Karin Nachbaur

Long‐term outcome of endoscopic treatment of biliary strictures after liver transplantation

Biliary strictures are one of the most common complications following liver transplantation (LT), with an incidence of 5.8‐34%. Endoscopic techniques have been successfully used to treat biliary complications; however, the long‐term efficacy and safety of this treatment option has not yet been fully elucidated. This prospective study was performed to determine the efficacy and safety of endoscopic management of biliary complications after LT and its impact on long‐term patient and graft survival. Biliary strictures were suspected in the presence of elevated liver parameters and/or abnormal abdominal sonography and subsequently diagnosed by endoscopic retrograde cholangiography (ERC). The mean follow‐up was 39.8 (range, 0.3‐98.2) months after first ERC. Between October 1992 and December 2003, a total of 515 patients underwent LT. Biliary complications were diagnosed in 84 patients (16.3 %). Anastomotic strictures (AS) alone were found in 65 (12.6%) and nonanastomotic strictures (NAS) in 19 patients (3.7%). Long‐term success was observed in 77% of patients with AS. In patients with NAS, partial long‐term responses could be achieved in 63% of patients. Five patients (6.2%) required a percutaneous and 6 (7.4%) patients a surgical approach.In conclusion, the long‐term outcome for patients with post‐liver transplant biliary strictures after endoscopic treatment is excellent, especially for patients with AS. Development of NAS reduces graft but not patient survival after endoscopic therapy. Liver Transpl 12:718–725, 2006.

Extensive Surveillance Promotes Early Diagnosis and Improved Survival of De Novo Malignancies in Liver Transplant Recipients

The aim of our study was to examine whether an extensive surveillance protocol will promote early diagnosis and improved survival in patients with de novo cancer following liver transplantation (LT). Of 779 consecutive LT recipients, 96 (12.3%) developed 105 malignancies. The cumulative risk for the development of de novo cancer was 10%, 24%, 32% and 42% at 5, 10, 15 and 20 years after LT, respectively. The most frequent tumor types were skin (17%), lung (16%), oropharyngeal (11%) and prostate cancer (11%). The overall standard incidence ratio as compared to that of the general population was 1.9 (95% CI: 1.5–2.3). The median survival of patients with de novo non‐skin cancers was 3.1 years after diagnosis. Only patients with skin cancers and solid tumors, diagnosed at early stages, showed an excellent outcome. After introducing an intensified surveillance protocol, the detection rate of de novo cancers increased from 4.9% to 13% and more de novo malignancies were diagnosed in earlier stages. For non‐skin cancers, the median tumor‐related survival significantly improved from 1.2 to 3.3 years as well as the median overall survival post‐LT. This study indicates that an extensive tumor surveillance program is highly recommendable in LT recipients.

Acute-on-chronic liver failure: excellent outcomes after liver transplantation but high mortality on the wait list.

Acute‐on‐chronic liver failure (ACLF) is characterized by high short‐term mortality. Liver transplantation (LT) is a potential therapy for patients who do not improve with supportive measures, but the efficacy of LT has not been shown. The aim of this study was to investigate the feasibility of LT and to determine the postoperative outcomes of patients with ACLF. All patients referred to our liver unit between 2002 and 2010 were registered in a database. The diagnosis of ACLF was made in accordance with the Asian Pacific Association for the Study of the Liver consensus. The post‐LT outcomes were compared with the outcomes of a cohort of patients with chronic liver disease who underwent transplantation for other indications during the same period. One hundred forty four of 238 patients fulfilled the ACLF criteria. In an intention‐to‐treat analysis, the median transplant‐free survival time was 48 days. Multiorgan failure was the most common cause of death. Ninety‐four patients (65%) were evaluated for LT, 71 patients (49%) were listed, and 33 patients (23%) finally underwent deceased donor LT; this resulted in a wait‐list mortality rate of 54%. Patients who developed infectious complications (particularly pneumonia and/or sepsis) and patients who received renal replacement therapy or mechanical ventilation were less likely to undergo LT. The 1‐ and 5‐year survival rates of 87% and 82% were comparable to the rates for non‐ACLF patients. In conclusion, this study shows that LT remains the only therapeutic option for the vast majority of patients with ACLF. However, LT was feasible in less than one fourth of the patients with a 5‐year survival rate greater than 80%. Liver Transpl 19:879‐886, 2013.

