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OBJECTIVES: Nonalcoholic steatohepatitis (NASH) and fibrosis play critical roles for the prognosis of patients with nonalcoholic fatty liver disease (NAFLD). Identification of patients at risk of NASH and fibrosis is therefore critical for disease management. NAFLD Fibrosis Score (NFS) and transient elastography (TE) have been suggested to exclude advanced fibrosis. However, there is increasing evidence that also patients with NASH and early fibrosis are at risk of disease progression and complications, emphasizing the need for improved noninvasive risk stratification in NAFLD. METHODS: Because hepatocyte apoptosis plays an early role in NASH pathogenesis, we evaluated whether the apoptosis biomarker M30 might identify NAFLD patients who are at risk of NASH and fibrosis despite low NFS or TE values. Serum M30 levels were assessed by enzyme-linked immunosorbent assay in combination with NFS and/or TE in an exploration (n = 103) and validation (n = 100) cohort of patients with biopsy-proven NAFLD. RESULTS: Most patients with low NFS (cutoff value < −1.455) revealed increased M30 levels (>200 U/L) in the exploration (62%) and validation (67%) cohort, and more than 70% of them had NASH, mostly with histological fibrosis. Vice versa, most patients with NFS < −1.455 but nonelevated M30 levels showed no NASH. NASH was also detected in most patients with indeterminate NFS (−1.455 to 0.676) but elevated M30 levels, from which ∼90% showed fibrosis. Similar results were obtained when using TE instead of NFS. DISCUSSION: The combination of the M30 biomarker with NFS or TE enables a more reliable identification of patients with an increased risk of progressed NAFLD and improves patient stratification.

Background A considerable proportion of patients receiving liver transplants for Budd-Chiari syndrome (BCS) suffer from myeloproliferative neoplasms (MPN). This study evaluated the long-term prognosis of liver-transplanted patients with BCS secondary to MPN and the effect of immunosuppression on MPN progression. Methods A total of 78 patients with BCS were evaluated between 1982 and 2013. Of those, 40 patients suffered from polycythaemia vera (PV) and essential thrombocythaemia (ET). One patient had primary myelofibrosis (PMF). All patients received the standard immunosuppressive regimen. We retrospectively evaluated the long-term survival, clinical course and laboratory parameters of patients with MPN. Results Exactly 29/41 patients (71%) with MPN survived ≥ 3 years [mean age 36 ± 11 years; females n = 27 (93%)]. Mean follow-up after orthotopic liver transplantation (OLT) was 12.4 ± 7.3 years (range 3–28 years). Five- and 10-year survival rates were not significantly different in patients with and without MPN (P = 0.81 and P = 0.66 respectively) or in patients with PV and ET (P = 0.29 and P = 0.55 respectively). Thrombosis and bleeding developed in 7/29 (24%) long-term MPN survivors with no significant difference between ET and PV (P = 0.18). In the long-term follow-up, there was no evidence of progression to overt myelofibrosis or acute myeloid leukaemia (AML). In the uni- and multivariate Cox-regression analyses, MPN did not influence survival after OLT. Conclusions Budd-Chiari syndrome patients with and without underlying MPN had similar long-term survival rates after OLT. There was no evidence of enhanced progression of MPN after OLT secondary to immunosuppressive therapy. However, major haemorrhage and recurrent thrombosis contributed to morbidity and mortality after OLT in those patients.

Hintergrund: Gastrointestinale Endoskopien werden in zunehmendem Umfang in Sedierung durchgefuhrt. Alle hierzu verwendeten Medikamente bergen ein gewisses Komplikationsrisiko. Die derzeit verfugbaren Daten bez. sedierungsassoziierten Morbiditats- und Letalitatsraten sind begrenzt und weisen in der Mehrzahl erhebliche methodische Limitationen auf. Ziel dieser Arbeit ist es, an einer grosen Anzahl gastrointestinaler Endoskopien schwere sedierungsassoziierte Komplikationen zu erfassen. Methoden: Es erfolgte eine multizentrische Datenerfassung schwerwiegender sedierungsassoziierter Komplikationen aus prospektiv gefuhrten Komplikationsregistern der teilnehmenden Kliniken (Dokumentationszeitraum median 27 Monate, Range 9 – 129 Monate). Ergebnisse: In die Studie wurden Daten von 388 404 Endoskopien aus 15 Abteilungen eingeschlossen. Schwere sedierungsassoziierte Komplikationen traten bei 57 Patienten (0,01 %) auf. 41 % der Komplikationen und 50 % aller Komplikationen mit letalem Ausgang (10/20 Patienten) ereigneten sich im Rahmen von Notfallendoskopien. Daruber hinaus zeigte sich, dass 95 % der Komplikationen und 100 % aller letalen Komplikationen Patienten betrafen, die der ASA-Klasse ≥ 3 zuzuordnen waren. Schlussfolgerung: Mit Einschluss von knapp 400 000 Endoskopien ist die vorliegende Studie die weltweit groste prospektive und multizentrische Erfassung von Sedierungskomplikationen. Die Auswertung zeigt, dass die Sedierung in der gastrointestinalen Endoskopie sicher durchgefuhrt wird. Die Morbiditats- und Letalitatsrate liegt deutlich niedriger als sie bisher in der Literatur bei ahnlichen Patientenkollektiven beschrieben worden ist. Risikofaktoren fur das Auftreten von gravierenden Komplikationen sind Notfalluntersuchungen und Patienten der ASA-Klasse ≥ 3.

