Gender and gut microbiota composition determine hepatic bile acid, metabolic and inflammatory response to a single fast-food meal in healthy adults.

BACKGROUND & AIMS: Regular consumption of fast-food (FF) as a form of typical Western style diet is associated with obesity and the metabolic syndrome, including its hepatic manifestation nonalcoholic fatty liver disease. Currently, it remains unclear how intermittent excess FF consumption may influence liver metabolism. The study aimed to characterize the effects of a single FF binge on hepatic steatosis, inflammation, bile acid (BA), glucose and lipid metabolism. METHODS: Twenty-five healthy individuals received a FF meal and were asked to continue eating either for a two-hour period or until fully saturated. Serum levels of transaminases, fasting BA, lipid profile, glucose and cytokine levels as well as transient elastography and controlled attenuation parameter (CAP; to assess hepatic steatosis) were analyzed before (day 0) and the day after FF binge (day 1). Feces was collected prior and after the FF challenge for microbiota analysis. RESULTS: The FF meal induced a modest increase in CAP, which was accompanied by a robust increase of fasting serum BA levels. Surprisingly, levels of cholesterol and bilirubin were significantly lower after the FF meal. Differentiating individuals with a relevant delta BA (>1 µmol/l) increase vs. individuals without (delta BA ≤1 µmol/l), identified several gut microbiota, as well as gender to be associated with the BA increase and the observed alterations in liver function, metabolism and inflammation. CONCLUSION: A single binge FF meal leads to a robust increase in serum BA levels and alterations in parameters of liver injury and metabolism, indicating a novel metabolic aspect of the gut-liver axis.

[Drug-induced liver injury-significance of pathology]. / Drug-Induced Liver Injury ­ Stellenwert der Pathologie.

Many different medical agents, herbal products, and dietary supplements can induce drug-induced liver injury (DILI) as a clinically relevant complication. DILI, which is direct toxic or idiosyncratic, can have a broad spectrum of clinical appearances from elevation of liver enzymes to acute liver failure. DILI is categorized clinically according to the pattern of serum parameters or pathologically according to the pattern of histomorphology. Histopathological patterns can be described as hepatitic, granulomatous, cholestatic, ductopenic, fibrotic, steatotic, steatohepatitic, and vascular. Correlation to the corresponding drug can be carried out with the corresponding databases (US National Library of Medicine, Liver Tox; www.ncbi.nlm.nih.gov/books/NBK547852/ ). Liver biopsy, in contrast to a clinical/serological diagnostic, has the advantage of an exact resolution with evidence of pathophysiology, activity, regeneration, chronification, and prognosis. Co-occurrence of underlying liver disease can be excluded or confirmed. Histological patterns of DILI are described and illustrated. A diagnostic algorithm for the interpretation of liver biopsies is provided.

Metaproteomics of fecal samples of Crohn's disease and Ulcerative Colitis.

Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic inflammatory bowel diseases (IBD) of the gastrointestinal tract. This study used non-invasive LC-MS/MS to find disease specific microbial and human proteins which might be used later for an easier diagnosis. Therefore, 17 healthy controls, 11 CD patients and 14 UC patients but also 13 Irritable Bowel Disease (IBS) patients, 8 Colon Adenoma (CA) patients, and 8 Gastric Carcinoma (GCA) patients were investigated. The proteins were extracted from the fecal samples with liquid phenol in a ball mill. Subsequently, the proteins were digested tryptically to peptides and analyzed by an Orbitrap LC-MS/MS. For protein identification and interpretation of taxonomic and functional results, the MetaProteomeAnalyzer software was used. Cluster analysis and non-parametric test (analysis of similarities) separated healthy controls from patients with CD and UC as well as from patients with GCA. Among others, CD and UC correlated with an increase of neutrophil extracellular traps and immune globulins G (IgG). In addition, a decrease of human IgA and the transcriptional regulatory protein RprY from Bacillus fragilis was found for CD and UC. A specific marker in feces for CD was an increased amount of the human enzyme sucrose-isomaltase. SIGNIFICANCE: Crohn's Disease and Ulcerative Colitis are chronic inflammatory diseases of the gastrointestinal tract, whose diagnosis required comprehensive medical examinations including colonoscopy. The impact of the microbial communities in the gut on the pathogenesis of these diseases is poorly understood. Therefore, this study investigated the impact of gut microbiome on these diseases by a metaproteome approach, revealing several disease specific marker proteins. Overall, this indicated that fecal metaproteomics has the potential to be useful as non-invasive tool for a better and easier diagnosis of both diseases.

