regression of fibrosis was observed in 8 patients treated with SOF/RBV. No premature termination of SOF became necessary. CONCLUSIONS: In this small group of patients, the preliminary results indicate that a regression of fibrosis is achievable within 24 weeks of therapy with SOF after OLT. SOF seems to be effective and safe in the treatment of OLT patients infected with HCV and will likely improve patient and transplant survival.

Complications after endoscopic sphincterotomy in liver transplant recipients: A retrospective single-centre study.

BACKGROUND AND STUDY AIMS: Biliary tract complications after liver transplantation are usually treated by endoscopic retrograde cholangiopancreatography. When biliary tract intervention is indicated, endoscopic sphincterotomy is often required. However, data regarding complication rates after endoscopic sphincterotomy in liver transplant recipients are limited. This study therefore investigated complication rates during the first 15 days after endoscopic sphincterotomy in liver transplant recipients. PATIENTS AND METHODS: This study retrospectively reviewed 157 consecutive liver transplant recipients who underwent endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy between January 1998 and August 2013 at the University Hospital of Münster, Germany. Complications that occurred within the first 15 days after the procedure were recorded, and complication rates were compared between patients who underwent conventional and precut endoscopic sphincterotomy. RESULTS: A total of 24 complications (15.2%) were recorded, including 9 cases (5.7%) of pancreatitis, 6 cases (3.8%) of bleeding, and 1 case (0.6%) of perforation. There were no procedure-related deaths. There were no significant differences in complication rates between the two sphincterotomy techniques. The rate of post-procedural pancreatitis decreased over time. CONCLUSION: Endoscopic sphincterotomy is a safe procedure in liver transplant recipients. The procedure-related complication rate is reasonable and most complications can be managed conservatively.

The tacrolimus metabolism rate influences renal function after kidney transplantation.

The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient's risk management strategies.