Outcome of patients with hepatocellular carcinoma is influenced by their histological grade. Invasive biopsy of the lesions is the gold standard in this regard.We therefore analysed the diagnostic accuracy of contrast enhanced ultrasound for non-invasive grading of hypervascular hepatocellular carcinoma in liver cirrhosis.According to the tumour perfusion kinetics on contrast enhanced ultrasound two grading groups were prospectively defined: well-differentiated hepatocellular carcinoma (US-G1) and higher grade hepatocellular carcinoma (US-G2/G3). Immediately after contrast enhanced ultrasound-grading, biopsies of hepatocellular carcinoma-lesions (n=95, 1.2-12.5 cm) were obtained and analysed for tumour grading (G). Descriptive statistics, sensitivity, specificity positive and negative predictive values, diagnostic likelihood ratios and interoperator reproducibility were calculated (κ).Histologically 77 (81.1%) patients had G2-G3 and 18 (18.9%) had G1 tumours. Higher grade hepatocellular carcinoma showed more often a washout in the portal or late phase (p0.0001). The sensitivity, specificity, positive predictive values and negative predictive values of contrast enhanced ultrasound for grading of hepatocellular carcinoma for all patients were 94% (CI: 72-99%), 95% (CI: 88-99%), 81% and 99% and for patients with tumours5 cm 100%(95% CI: 79-100), 96% (95% CI: 80-99), 92% and 100%. Positive and negative diagnostic likelihood ratios' were 18 and 26 and 0.06 and 0, respectively. κ=0.941 (p0.001).Contrast enhanced ultrasound has a high diagnostic value and reproducibility for non-invasive grading of hypervascular hepatocellular carcinoma1cm in patients with liver cirrhosis.

Objective. The degree of liver fibrosis determines the prognosis and treatment of patients with chronic viral hepatitis. Transient elastography (TE) has been accepted as a noninvasive method for assessment of liver fibrosis. Sound velocity (SV) changes are also dependent on elastic properties of tissue. The aim of this pilot study was to evaluate whether SV estimation of liver tissue allows the determination of fibrosis stages in patients with chronic viral hepatitis. Methods. Prospectively, 50 healthy volunteers and 149 patients received stiffness (TE, 50-Hz vibrator, 5-MHz array) and SV (conventional ultrasound, C5-2-MHz transducer) measurements. Eighty-four patients received representative liver biopsies. The estimated SV and stiffness were compared using liver biopsy as a reference (METAVIR fibrosis stage [F] scoring system [Hepatology 1996; 24:289-293]). Descriptive statistics, analysis of variance, receiver operating characteristic curve analysis, and box plot analysis as well as intra-operator and interoperator reproducibility analyses were performed. Results. The SV ranged from 1540 to 1650 m/s. The mean SV ± SD was significantly different between healthy volunteers (1559 ± 11 m/s) and patients with FO-F3 (1575 ± 21 mm/s) and F4 (1594 ± 18 m/s) disease (P < .001). For detection of liver cirrhosis, the area under the receiver operating characteristic curve for SV was 0.80 (95% confidence interval, 0.69-0.89). With a cutoff value of 1589 m/s, the sensitivity, specificity, and positive and negative predictive values of SV for detection of liver cirrhosis were 82%, 76%, 70%, and 86%, respectively. Sound velocity measurements were reproducible (15%) and had acceptable operator independence (19%). Conclusions. The SV of liver tissue depends on the fibrosis stage. An SV of 1589 m/s or higher detects cirrhosis with high sensitivity. Therefore, SV measurement appears to be a promising new method for noninvasive quantification of liver fibrosis.

A 21-year-old male presented at the emergency room with jaundice, itching, dry cough, malaise and weight loss of 10 kg during the preceding four weeks. Eighteen months earlier, the patient had suffered an automobile accident leading to polytrauma. Serological markers for viral or other causes of hepatitis were absent. For suspected secondary sclerosing cholangitis, ultrasound and ERCP were performed but failed to reveal pathological findings. A liver biopsy showed cholestatic liver disease without signs of portal field-associated hepatitis. Hepato-biliary scintigraphy demonstrated hepatocellular dysfunction. The patient finally mentioned his guinea pig farm with around 50 animals, 20 of which had recently died for unknown reasons. The patient and three of his guinea pigs were subsequently tested for serological evidence of leptospirosis. IgG and IgM antibodies reacting with Leptospira interrogans were detected in the patient's serum, and all 3 guinea pigs were serologically positive for serovar Bratislava. Bacterial culture was not successful, and also PCR tests remained negative. The clinical symptoms quickly resolved after the initiation of antibiotic therapy with amoxicillin.

Background and aims: Transient elastography is increasingly being used in patients with chronic liver disease. It has proven particularly useful to identify patients with advanced fibrosis or cirrhosis, while classification of no or little fibrosis appears to be difficult. In general, stiffness values

Treatment of chronic hepatitis C with type I interferons and ribavirin can be associated with exacerbation of hepatitis and sometimes liver decompensation. We report two patients with chronic hepatitis C virus infection who experienced a severe increase of bilirubin levels of up to 17 times upper the limit of normal value in the absence of deterioration of hepatic function during therapy with pegylated-interferon and ribavirin. A genetic disposition for Gilbert's syndrome explained the adverse events and permitted a continuation of therapy leading to a sustained clearance of chronic hepatitis C infection. Since one patient jaundiced already during a lead-in treatment period with ribavirin monotherapy we suggest that hyperbilirubinaemia during combination therapy is primarily caused by ribavirin rather than by effects of interferon alpha on UDP-glucuronosyltransferase activities. Of note, both patients recovered from their initial unconjugated hyperbilirubinemia despite continuation of ribavirin therapy, which indicates that compensatory mechanisms leading to a normalization of UGT1A1 activity are likely.