Patients with ultrasound diagnosis of hepatic steatosis are at high metabolic risk.

Background and aims: Hepatic steatosis is the basis of non-alcoholic fatty liver disease (NALFD). Mere fat accumulation within hepatocytes is considered the mild form of NAFLD, but can progress in some patients to advanced steatohepatitis (NASH), which may lead to fibrosis, cirrhosis or hepatocellular carcinoma. However, even hepatic steatosis alone may be a risk factor for cardiovascular disease (CVD). Patients and methods: In the present real life study 106 patients from the outpatient clinic of the Department for Gastroenterology and Hepatology with either NAFLD (n = 60) or other typical diagnoses (n = 46) were included. Ultrasound examination identified 77 patients with hepatic steatosis. Liver enzymes, lipid profile, surrogate cell death markers, and adiponectin were determined. Transient elastography (Fibroscan®) and bioelectrical impedance analysis (BIA) were performed. Results: Mean patient age was 46 years (23 - 62) for non-NAFLD and 53 years (18 - 71) for the NAFLD group. ALT and AST did not differ significantly between the two groups. Adiponectin and HDL were significantly lower in NAFLD (p < 0.05) and BIA profiles showed higher fat and fat free mass. Non-NAFLD patients with steatosis also exhibited an adverse metabolic profile. Overall steatosis was associated with factors of metabolic syndrome (MS) and CVD. Prevalence of CVD and factors of MS hint to steatosis as an early event for these conditions. Conclusion: Patients with steatosis are at higher cardiovascular and metabolic risk without differences in transaminases levels compared to those without steatosis. Steatosis diagnosed by ultrasound needs to rise attention for further metabolic alterations including CVD.

Treatment of fulminant acute Hepatitis B with nucles(t)id analogues is safe and does not lead to secondary chronification of Hepatitis B.

Background: Acute hepatitis B virus (HBV) infection is still a major cause of acute liver failure (ALF), necessitating a high rate of emergency liver transplantation (LTx). Acute infection is followed by high viral replication rates leading to hepatocyte death and, ultimately, ALF. The objective of treating HBV-induced ALF thus is to eliminate, or significantly suppress, HBV replication and therefore reduce cell death and support regeneration. Objective: In this retrospective study, we want to evaluate the timing, the safety, and the long-term virological outcome of this approach. Methods/results: In this study, we included 32 patients (16 female and 16 males; median age 39.5 years) with ALF due to hepatitis B, who were transferred to the university hospital Essen, Germany between January 2009 and December 2013. Before treatment, transaminases were highly elevated, bilirubin was increased, and elevated international normalized ratio (INR) revealed impaired liver function. HBV-DNA and HBsAg were positive. All 32 patients received oral antiviral treatment (3 lamivudine, 21 entecavir, and 8 tenofovir) between 1 day and 4 months after diagnosis of acute hepatitis B. One patient died, 2 were transplanted, one died shortly after LTx the other patient survived after LTx. These 3 patients received treatment in a state of advanced liver failure, and 1 patient 4 months after initial diagnosis of hepatitis B. Twenty-nine patients survived without LTx. Five patients were discharged without further follow-up. All 24 remaining patients became HBV-DNA negative in median of 100 days. Twenty-two patients were followed further, and all patients lost their HBsAg in median of 108 days. Sixteen of the 22 patients experienced a seroconversion to anti-HBs in median of 137 days. Four patients who were followed for 1 more year after HBsAg did not develop anti-HBs. None of the patients developed chronic hepatitis B. Conclusion: Immediate treatment of HBV-induced ALF with nucleos(t)id-analogues (NUCs) appears save and prevents LTx and death, and there is no indication for increased chronicity.