Early viral load and recipient interleukin‐28B rs12979860 genotype are predictors of the progression of hepatitis C after liver transplantation

There have been few detailed studies of viral kinetics after liver transplantation (LT), and conflicting data have been reported on viral loads and the severity of recurrent hepatitis C virus (HCV) disease. This long‐term study aimed to examine (1) the impact of HCV RNA levels at specific points in time within the first year and (2) the influence of interleukin‐28B (IL‐28B) genotypes on patient outcomes and the severity of recurrent HCV disease. The viral loads were measured 2, 4, 12, 24, and 48 weeks after LT, and the recipient/donor IL‐28B genotypes of 164 patients were determined. A Cox regression analysis showed that the viral load at week 2 was an independent negative predictor of recipient outcomes. A week 2 viral load ≥ 6.0 log10 IU/mL was significantly associated with reduced patient survival. After a mean follow‐up of 6.5 years, 21 of 164 patients (12.8%) developed a cholestatic type of HCV recurrence and/or rapidly progressed to cirrhosis within 1 year. A multivariate binary regression analysis showed that HCV viremia at week 2 and a non‐C/C recipient IL‐28B genotype were independent risk factors for cholestatic recurrent HCV. No predictive factors could be found for the occurrence of recurrent liver cirrhosis 5 and 10 years after LT. Our study shows that the HCV RNA level at week 2 and the recipient IL‐28B genotype are independent, statistically significant risk factors for post‐LT cholestatic HCV, and it emphasizes the importance of viral load monitoring and IL‐28B genotyping for identifying HCV recipients at risk for severe HCV recurrence. Liver Transpl 18:671–679, 2012.

Transjugular intrahepatic portosystemic shunt (TIPS) augments hyperinsulinemia in patients with cirrhosis

BACKGROUND/AIMS Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinemia. Both increased insulin secretion and decreased insulin clearance appear to contribute to hyperinsulinemia in cirrhotic patients. A decrease in hepatic insulin extraction rate may be due either to hepatocellular dysfunction or to portosystemic shunting with decreased first-pass insulin clearance. METHODS To specifically address the contribution of portosystemic shunting to the pathogenesis of hyperinsulinemia in cirrhotic patients, we analyzed glycemic control and insulin levels in fasting serum in 23 cirrhotic patients before and after transjugular intrahepatic portosystemic shunt (TIPS). RESULTS Compared to respective values in healthy controls, C-peptide, insulin and proinsulin concentrations at baseline were increased by 340%, 120% and by 100% in cirrhotic patients (all p<0.05). In cirrhotic patients insulin levels before TIPS averaged 104+/-73 pmol/l and increased by more than 50% to 163+/-118 pmol/l after TIPS (p<0.01), whereas levels of C-peptide and proinsulin showed no significant change. Glucose and fructosamin levels also remained unchanged after TIPS. CONCLUSION Our data demonstrate that TIPS does not impair glycemic control in cirrhotic patients and that an increase in portosystemic shunting augments hyperinsulinemia, most likely by decreasing hepatic insulin clearance.

Life‐threatening gastrointestinal bleeding after liver transplatation due to hepatic artery pseudoaneurysm perforating into the common bile duct. A case report

A 54-year-old male presented with acute rejection and life-threatening gastrointestinal bleeding 2 months following orthotopic liver transplantation. Since no bleeding was identified in the entire gastrointestinal (GI) tract, hematobilia was first suspected and an arteriocholedochal fistula angiographically confirmed. Two days after resection of a pseudoaneurysm of the hepatic artery (HA) with primary repair and closure of the bile duct fistula, hepatic artery thrombosis (HAT) occurred. Various attempts to revascularize the HA eventually failed. Two weeks later, a CT scan showed necrotic areas within the two left lateral segments. At relaparotomy, major parts of the bile duct were found to be necrotic, and the biliary anastomosis was therefore abandoned and necrotic tissue removed. HAT was otherwise well tolerated by the graft and, at a further relaparotomy some weeks later, a hepaticojejunostomy was performed. Two years after transplantation the patient is well with a normally functioning graft.

Fatal course of parvovirus B19-associated myocarditis in a female liver transplant recipient.

Acute myocarditis may result in severe hemodynamic compromise with fatal outcome. Furthermore, recent studies suggest myocarditis as a major cause of sudden unexpected death. A variety of cardiotropic viral, rickettsial, and bacterial infectious agents have been identified to date. Parvovirus B19 (PVB19) is usually benign in childhood, but it may also cause death due to myocarditis. We present here the case of an adult female who presented with fatigue, dyspnea on exertion, and orthostatic dizziness 8 months after successful liver transplantation. Cardiologic work‐up, including left ventricular endomyocardial biopsy, revealed acute myocarditis secondary to PVB19. Since no specific therapy for this virus is available, the patient was treated symptomatically with an angiotensin‐converting enzyme inhibitor plus beta‐blocker and diuretics. After a period of stabilization, new‐onset rapid atrial fibrillation caused acute low‐output syndrome within 14 days after hospital admission. The patient eventually died because of refractory cardiogenic shock. In conclusion, to our knowledge this is the first report of PVB19‐induced myocarditis confirmed by detection of viral genome in myocardium in a liver transplant recipient. (Liver Transpl 2005;11:463–466.)

