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Background: Non-alcoholic steatohepatitis (NASH) and fibrosis are the main prognostic factors in non-alcoholic fatty liver disease (NAFLD). The FIB-4 score has been suggested as an initial test for the exclusion of progressed fibrosis. However, increasing evidence suggests that also NASH patients with earlier fibrosis stages are at risk of disease progression, emphasizing the need for improved non-invasive risk stratification. Methods: We evaluated whether the apoptosis biomarker M30 can identify patients with fibrotic NASH despite low or intermediate FIB-4 values. Serum M30 levels were assessed by ELISA, and FIB-4 was calculated in an exploration (n = 103) and validation (n = 100) cohort of patients with histologically confirmed NAFLD. Results: The majority of patients with low FIB-4 (cut-off value < 1.3) in the exploration cohort revealed increased M30 levels (>200 U/L) and more than 80% of them had NASH, mostly with fibrosis. NASH was also detected in all patients with intermediate FIB-4 (1.3 to 2.67) and elevated M30, from which ~80% showed fibrosis. Importantly, in the absence of elevated M30, most patients with FIB-4 < 1.3 and NASH showed also no fibrosis. Similar results were obtained in the validation cohort. Conclusions: The combination of FIB-4 with M30 enables a more reliable identification of patients at risk for progressed NAFLD and might, therefore, improve patient stratification.

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.

Als Budd-Chiari-Syndrom (BCS) wird eine Behinderung des lebervenosen Abstroms zwischen den kleinsten Lebervenen und der Grenze von V. cava inferior und rechtem Vorhof bezeichnet. Die Definition gilt unabhangig von der Ursache des Abflusshindernisses. Ausgeschlossen aus dieser Definition sind das sinusoidale Obstruktionssyndrom (synonym venookklusive Erkrankung der Leber) aufseiten der kleinsten Lebervenen sowie kardiale und perikardiale Erkrankungen (Janssen et al. 2003).

Die hereditare hamorrhagische Teleangiektasie(HHT) ist eine autosomal dominant vererbte Erkrankung, die sich durch mukokutane und viszerale Angiodysplasien mit hoher Penetranz (>95 %) manifestiert. Nach den ersten Beschreibern wird sie auch als Morbus Osler-Weber-Rendu bezeichnet. Wichtige Manifestationen der HHT sind die Nasenschleimhaut (Epistaxis), die Haut sowie verschiedene innere Organe (s. u.).

PURPOSE To date, the use of transient elastography has been limited to the liver. Acoustic radiation force impulse imaging (ARFI) is a new technology offering elastography of different tissues. Here, we present initial spleen elastography data and evaluate its influencing factors, especially portal hypertension. MATERIALS AND METHODS Elastography of the spleen and liver using the ARFI method was performed in 30 patients with portal hypertension, 70 patients with chronic liver disease without portal hypertension and 25 healthy controls. RESULTS ARFI elastography of the spleen was feasible in 99% of patients and valid in 78%. The mean propagation velocity inside the spleen was 2.95 ± 0.60 m/sec, thus much higher than in the normal liver (< 1.10 m/sec). Spleen stiffness was higher in the patients with portal hypertension (p < 0.008) but did not correlate to spleen size. Spleen stiffness increased with patient age and liver stiffness (both p < 0.0001) as confirmed by multivariate analysis (R2 = 0.19, p < 0.01). In ROC analysis, spleen elastography was inferior to liver elastography for the detection of portal hypertension (area under the curve 0.68 vs. 0.90). CONCLUSION The new ARFI method allows accurate elastography of the spleen. The stiffness of the normal spleen is much higher than that of the normal liver and increases with age. However, spleen elastography is inferior to liver elastography for the detection of portal hypertension.

Fibrosis and steatosis are major histopathological alterations in chronic liver diseases. Despite various shortcomings, disease severity is generally determined by liver biopsy, emphasizing the need for simple noninvasive methods for assessing disease activity. Because hepatocyte cell death is considered a crucial pathogenic factor, we prospectively evaluated the utility of serum biomarkers of cell death to predict different stages of fibrosis and steatosis in 121 patients with chronic liver disease. We compared the M30 enzyme-linked immunosorbent assay (ELISA), which detects a caspase-cleaved cytokeratin-18 (CK-18) fragment and thereby apoptotic cell death, with the M65 ELISA, which detects both caspase-cleaved and uncleaved CK-18 and thereby overall cell death. Both biomarkers significantly discriminated patients with different fibrosis stages from healthy controls. However, whereas both markers differentiated low or moderate from advanced fibrosis, only the M65 antigen could discriminate even lower stages of fibrosis. The M65 assay also performed better in distinguishing low (≤10%) and higher (>10%) grades of steatosis. In a subgroup of patients, we evaluated the biomarkers for their power to predict nonalcoholic steatohepatitis (NASH). Importantly, both markers accurately differentiated healthy controls or simple steatosis from NASH. However, only serum levels of M65 antigen could differentiate simple steatosis from healthy controls. Conclusion: Cell death biomarkers are potentially useful to predict fibrosis, steatosis, or NASH. Compared with the widely used apoptosis marker M30, the M65 assay had a better diagnostic performance and even differentiated between lower fibrosis stages as well as between healthy individuals and patients with simple steatosis. (HEPATOLOGY 2012)

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.