Multimodal therapy of recurrent and refractory bleeding from esophageal varices - case report and review of the literature.

Bleeding from esophageal varices is a major cause of mortality in patients with advanced liver disease. Although standard treatment and secondary prophylaxis are effective, in some patients sustained hemostasis cannot be achieved. We report the case of a woman with alcoholic liver disease in whom pharmacological, endoscopic, and intravascular therapies failed to control variceal bleeding. Only a combination of (repeated) band ligation, insertion of a self-expanding metal stent, TIPS implantation and redilatation, transjugular variceal embolization, and finally implantation of a portocaval shunt proved to be successful. We discuss the stepwise approach to this situation and the challenges encountered in the process.

[Hepatic steatosis : Differential diagnostics and current aspects]. / Hepatische Steatosen : Differenzialdiagnostik und aktuelle Aspekte.

The frequency of non-alcoholic fatty liver disease (NAFLD) has continously increased over the last few decades in parallel with the increasing prevalence of metabolic syndrome. With the increasing frequency of obesity and type 2 diabetes an increase in non-alcoholic steatohepatitis (NASH) is also to be expected. The NASH-associated liver cirrhosis and primary hepatocellular carcinoma (HCC) are indications for liver transplantation (LTX), which is gaining importance in Germany. In contrast, liver cirrhosis as a result of alcoholic steatohepatitis (ASH) is already the leading cause for LTX in Germany. A significant number of patients with ASH cirrhosis develop HCC. Less common causes of hepatic steatosis are secondary and include chemotherapy-associated steatohepatitis (CASH). In this article the causes, diagnostics and novel therapeutic approaches for the various forms of steatosis are discussed.

[Coagulation management in patients with liver disease]. / Gerinnungsdiagnostik und -therapie bei Leberinsuffizienz.

BACKGROUND: End-stage liver disease is associated with complex alterations in hemostasis. Whereas prognosis is essentially affected by life-threatening bleeding complications in some patients, others, especially those with cholestatic liver diseases, suffer from thromboembolic complications. Standard laboratory values (SLVS; prothrombin time, activated partial thrombin time, platelet count) cannot sufficiently reflect the altered balance of pro- and anticoagulatory factors. Moreover, a couple of studies indicated that SLVS are not able to predict bleeding complications in patients with acute liver failure or decompensated liver cirrhosis. DIAGNOSIS AND THERAPY: Use of bed-side coagulation diagnostics such as thrombelastometry/-graphy, detection of thrombocyte function by multiple electrode aggregometry and selective measurement of single factors allows a targeted and causal therapy of hepatic coagulopathies especially in the context of bleeding complications or surgical interventions. In recent years, coagulation management guided by these new devices has contributed to a reduction in transfusion of allogenic blood products, which may be associated with undesirable side effects. DISCUSSION: The current review summarizes the complex pathophysiological alterations of hemostasis associated with advanced liver insufficiency and discusses recent upcoming diagnostics and coagulation management in this patient cohort.