Case Report: Spontaneous Bacterial Pleural Empyema in Liver Cirrhosis

Patients with liver cirrhosis are known to suffer from a varie ty of immune defects, ie, complement de ® ciency, neutrophil dysfunction, and reticuloe ndothe lial cell dysfunction (1). These defects predispose live r cirrhosis patients to opportunistic infections. The most prominent of these is spontane ous bacterial peritonitis, which has attracted considerable scienti® c inte rest over the last decade (for review see 1). Pathogenesis of spontane ous bacterial peritonitis involve s several steps: ® rst, translocation of bacte ria from the gut into lymphatics and then into the blood; second, prolonge d bacteriemia, and third, infection of ascites. A second bacte rial infection, spontane ous bacterial pleural empyema has been reported only once in the literature (2). We here report on two patients with end-stage live r cirrhosis awaiting transplantation, who developed spontaneous bacterial pleural empyema without classical signs of in ̄ ammation. Both patients had concomitant ascite s without evidence of bacterial infection of this ̄ uid.

Fulminant hepatic failure after high-dose cytosine arabinoside and mitoxantrone treatment for relapse of acute myelogenous leukaemia.

To the editor: Despite intensive induction chemotherapy, most patients with acute myelogenous leukaemia (AML) still die of relapsing disease. Cytosine arabinoside (AraC), a mainstay in current treatment, represents the single most active agent apart from anthracyclines and their derivatives. In vitro studies showed a synergistic effect of HD-Ara-C and mitoxantrone (l), a synthetic aminoanthraquinone with great antineoplastic activity. Side effects from a combination therapy of HD-Ara-C and mitoxantrone are well known, including gastrointestinal, pulmonary, ophthalmologic, dermatologic, cardiac as well as CNS toxicity and bone marrow depression (2, 3). Hepatic toxicity has also been reported, consisting of reversible elevation of transaminases, bilirubin and alkaline phosphatase (4). In the present case, we describe a young patient with fulminant liver failure after HDAra-C and mitoxantrone therapy. A previously healthy 15-year-old girl was referred for treatment of AML of the M2 type. Complete remission (CR) was achieved after two TAD-9 courses for induction therapy consisting of thioguanine 200 mg/m2/day on d 3 to 9, Ara-C 100 nig/m2/d by continuous infusion on d 1 and 2, followed by short-term infusions of Ara-C 100 mg/m2/d every 12 hours on d 3 to 8 and daunorubicin 60 mg/m2/d on d 3 to 5 . This was followed by maintenance therapy consisting of conventional dose Ara-C (100-200 mg/ m’) and cyclophosphamide. Five months later, the patient received another TAD-9 course for relapsing leukaemia. Further chemotherapy had to be stopped because of a recurrent pneumonic infiltration. At this time, the girl’s parents decided to withdraw her from further treatment. Six months later, the girl presented with the second relapse of AML. A combination therapy with high-dose cytosine arabinoside 3 g/m2 every 12 h by 3-h infusion on d 1 to 4 and mitoxantrone 12 mg/ m2/d as a 30-minute infusion on d 3 ,4 and 5 (HAM) was started. CR was achieved and the girl was considered for autologous bone marrow transplantation. At this stage, hepatic toxicity was seen for the first time. Fourteen days after chemotherapy, a mild but progressive increase in transaniinases was observed (WHO grade I). ALT had risen to 110 U/l (normal: less than 22 Ujl), alkaline phosphatase up to 2 times normal, whereas bilirubin was only slightly elevated. For consolidation, the girl received a second HAM course after normalization of transaminase values. This time, however, the dosage was reduced by 25% to HD-Ara-C 3 g/m2/twice a day for 3 d and mitoxantrone 12 mg/m2/d for 2 d. After this treatment, WHO grade I1 hepatic toxicity occurred. Transaminase values had normalized 2 weeks after chemotherapy. A bone marrow aspiration performed 4 wk after starting the second HAM course confirmed complete remission of AML. Soon after discharge, 25 d after the end of the second HAM cycle, the patient was readmitted with severe abdominal pain, vomiting, diarrhoea, jaundice and encephalopathy grade I. The liver was palpable 10 cm below the right costal margin. The transaminase values had extensively increased AST 4500U/1 (normal: less than 18 U/l) and ALT 3330 Ujl (normal: less than 22 Ujl). Serum lactic dehydrogenase (LDH) had risen up to 15030 Ujl (normal: less than 240 Ujl), alkaline phosphatase up to 324Uj1 (normal: between 60 and 170U/1) and bilirubin up to 2.6 mg% (WHO grade III-IV). Prothrombin time had fallen to less than 10% (normal: 70% to 110%), heralding liver failure. An ultrasound examination was performed to differentiate parenchymatous disease from venous outflow bloc of the liver. It showed massive hepatomegaly with a homogeneous echogenic parenchymal pattern, patent hepatic veins, normal-sized portal vein and no signs of mechanical cholestasis. These findings, together with a normal caudate lobe, made veno-occlusive disease and Budd-Chiari’s syndrome highly unlikely. The serum of the patient tested negative for markers of viral hepatitis. The disease progressed and the girl fell into grade