de Boer JF, Bahr MJ, Boker KHW, Manns MP, Tietge UJF. Plasma levels of PBEF/Nampt/visfatin are decreased in patients with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 296: G196-G201, 2009. First published December 12, 2008; doi:10.1152/ajpgi.00029.2008.-Liver cirrhosis is a catabolic disease associated with a high incidence of insulin resistance and diabetes mellitus. Pre-B cell colony-enhancing factor/nicotinamide phosphoribosyltransferase/visfatin has been characterized as a novel adipokine with a potential role in glucose metabolism and nicotinamide dinucleotide (NAD) generation. We studied plasma levels and metabolic relevance of visfatin in 19 patients with cirrhosis and 19 body mass index-, age-, and sex-matched controls. In addition, hepatic mRNA expression was assessed by qPCR in livers of seven patients with cirrhosis and four controls. Circulating visfatin was 78% lower in cirrhotics (P

Background. Transjugular liver biopsy (TJLB) is frequently used to obtain liver specimens in high-risk patients. However, TJLB sample size possibly limits their clinical relevance.Methods. 102 patients that underwent TJLB were included. Clinical parameters and outcome of TJLB were analyzed. Control samples consisted of 112 minilaparoscopic liver biopsies (mLLBs) and 100 percutaneous liver biopsies (PLBs).Results. Fewer portal tracts were detected in TJLB (4.3±0.3) in comparison with PLB (11.7±0.5) and mLLB (11.0±0.6). No difference regarding the specification of indeterminate liver disease and staging/grading of chronic hepatitis was observed. In acute liver failure (n=32), a proportion of hepatocellular necrosis beyond 25% was associated with a higher rate of death or liver transplantation.Conclusions. Despite smaller biopsy samples the impact on the clinical decision process was found to be comparable to PLB and mLLB. TJLB represents a helpful tool to determine hepatocellular necrosis rates in patients with acute liver failure.

Summary Background Alteration of the leptin system appears to play a role in the inflammatory–metabolic response in catabolic diseases such as chronic liver diseases. Aim To investigate the association between leptin components, inflammatory markers and hepatic energy and substrate metabolism. Methods We investigated in vivo hepatic substrate and leptin metabolism in 40 patients employing a combination of arterial and hepatic vein catheterization techniques and hepatic blood flow measurements. In addition to metabolic, inflammatory and neuroendocrine parameters, circulating levels of free leptin, bound leptin and soluble leptin receptor were determined. Results Compared with controls, bound leptin and soluble leptin receptor levels were significantly elevated in cirrhosis, while free leptin did not increase. In cirrhosis bound leptin was correlated with soluble leptin receptor (r = 0.70, P

OBJECTIVE Acute cryptogenic hepatitis may represent both a self-limited disease as well as the onset of chronic hepatitis. The aim of this analysis was to evaluate the effect of steroid treatment in patients with acute cryptogenic hepatitis. METHODS We retrospectively analyzed four patients with acute cryptogenic hepatitis. Histories were negative for alcohol and hepatotoxic drug intake. Markers of metabolic liver disease, liver-related autoantibodies, and viral markers were negative in all patients. Gamma globulins were in the normal range. ALT rose above 1000 U/L in all patients and bilirubin levels were elevated to more than 400 micromol/L. Histopathological assessment revealed minimal infiltration with plasma cells, eosinophils and bile duct lesions. Using the international scoring system for the diagnosis of autoimmune hepatitis, all patients were classified as 'probable disease' in the absence of specific markers. RESULTS We started immunosuppressive treatment with prednisolone because of persisting high aminotransferases and impaired liver function. All patients responded to steroids with normalization of liver function and a rapid decrease of aminotransferases. In one patient, additional treatment with azathioprine was necessary due to rebounding aminotransferases during steroid tapering. CONCLUSION Steroids have to be taken into account in the therapy for severe acute cryptogenic hepatitis. The response to steroid treatment could be indicative for an autoimmune genesis of the disease.

A 40-year-old female patient was admitted for work-up of multiple abdominal masses. The lymphoma-mimicking tumors were detected accidentally during an ultrasound course. The past medical history was unremarkable besides a status post-traumatic splenic rupture and splenectomy. The patient was asymptomatic, especially there were no complaints of fever, night sweats or weight loss. Laboratory tests did not show pathological results. Ultrasound of the abdomen revealed multiple hypoechoic mesenterial and peritoneal enlarged tumors as well as a subhepatic mass (30 x 20 mm). Transmission computed tomography (CT) showed a normal chest, excluded abnormal thoracal masses and confirmed the multiple abdominal nodules. Microparticles were trapped only by tissue with phagocytosis function as cells of the reticulohistiocytary system in liver and spleen. Uptake of (99 m)Tc-labeled microparticles is specific for splenic tissue. All abdominal masses were detectable by single photon emission computed tomography (SPECT) after intravenous administration of this radiotracer. Ultrasound-guided biopsy proved the presence of spleen tissue with follicular hyperplasia. In conclusion, we report a case of post-traumatic splenosis. In 16 - 67 % of patients who experienced traumatic splenic rupture autotransplanted spleen tissue can be detected. Splenosis therefore is an important differential diagnosis of abdominal masses in splenectomized patients.