The diagnosis and treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of metabolic syndrome and frequently accompanied with obesity, insulin resistance, hyperlipidemia and hypertension. NAFLD comprises a variety of clinical conditions ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH), with significant hepatic injury and possible progression to cirrhosis and hepatocellular carcinoma. The traditional "second hit" and the recent "multiple parallel hit" theories are the most popular explanations for the pathogenesis of NASH. NAFLD is usually diagnosed by ultrasonographic examination of the liver. For specific diagnosis of the extent and severity of NAFLD, in particular to determine NASH, the gold standard is still liver biopsy. Though, there are some promising non-invasive markers emerging for NAFLD diagnosis and assessment. Currently there is no specific therapy for NAFLD or NASH itself. Thus management of NAFLD mainly relies on initiating weight loss and on treatment of accompanying factors e.g. insulin resistance, hypertension or hyperlipidemia. In the present overview we aimed to summarize options for diagnosis and treatment of NAFLD and NASH based on the current literature.

[Liver dysfunctions in intensive care patients--consequences for the treatment of invasive Candida infections]. / Leberfunktionsstörungen in der Intensivmedizin - Konsequenzen für die Therapie invasiver Candidainfektionen.

Liver dysfunction is common among patients on intensive care units (ICU) due to sepsis, chronic liver disease, ischemic hepatitis, drug toxicity and intensive care measures. Critically ill patients with invasive fungal infections should therefore be treated with antifungals that are not metabolized by the liver. This may help to avoid therapeutic complications by drug accumulation, inadequate dosages or drug-drug interactions. Echinocandins are established as the antifungal class of choice in the treatment of invasive Candida infections. Anidulafungin is not hepatically metabolized and may be used without dose adjustments in patients with severe liver dysfunction. It has no known clinically relevant drug interactions. In the primary endpoint of the randomized pivotal trial in patients with candidemia or invasive candidiasis, anidulafungin was statistically superior versus the former standard therapy (fluconazole), with a favourable overall safety profile. More recent study data particularly in ICU patients confirm the efficacy of anidulafungin for these patient groups. Therefore, anidulafungin is an important antifungal treatment option for patients with liver dysfunction.

Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice.

BACKGROUND: Chronic liver injury triggers a progenitor cell repair response, and liver fibrosis occurs when repair becomes deregulated. Previously, we reported that reactivation of the hedgehog pathway promotes fibrogenic liver repair. Osteopontin (OPN) is a hedgehog-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesised that OPN may modulate liver progenitor cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralisation on murine liver fibrosis. METHODS: Liver progenitors (603B and bipotential mouse oval liver) were treated with OPN-neutralising aptamers in the presence or absence of transforming growth factor (TGF)-ß, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralisation (using OPN-aptamers or OPN-neutralising antibodies) on liver progenitor cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3,5,-diethoxycarbonyl-1,4-dihydrocollidine diet) by quantitative real time (qRT) PCR, Sirius-Red staining, hydroxyproline assay, and semiquantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease. RESULTS: OPN is overexpressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound healing by modulating TGF-ß signalling. In vivo, OPN-neutralisation attenuates the liver progenitor cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis. CONCLUSIONS: OPN upregulation during liver injury is a conserved repair response, and influences liver progenitor cell function. OPN-neutralisation abrogates the liver progenitor cell response and fibrogenesis in mouse models of liver fibrosis.

[Comparison of extracorporeal liver assist devices - albumin dialysis versus plasma exchange - in acute-on-chronic liver failure]. / Vergleich extrakorporaler Leberunterstützungsverfahren - Albumin-Dialyse versus Plasmaaustausch - bei akut-auf-chronischem Leberversagen.

BACKGROUND AND AIM: Extracorporeal liver assist devices are besides causal and symptomatic approaches important therapeutic options in acute-on-chronic (AOC) liver failure. In this retrospective analysis, albumin dialysis was compared to therapeutic plasma exchange (TPA) under various aspects. PATIENTS AND METHODS: Data from 20 patients per group (10 women, 10 men in each group, mean age 51 ±â€…12,6 years and 48,2 ±â€…15,2 years, respectively) treated over a period of 3 months were analyzed. During the first treatment, 5 sessions of dialysis were performed (week 1) for both procedures, 3 more sessions were completed in the second and in the third week each. Data were acquired on days 1, 8, 13, 20, 28 and 90. RESULTS: After 28 days, 13 out of 20 patients following albumin dialysis and 7 out of 20 patients following plasma exchange had survived (p = 0,11). After 90 days, 10 patients following albumin dialysis and 5 patients following plasma exchange were alive (p = 0,19). Degree of hepatic encephalopathy (HE) had not improved significantly. Rates of complication (infections, bleeding or system clotting) were similar under both procedures. CONCLUSION: Extracorporeal liver assist devices can be considered equally well as a therapeutic option in acute-on-chronic liver failure. Differences in 90-day survival were not observed in our study.