Background— High-density lipoprotein (HDL)–raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL. Methods and Results— HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy with ER niacin (1500 mg/d) or placebo, and endothelial effects of HDL were characterized. HDL from healthy subjects stimulated endothelial nitric oxide production, reduced endothelial oxidant stress, and improved endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair. In contrast, these beneficial endothelial effects of HDL were not observed in HDL from diabetic patients, which suggests markedly impaired endothelial-protective properties of HDL. ER niacin therapy improved the capacity of HDL to stimulate endothelial nitric oxide, to reduce superoxide production, and to promote endothelial progenitor cell–mediated endothelial repair. Further measurements suggested increased lipid oxidation of HDL in diabetic patients, and a reduction after ER niacin therapy. Conclusions— HDL from patients with type 2 diabetes mellitus and metabolic syndrome has substantially impaired endothelial-protective effects compared with HDL from healthy subjects. ER niacin therapy not only increases HDL plasma levels but markedly improves endothelial-protective functions of HDL in these patients, which is potentially more important. Clinical Trial Registration— clinicaltrials.gov. Identifier: NCT00346970.

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

Summary Objective Patients with liver cirrhosis have a high incidence of insulin resistance and diabetes. This study was designed to determine circulating levels and hepatic production of retinol-binding protein 4 (RBP4) in relation to parameters of hepatic and systemic metabolism in patients with liver cirrhosis. Design and method Circulating RBP4 levels were measured in 19 patients with liver cirrhosis at different clinical stages of the disease and in 20 age-, sex- and body mass index (BMI)-matched controls. Hepatic production rates of RBP4 and glucose were assessed by measuring the arterial hepatic venous concentration difference together with hepatic blood flow. Insulin resistance was determined by the Quantitative Insulin Sensitivity Check Index (QUICKI) and the homeostasis model assessment of insulin resistance (HOMA-IR), energy expenditure by indirect calorimetry and body composition by bioelectrical impedance analysis (BIA). Results Compared with controls, RBP4 levels in cirrhosis were decreased (8·1 ± 1·8 vs. 22·6 ± 2·4 mg/l, 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.

Die Erfolge der Transplantationsmedizin mit gutem Langzeituberleben sind eng mit der medikamentosen Moglichkeit einer iatrogenen Immunsuppression verbunden. Fortschritte der Immunsuppression verbinden grundlagenwissenschaftliche Erkenntnisse der Alloimmunitat mit dem praktischen klinischen Management transplantierter Patienten, ihren Grunderkrankungen und den Nebenwirkungen der Immunsuppressiva. Basis der gangigen Immunsuppression bei der Lebertransplantation ist der Einsatz von Kalzineurininhibitoren und Steroiden. Zur Vermeidung von Steroidnebenwirkungen und vor allem der Nephrotoxizitat hat die Rolle der Antimetaboliten, wie der Mycophenolsaure, und der Kalzineurininhibitorreduktion zugenommen. Die Entwicklungen der 1990er Jahre haben uberdies durch gezielte Antikorper gegen den Interleukin-2-Rezeptor zur Entwicklung von Induktionsprotokollen gefuhrt, die eine verzogerte Gabe von Kalzineurininhibitoren ermoglichen und Nebenwirkungen vermeiden konnen. Vor dem Hintergrund eines Spektrums von Indikationen, das von chronischer Virusinfektion bis hin zu Tumoren reicht, sind die Fortschritte der Immunsuppression durch die sinnvolle Kombination synergistischer Einzelimmunsuppressiva gekennzeichnet. Neue Wirkprinzipien sowie Strategien zur Toleranzinduktion sind in Entwicklung.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. Conclusion: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases. (HEPATOLOGY 2007.)

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.

Background The risk of hepatitis C virus (HCV) infection after occupational exposure is low with seroconversion rates between 0 and 5%. However, factors associated with natural resistance against HCV after needle stick injury are poorly defined. HCV-specific T-cell responses have been described in cross-sectional studies of exposed HCV-seronegative individuals. Materials and methods In this study, we prospectively followed 10 healthcare professionals who experienced an injury with an HCV-contaminated needle. Blood samples were taken on the day or the day after the event and at different time points during follow-up for up to 32 months. HCV-specific T-cell responses were investigated directly ex vivo and in T-cell lines. Results None of the individuals became positive for HCV-RNA in serum tested with the highly sensitive transcription-mediated amplification (TMA)-assay or in peripheral blood mononuclear cells (PBMC). All of them remained anti-HCV negative throughout follow-up. At the time of injury, HCV-specific CD4+ T-cell responses were already detectable in two individuals and became detectable thereafter in three additional persons. Transient HCV-specific CD8+ T-cell responses developed in two HLA-A2 positive patients, which became negative until the most recent follow-up after 5 and 17 months, respectively. Conclusion We demonstrate the development of HCV-specific T cells in HCV-exposed individuals after needle stick injury indicating subinfectious exposure to HCV. T-cell immunity against HCV may contribute to the low prevalence of HCV in medical healthcare professionals in Western countries.