Currently, we are faced with an increasing number of patients with HCV-induced end-stage liver disease. Per year, up to 4% of the patients with compensated cirrhosis develop complications subsequently leading to a substantial decrease in survival. Decompensated liver cirrhosis due to hepatitis C is the leading indication for liver transplantation (OLT). However, reinfection of the graft is common with an accelerated course of the disease in many patients. Depending on the disease stage, the aims of antiviral therapy may differ between patients with HCV-induced liver cirrhosis. Antiviral therapy can reverse the extent of fibrosis. Even without viral clearance, the incidence of hepatocellular carcinoma is lowered by interferon. In naive patients with compensated HCV-induced cirrhosis, sustained virological responses can be achieved in up to 50% of the cases. Retreatment of non-responders may clear the virus in about 10% of the patients. Though elimination of HCV prior to OLT is certainly desirable, treatment is often limited by severe cytopenia and decompensation of liver function. Of the eligible patients 20% sustain viral clearance after OLT.

The clinical presentation of metabolic liver disease is highly variable, covering acute liver failure, liver cirrhosis, hepatic cancer and various extrahepatic manifestations. Both natural course and prognosis after liver transplantation are substantially influenced by extrahepatic manifestations. In many types of metabolic liver disease, timely diagnosis allows for successful medical treatment. However, progressive liver failure and severe extrahepatic damage can be the indication for liver transplantation. In general, standard transplantation criteria also apply for metabolic liver disease. They have to be modified by disease-specific criteria, and extrahepatic damage may necessitate multiorgan transplantation. The overall prognosis after liver transplantation for metabolic liver disease is favorable. Furthermore, several metabolic defects are phenotypically cured by liver transplantation. Alternative treatments like hepatocyte transplantation or gene therapy are still in the experimental stage.

With increasing long-term survival rates after orthotopic liver transplantation (OLT), metabolic alterations complicating the clinical course, such as diabetes mellitus (DM), become increasingly important. Liver cirrhosis is associated with severe alterations in glucose metabolism. However, it is currently unclear whether these changes are reversed by successful OLT. We therefore characterized glucose metabolism in patients with liver cirrhosis and normal fasting glucose levels before OLT (cir), in the clinically stable long-term course after OLT (OLT), and control subjects (con) using oral glucose tolerance tests (cir = 100, OLT = 62, con = 32), euglycemic-hyperinsulinemic clamps (cir = 10, OLT = 27, con = 14), and positron emission tomography (PET) scan analysis with 18F-fluorodeoxyglucose (FDG) as a tracer (cir = 7, OLT = 7, con = 5). Fasting insulin and C-peptide levels were significantly elevated in patients with liver cirrhosis compared with both control subjects (P

Autoimmune hepatitis (AIH) is a chronic inflam- matory disease of unknown etiology characterized by a loss of tolerance toward the hepatocellular epithelium.AIH is associated with hypergamma- globulinemia and circulating autoantibodies, and the majority of patients respond to immunosup- pressive treatment.The disease is most prevalent among women, displays an immunogenetic association with the human leukocyte antigen (HLA) A1-B8-DR3 or DR4 haplotypes (1), and the presence of extrahepatic syndromes (2).Auto- Abstract: Background: Liver transplantation is the final therapeutic option for about 10% of patients with autoimmune hepatitis (AIH) who do not respond to medical therapy.The aim of this study was to evaluate the long- term outcome in serologically defined subgroups of AIH after transplantation. Methods: Pre- and post-transplantation data of 28 patients with AIH transplanted between 1987 and 1999 were retrospectively analyzed and compared with 24 patients, who underwent liver transplantation because of Wilson's disease and glycogen storage disease type 1. Results: Serological analyses identified patients with AIH type 1 (n ¼ 13), type 2 (n ¼ 5), and type 3 (n ¼ 10).The 5-yr patient survival rate after liver transplantation was 78.2%, which was not significantly different from the control group.Six AIH patients and four control patients required re-transplantation because of initial non-function, chronic rejection or AIH recurrence.Patients transplanted for AIH (88%) had more episodes of acute rejection when compared with patients transplanted for genetic liver diseases (50%).Clinical and histological features of chronic rejection were present in four patients, which did not differ significantly from the controls. Recurrence of AIH was diagnosed in nine patients (32%) based upon the presence of autoantibodies, increased c-globulins, steroid dependency, and histological evidence of chronic hepatitis.These combined features were not found in any of the controls. Conclusions: Our data do not suggest that AIH subtypes influence prog- nosis after liver transplantation.Despite a high frequency of acute cellular rejection episodes and disease recurrence, transplantation for AIH has a 5-yr survival rate, which does not differ from that observed in patients transplanted for genetic liver diseases.

Background/Aims : Extracorporeal detoxification systems for supportive therapy of liver failure have recently gained much interest. We herein report results from the first clinical application of Prometheus ® , a new liver support system in which albumin-bound substances are directly removed from blood by special adsorber. In a simultaneous step, high-flux hemodialysis is performed. We assessed safety, adsorber efficiency and clinical efficacy of the Prometheus ® system. Methods : Eleven patients with acute-on-chronic liver failure and accompanying renal failure were treated with Prometheus ® on 2 consecutive days for >4 h. Results : Prometheus ® treatment significantly improved serum levels of conjugated bilirubin, bile acids, ammonia, cholinesterase, creatinine, urea and blood pH. There were no significant changes in hemoglobin and platelet levels, whereas leucocytes increased without signs of systemic infection. No treatment-related complications except a blood pressure drop in two patients with systemic infection were noted. In one patient (Child-Pugh score: 15) Prometheus ® treatment could not be completed due to onset of uncontrolled bleeding 16 h after dialysis. Conclusions : Prometheus ® is a safe supportive therapy for patients with liver failure. A significant improvement of the biochemical milieu was observed already after two treatments. Prospective controlled studies with the Prometheus ® system are necessary to evaluate hard clinical end-points.

Background. Patients suffering from hepatic metastases of neuroendocrine tumors (NET) are potential candidates for orthotopic liver transplantation. Because recurrence rates are high and outcome is variable, prognostic indicators are required. The aim of our study was to identify predictors of long-term survival with a focus on the impact of tumor biology. Methods. We retrospectively analyzed 19 patients who received an orthotopic liver graft for metastatic NET at the Medizinische Hochschule Hannover. Expression of Ki67, E-cadherin, and p53 was studied immunohistochemically in metastases of neuroendocrine tumors of the explanted livers. Results. Patients were followed up to 146 months after liver transplantation. Six patients died during follow-up. The resulting 1-, 5-, and 10-year survival rates are 89%, 80%, and 50%, respectively. All deaths during long-term follow-up were tumor-associated. Recurrence was diagnosed in 12 patients between 2 weeks and 48 months after liver transplantation. Three patients are without tumor recurrence more than 8 years after liver transplantation. Survival in the 5 patients with low Ki67 and regular E-cadherin staining was significantly better than in the 12 patients with high Ki67 or aberrant E-cadherin expression (7-year survival 100% vs. 0%, respectively, log rank P=0.007). p53 expression did not significantly improve prognostic accuracy. Conclusions. We conclude that analysis of Ki67 and E-cadherin expression may improve the identification of patients with a favorable prognosis after liver transplantation for metastatic neuroendocrine tumors.

The aim of this study is to (1) characterize the impact of orthotopic liver transplantation (OLT) on splanchnic and systemic oxygen uptake (V O 2 ) in patients with liver cirrhosis, and (2) investigate possible influencing factors, as well as metabolic consequences, of reduced splanchnic V O 2 in patients with cirrhosis. Therefore, we measured systemic V O 2 (indirect calorimetry), portal pressure (hepatic venous pressure gradient), hepatic blood flow (HBF; primed continuous infusion of indocyanine green), and hepatic turnover (arteriohepatic venous concentration differences multiplied by HBF) of oxygen, glucose, free fatty acids (FFAs), and aromatic amino acids (AAAs) in 52 patients with advanced cirrhosis and 16 patients with a clinically stable long-term course after OLT. Systemic V O 2 was significantly increased in patients with cirrhosis (261 [plusmn] 7 mL/min) and normalized after OLT (216 [plusmn] 8 mL/min; P [lt ] .001). Arterial and hepatic venous oxygen saturation and splanchnic oxygen extraction (in percent) were not different between patients with cirrhosis and after OLT. Splanchnic V O 2 was decreased in patients with cirrhosis (41 [plusmn] 3 mL/min, representing 16% [plusmn] 1% of systemic V O 2 ) and normalized after OLT (69 [plusmn] 6 mL/min; P [lt ] .001, representing 32% [plusmn] 3% of systemic V O 2 ; P [lt ] .001). In patients with cirrhosis, a decrease in HBF was associated with decreased splanchnic V O 2 ( r = 0.74; P [lt ] .001). Conversely, decreased splanchnic V O 2 reflected a decrease in hepatic glucose production ( r = 0.34; P = .01) and hepatic extraction of FFAs ( r = 0.40; P [lt ] .01) and AAAs ( r = 0.30; P [lt ] .05). These results show that (1) splanchnic and systemic V O 2 normalize after OLT, indicating correction of hepatic and extrahepatic metabolic derangements; (2) in cirrhosis, HBF becomes limiting for hepatic oxygen supply; and (3) impaired splanchnic V O 2 reflects a decrease in metabolic liver function. ( Liver Transpl 2001;7:1015-1022 .)

Malfunction of the immune system at different levels is typical for patients with liver cirrhosis. Both non-specific as well as antigen-specific functions may be compromised. The best studied and clinically most important problem is the diminished clearance capacity of the reticulo-endothelial system in liver cirrhosis. This transfers into a significantly higher rate of bacterial infections associated with a poorer prognosis in these patients. The clinical relevance of concomitant immune disorders like neutrophil dysfunction is less clear. An impaired activation of natural killer cells (NK) and lymphokine-activated killer cells (LAK) may have a role in the development of hepatocellular carcinoma but additional studies are needed. Clinically important is a moderately reduced efficacy of standard immunization protocols, which can be overcome by an increased dose in most vaccines.

Background/Aims: Reinfection with hepatitis B virus (HBV) after liver transplantation (OLT) is associated with an unfavourable clinical course. Lamivudine/hepatitis B immune globulin (HBIG) combination treatment reduces reinfection rates. However, it is unclear at what time point lamivudine should be started and which HBIG doses are sufficient. Methods : Twenty-one patients receiving combination treatment were studied. Lamivudine was started up to 16.5 months before OLT and continued thereafter. HBIG was started intraoperatively and continued according to anti-HBs-titers. Median follow-up after OLT was 20 months. Results : Eleven patients received lamivudine pretreatment for >2 (median 6) months due to initial HBV-DNA-positivity (median 749 pg/ml). After initial lamivudine response HBV-DNA increased in two of them to concentrations above 10 pg/ml prior to OLT. Both had developed mutations in the YMDD motif and suffered from HBV reinfection 13 and 75 days postoperatively. Individual HBIG consumption was highly variable (range 787–4766 IU/month). Twenty-two percent of anti-HBs titers measured before HBIG administration were below 100 IU/l. Conclusions : Combined reinfection prophylaxis with lamivudine and HBIG is effective in patients with controlled viral replication at the time of OLT. However, pretransplantation lamivudine resistance is a risk factor for reinfection. Low dose HBIG maintenance therapy individualized according to anti-HBs-titers appears to be tenable.