The adipokine resistin has been implicated in obesity and insulin resistance. Liver cirrhosis is associated with decreased body fat mass and insulin resistance. We determined plasma resistin levels in 57 patients with cirrhosis, 13 after liver transplantation, and 30 controls and correlated these with hemodynamic as well as hepatic and systemic metabolic parameters. Patients with cirrhosis had, dependent on the clinical stage, an overall 86% increase in resistin levels ( P < 0.001) with hepatic venous resistin being higher than arterial levels ( P < 0.001). Circulating resistin was significantly correlated with plasma TNF-α levels ( r = 0.62, P < 0.001). No correlation was observed between resistin and hepatic hemodynamics, body fat mass, systemic energy metabolism, and the degree of insulin resistance. However, plasma resistin in cirrhosis was negatively associated with hepatic glucose production ( r = −0.47, P < 0.01) and positively with circulating free fatty acids (FFA; r = 0.40, P < 0.01) and ketone bodies ( r = 0.48, P < 0.001) as well as hepatic ketone body production ( r = 0.40, P < 0.01). After liver transplantation, plasma resistin levels remained unchanged, whereas insulin resistance was significantly improved ( P < 0.01). These data provide novel insights into the role of resistin in the pathophysiological background of a catabolic disease in humans and also indicate that resistin inhibition may not represent a suitable therapeutic strategy for the treatment of insulin resistance and diabetes in patients with liver cirrhosis.

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.

Mittels molekularer Techniken gewonnene Erkenntnisse haben in den letzten Jahren erheblichen Einfluss auf die Behandlung gastrointestinaler und hepatologischer Erkrankungen gewonnen. Die Diagnose bestimmter Erkrankungen wird nicht mehr allein phanotypisch, sondern aufgrund des Genotyps gestellt. Dies betrifft sowohl monogene Erkrankungen als auch die Identifikation von genetischen Risikokonstellationen (z. B. NOD2/CARD15-Mutation bei M. Crohn). Auch fur die Therapieplanung bei viralen Erkrankungen wird eine erweiterte molekulare Diagnostik eingesetzt. Die Versuche, die Lebertransplantation in der Behandlung hereditarer Lebererkrankungen durch gezielte genetische Eingriffe (z. B. mittels viraler Vektoren) zu ersetzen, sind noch in der experimentellen Phase, aber die verwendeten Methoden haben bereits wegweisende Verbesserungen erfahren. Mit der molekularen Identifikation neuer Zielstrukturen war die Entwicklung masgeschneiderter Therapien moglich. Diese finden insbesondere in der Behandlung chronisch entzundlicher Darmerkrankungen und gastrointestinaler Tumorerkrankungen Anwendung.

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 The amino acid (AA) metabolism in cirrhosis is deranged, reflected by an altered plasma AA profile. Alanine is a unique AA with predominant production by muscle and the highest hepatic extraction rate. METHODS We studied circulating levels and hepatic alanine extraction in 52 patients with advanced cirrhosis, 16 stable patients more than 6 months after orthotopic liver transplant (OLT), and 50 controls. In addition, hepatic hemodynamics (portal pressure, hepatic blood flow, and splanchnic percent indocyanine green extraction) and parameters of hepatic metabolism (splanchnic oxygen uptake and splanchnic glucose production) were assessed. RESULTS Circulating alanine levels decreased independently of the clinical stage in cirrhosis (262+/-15 micromol/L vs. 330+/-14 micromol/L in controls, P

Liver cirrhosis is characterized by substantial changes in amino acid (AA) metabolism, resulting in a deranged plasma AA profile. To investigate the effect of liver transplantation (OLT), we studied arterial AA profiles in 52 patients with advanced cirrhosis, 16 stable patients over 6 months after OLT and 48 controls. Changes in AA levels were correlated with portal pressure (hepatic venous pressure gradient), functional hepatic blood flow (indocyanine green extraction) and circulating hormone levels (catecholamines, insulin, C-peptide). Fourteen of 18 measured AA were significantly altered in cirrhosis and 11 of 18 remained abnormal after OLT compared with controls. Aromatic AA (AAA) and methionine were elevated in cirrhosis (p < 0.001 each), increasing with disease stage, and normalized after OLT. Branched chain AA (BCAA) levels were decreased in cirrhosis (p < 0.001) and were unrelated to disease stage. After OLT, BCAA levels remained subnormal (p < 0.01), although higher than in cirrhosis (p < 0.001). AAA levels increased with decreasing functional hepatic blood flow (r = -0.67; p < 0.001) and increasing portal pressure (r = 0.59; p < 0.001). BCAA levels decreased with increasing catecholamine (r = - 0.54, p < 0.001) and insulin levels (r = - 0.40, p = 0.001). We conclude that despite normal liver function, AA metabolism is only partially normalized after OLT. AAA levels mainly determined by hepatic metabolic function and functional liver blood flow return to normal, while BCAA levels remain subnormal, indicating persistent changes in muscular AA metabolism after OLT.