To the Editor: Transplant recipients receiving immunosuppressive therapy have a high risk of developing post-transplant lymphoproliferative disorders. The majority of these are B-cell-derived non-Hodgkin's lymphomas (1). In contrast, primary cutaneous lymphoma after transplantation is rare (1). We report a case of mycosis fungoides (MF) after liver transplantation in an adult.

Objective: Local percutaneous tumor ablation with ethanol injection (PEI) under general anesthesia is an established therapy for patients with advanced nonresectable hepatocellular carcinoma (HCC). There are reports of sudden hypotension immediately after PEI therapy, which was attributed to an acute increase in pulmonary vascular resistance. The aim of our study was to objectively confirm pulmonary hypertension by right heart catheterization and to evaluate biochemical markers with relevance to the pulmonary circulation. Design: Cross-sectional clinical study. Setting: Interventional Gastroenterology in a tertiary care center. Patients: We studied 40 patients with HCC who underwent percutaneous ethanol injection under general anesthesia for the treatment of nonresectable HCC. Results: In patients with HCC, PEI leads to a significant increase in pulmonary arterial pressure. Concomitantly, free hemoglobin and blood ethanol level significantly increased, whereas the L-arginine/asymmetric dimethylarginine ratio, a parameter of nitric oxide (NO) production capacity, and nitrite, a marker of NO synthesis, significantly decreased. Conclusion: Procedure-related pulmonary hypertension in patients undergoing PEI is multifactorial. Plasma concentrations of the NO precursor L-arginine are reduced by arginase released from lysed erythrocytes, a condition further exacerbated by the increased concentrations of symmetric dimethylarginine, which may compete with the cellular uptake of L-arginine. The result would be reduced synthesis of NO, the concentration of which would be further decreased extracellularly through free hemoglobin. Predictably, the result would be severe endothelial dysfunction and pulmonary hypertension in patients undergoing PEI. These mechanisms might also be relevant in other states of (sudden) hemolysis. (Crit Care Med 2009; 37:000‐000)

We analyzed the long-term clinical course of 71 patients with RNA-positive hepatitis C virus (HCV) infection after liver transplantation. Patients with reinfection after transplantation for HCV-related liver disease, or de novo infection at transplantation were followed for up to 12 years. Cumulative survival for patients with HCV infection at 2, 5, and 10 years after transplantation was 67%, 62%, and 62%, respectively. It was not significantly different from that in patients transplanted for other nonmalignant diseases without HCV infection. The main factor determining long-term survival was the presence or absence of hepatocellular carcinoma (HCC) at transplantation. The 5-year survival rate for HCV patients with or without HCC was 35% versus 73%, respectively (P < .05). No deaths because of viral hepatitis of the graft were observed. Deaths in the first year after transplantation were caused by infectious complications, cardiovascular problems, or rejection; deaths after more than 12 months were exclusively because of recurrence of HCC. Biochemical and histological evidence of hepatitis was found in the majority of the patients, only 16% had normal alanine aminotransferase (ALT) values throughout. Twenty-two percent of patients complained of symptoms, with hepatitis C being the cause in 82% of these. Two patients lost their HCV-RNA for prolonged, ongoing periods of time. The severity of the posttransplantation hepatitis was unrelated to age, sex, severity of liver disease before transplantation, cold ischemic time of the graft, duration of the operation, transfusions, the number of rejection episodes, or the long-term immunosuppressive regime. Only initial short-term therapy with interleukin 2 (IL2) receptor antibodies adversely influenced inflammatory activity. Viral genotype did not influence the course of the graft hepatitis in our series. Histology showed inflammation in 88% of the biopsies and signs of fibrosis in 24%. Mean ALT values correlated with inflammation but not with fibrosis in the biopsies. Porto-portal bridging was observed in six patients, one patient developed cirrhosis within 2 years after orthotopic liver transplantation (OLT). We conclude that chronic hepatitis develops in the majority of patients with HCV infection after liver transplantation. Carrier states without significant laboratory abnormalities are observed in approximately 16%, biochemical abnormalities without symptoms are seen in 60%, and symptomatic disease develops in a quarter of the patients. The disease course closely resembles that seen in nontransplanted hepatitis C patients. It is generally mild but little over 10% of patients develop signs of fibrosis of the graft during the first decade.

Background and Aims: Chronic liver diseases are characterized by inflammatory and fibrotic liver injuries that often result in liver cirrhosis with its associated complications such as portal hypertension and hepatocellular carcinoma. Liver biopsy still represents the reference standard for fibrosis staging, although transient elastography is increasingly used for non-invasive monitoring of fibrosis progression. However, this method is not generally available and is associated with technical limitations emphasizing the need for serological biomarkers staging of liver fibrosis. The enhanced liver fibrosis (ELF) score was shown to accurately predict significant liver fibrosis in different liver diseases, although extracellular matrix components detected by this score may not only mirror the extent of liver fibrosis but also inflammatory processes. Methods: In this prospective biopsy-controlled study we evaluated the utility of the ELF score in comparison to transient elastography to predict different stages of fibrosis in 102 patients with chronic liver diseases. Results: Both techniques revealed similar area under receiver operating characteristic curve values for prediction of advanced fibrosis stages. Compared to transient elastography, the ELF score showed a broader overlap between low and moderate fibrosis stages and a stronger correlation with inflammatory liver injury. Conclusions: Both the ELF score as well as transient elastography allowed for high quality fibrosis staging. However, the ELF score was less discriminative in low and moderate fibrosis stages and appeared more strongly influenced by inflammatory liver injury. This should be considered when making clinical interpretations on the basis of ELF score values.

Background & Aims Progressive fibrosis is a major cause of morbidity and mortality in chronic liver disease. To replace liver biopsy for disease staging, multiple serum markers are under evaluation with multiparametric panels yielding the most promising results. The Enhanced Liver Fibrosis (ELF) score is an ECM marker set consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA) showing good correlations with fibrosis stages in chronic liver disease. Methods The ELF score was measured in 400 healthy controls and 79 chronic hepatitis C patients using an ADVIA Centaur automated system. The ELF score was calculated using the published algorithm combining TIMP-1, PIIINP and HA values. Patients' fibrosis stage was defined histologically. ROC analyses were performed to study marker validity. Reference values and influence factors for the ELF score were validated. Results ELF score reference values ranged from 6.7 to 9.8 and were significantly higher for men vs. women (7.0–9.9 vs. 6.6–9.3, respectively). Afternoon values were slightly higher than morning values (6.7–9.9 vs. 6.6–9.5, respectively). Age was a notable influence factor. We identified three cut-off values: 7.7 for a high sensitivity exclusion of fibrosis, 9.8 for a high specificity identification of fibrosis (sensitivity 69%, specificity 98% for moderate fibrosis), and 11.3 to discriminate cirrhosis (sensitivity 83%, specificity 97%). ELF score validity was superior to the results of the single tests. Conclusions The ELF score can predict moderate fibrosis and cirrhosis. However, influence factors such as gender and age need to be taken into account.

Transient elastography is increasingly used for assessment of liver fibrosis. Acoustic radiation force impulse imaging (ARFI) is a new technology to perform liver elastography.We evaluated the clinical feasibility, validity and accuracy of the ARFI method and compared it to Fibroscan(®) and liver histology.Ultrasonographic elastography of the liver using ARFI was performed in 29 patients with liver cirrhosis, 70 patients with liver disease and 23 healthy controls.ARFI was feasible in all patients providing a mean propagation velocity of 1.65±0.93 m/s. ARFI results of the right and left liver lobes were comparable (p0.001). In cirrhotic patients, ARFI gave significantly higher values than in the other patients (p0.001). Rate of invalid measurements was lower in ARFI than in Fibroscan(®) (p0.04). Both elastography methods were highly correlated to each other (p0.001). Furthermore, ARFI correlated to histological grading of liver fibrosis (p0.001) and to inflammatory activity (p0.05). Liver steatosis had no statistical influence on ARFI results (p=0.2) in contrast to Fibroscan(®) (p0.05).The new ultrasonographic method of ARFI elastography allows valid, accurate and flexible evaluation of liver stiffness. It seems more feasible in patients with liver cirrhosis than Fibroscan(®). ARFI elastography of the left liver lobe is also possible. Liver steatosis does not seem to influence ARFI elastography.

Budd-Chiari syndrome (BCS) is characterized by an obstruction of hepatic venous outflow. Membranous obstruction of the inferior vena cava (IVC) is a curable cause of primary BCS but is very rare in Western Europe. To date, there is only very limited information on membranous BCS in the Western world. We here report the diagnosis and management of five Caucasian patients with membranous BCS.Out of 23 patients with BCS diagnosed between 2004 and 2007 we identified five with a membranous web of the IVC. Diagnostic evaluation of BCS included laboratory tests, ultrasound Doppler imaging, CT and MRI.The clinical presentation of membranous BCS was heterogeneous. The time frame from first clinical symptoms to diagnosis ranged from 3 weeks to 60 years. Liver cirrhosis was misdiagnosed in 4/5 patients. CT did not establish the correct diagnosis of membranous BCS in any of our patients. In contrast, abdominal Doppler ultrasonography showed collaterals and a web in the IVC which was confirmed by Doppler-MRI and hepatovenography. Four patients underwent interventional treatment with balloon dilatation of short-segment venous stenoses or complete occlusions. Therapy was successful: in all cases it resulted in a normalized extrahepatic blood flow and reduction of spleen size.Membranous BCS may be underdiagnosed in Caucasians. Doppler ultrasound should be used as the initial diagnostic procedure for membranous BCS. Although CT is considered the "gold standard" in addition to angiography, it could not detect membranous obliteration in our cases. Patients can be effectively treated by interventional endovascular therapy.

Der Grad der Leberfibrose beeinflusst die Therapie und Prognose der Patienten mit chronischer Hepatitis. Fibroscan hat sich in den letzten Jahren als eine nicht invasive Methode zur Abschatzung des Leberfibrosegrades etabliert. Der Gold-Standard ist weiterhin die Leberbiopsie. Eine neue Ultraschalltechnologie ermoglicht nun die Abschatzung der Ultraschallgeschwindigkeit im Gewebe (ZSI). Es ist bekannt, dass die Schallgeschwindigkeit abhangig von den elastischen Eigenschaften des Gewebes ist. Unsere Frage lautete deshalb, ob die Ultraschallgeschwindigkeit im Lebergewebe den Fibrosegrad der chronisch erkrankten Leber wiedergibt. Prospektiv wurden 149 Patienten mit chronischer Virushepatitis mittels Zonare und Fibroscan untersucht. 82 Patienten erhielten eine reprasentative Leberbiopsie. Die ZSI-Messungen mittels Zonare wurden mit Dichtemessungen mittels Fibroscan und Fibrosegrad in der Histologie verglichen (METAVIR-Score). Anschliesend erfolgten folgenden Analysen: Haufigkeiten, Mittelwerte, ANOVA, AUROC sowie die Inter- und Intraobservervariabilitat. Die ZSI-Werte variierten zwischen 1540–1650cm/s und waren signifikant unterschiedlich zwischen: F0 versus F4 (p=0,05), F1 versus F4 (p=0,004) und F2 versus F4 (p=0,004). Fur die Detektion von Leberzirrhose war die AUROC fur ZSI im Vergleich zu Fibroscan 0,72 (95%CI; 0,63–0,80), im Vergleich zur Histologie 0,80 (95%CI; 0,69–0,89). Bei einer Schallgeschwindigkeit ≥1589cm/s betrugen die Sensitivitat und Spezifitat der ZSI-Messung in Zirrhosedetektion 82% und 76%. ZSI-Messungen waren reproduzierbar (15%) mit einer Interobservervariabilitat von 19%. Erstmalig konnen wir zeigen, dass die Schallgeschwindigkeit in der Leber abhangig vom Fibrosegrad ist. Bei einer Schallgeschwindigkeit ≥1589cm/s liegt sehr wahrscheinlich eine Leberzirrhose vor. Die ZSI-Messung erweist sich als eine viel versprechende neue Methode zur Bestimmung des Leberfibrosegrades.

2. YilmazY,DolarE,UlukayaE,AkgozS,KeskinM,KiyiciM,etal.Solubleforms of extracellular cytokeratin 18 may differentiate simple steatosisfrom nonalcoholic steatohepatitis. World J Gastroenterol 2007;13:837-844.3. Yilmaz Y, Ulukaya E, Gul OO, Arabul M, Gul CB, Atug O, et al. De-creased plasma levels of soluble receptor for advanced glycation endprod-ucts (sRAGE) in patients with nonalcoholic fatty liver disease. ClinBiochem 2009; doi:10.1016/j.clinbiochem.2009.02.003.4. Yoneda M, Uchiyama T, Kato S, Endo H, Fujita K, Yoneda K, et al.Plasma Pentraxin3 is a novel marker for nonalcoholic steatohepatitis(NASH). BMC Gastroenterol 2008;8:53.5. Younossi ZM, Jarrar M, Nugent C, Randhawa M, Afendy M,Stepanova M, et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes Surg 2008;18:1430-1437.

Hereditary haemorrhagic telangiectasia (HHT) is a heterogeneous multisystemic dysplasia of the vascular tissue. This autosomal dominant inherited disorder shows a wide variation in its phenotypic expression. Between 8 and 78% of the HHT patients show arteriovenous malformations of the liver. The molecular basis for hepatic manifestation is still unknown. Two genes are known to play a major role in the development of HHT: activin A receptor type II-like 1 gene (ACVRL1) and ENG. Previously, we and others showed that hepatic involvement is associated with mutations in the ACVRL1 gene, but rarely caused by ENG mutations. Here, we report about the sequencing analysis of a new cohort of 18 adult HHT patients. In these patients, we identified eight novel (four in ACVRL1 and four in ENG) and eight already known mutations. Statistical analysis of our entire data revealed significant differences in the distribution of ACVRL1 and ENG mutations among HHT patients with and without liver involvement (p = 0.0016). The positive predictive value for type 2 HHT (ACVRL1 positive) patients to develop liver disease until the age of 52 years is 68.4%. We conclude that molecular genetic testing of HHT patients is important for prognosis with respect to liver disease.

Background & Aims: Among the potentially helpful indicators of poor prognosis in acute liver failure (ALF) are etiology, encephalopathy grade, blood lactate, and King's College Criteria (KCC). The accuracy of these parameters in predicting transplantation or death shows significant variation in different countries. Methods: We retrospectively analyzed 102 patients with ALF treated at our institution between 1996 and 2005. Baseline parameters, simplified acute physiology score III (SAPS-III), KCC, Model for End-Stage Liver Disease (MELD) score, and a novel score of bilirubin, lactate, and etiology (BiLE score) were compared between transplant-free survivors and patients who required liver transplantation or died, by using multivariate linear regression analysis and receiver operating characteristics (ROC). Results: The most common causes of ALF were indeterminate liver failure (21%), acute hepatitis B (18%), acetaminophen ingestion (16%), and Budd-Chiari syndrome (9%). Transplantation-free survival was 38%, 44% of patients underwent liver transplantation, and 18% died without transplantation. Eight-week survival was 77%. The BiLE score was the best predictor of death or need of transplantation, with 79% sensitivity and 84% specificity. ROC analysis revealed a better performance of BiLE score when compared with bilirubin, lactate, MELD score, and SAPS-III (area under the curve: 0.87 ± 0.04, 0.73 ± 0.51, 0.73 ± 0.52, 0.71 ± 0.05, and 0.68 ± 0.59, respectively). Conclusions: The simple, combined BiLE score emerged as the best predictor of poor outcome in our patient cohort and should be prospectively evaluated in other populations.