Tacrolimus as a reasonable alternative in a patient with steroid-dependent and thiopurine-refractory autoimmune pancreatitis with IgG4-associated cholangitis.

BACKGROUND: More recently, autoimmune pancreatitis (AIP) in association with IgG4-positive cholangitis (IAC) has been recognised as a new and challenging entity. Currently, initiation of high dose steroids (e.g., prednisolone 0.5 - 1 mg/kg/day) followed by a steroid dose taper in combination with purine antagonists (e.g., azathioprine or 6-mercaptopurine) after resolution has been recommended as standard therapy. CASE REPORT: A 68-year-old male patient was referred to our institution in February 2012 for therapy evaluation of a steroid-dependent course of autoimmune pancreatitis type 1 with IgG4-associated cholangitis. Since the first diagnosis in March 2011, the patient was treated with high-dose steroids with good response. Whenever steroids were tapered down to a daily dose <20 mg, cholestatic liver enzymes increased dramatically despite concurrent immunosuppressive therapy primarily with azathioprine and 6-MP thereafter. Therefore, we restarted steroid therapy (1 mg/kg/day) in combination with tacrolimus achieving a target level of 5 - 7 ng/mL. During the down-tapering phase, follow-up examinations presented a patient in good general condition without jaundice. Moreover, liver and pancreatic enzymes and also immunoglobulins returned to normal values without any evidence of relapse up today (66 weeks). CONCLUSION: In this case, the combination of steroids with tacrolimus seems to be a reasonable alternative in a patient with steroid-dependent and thiopurine-refractory autoimmune pancreatitis with IgG4-associated cholangitis. To date, this is the first description of such a therapeutic approach for this entity.

[Drug-induced liver injury as predominant cause of acute liver failure in a monocenter study]. / Medikamentös-toxische Schädigung als wichtigste Ätiologie des akuten Leberversagens.

BACKGROUND AND AIM: Clinical course and mortality of acute liver failure (ALF) are determined by its causes. Traditionally, fulminant hepatitis B infection (HBV) was thought to be the predominant etiology of ALF in Germany. However, recent studies, conducted in American and European cohorts pointed to drug-induced liver injury (DILI) as the major cause. Aim of this study was to identify currently predominant etiologies of ALF in a monocenter study at a leading transplant center in Germany. PATIENTS AND METHODS: The data of 161 patients admitted with ALF from 1/2002 to 12/2012 were analyzed retrospectively. All patients fulfilled the criteria of the "Acute Liver Failure Study Group Germany" (international normalized ratio (INR) ≥ 1.5, hepatic encephalopathy ≥ stage 1). RESULTS: DILI was the leading cause of ALF in this cohort. About 20 % of ALF patients with DILI died or received liver transplantats. Mortality rate was highest in ALF patients with unknown etiology and those without specific therapy available. CONCLUSIONS: In Europe ALF etiologies exhibit a North-South divide. In Germany the most common cause for ALF is idiosyncratic pharmacological intoxication followed by acute hepatitis B.

[Cytokeratin 18 as marker for non-invasive diagnosis and prognosis of acute and chronic liver diseases]. / Zytokeratin-18 als Marker zur nichtinvasiven Diagnostik und Prognose akuter und chronischer Lebererkrankungen.

INTRODUCTION: Currently liver biopsy represents the gold standard to assess severity and fibrosis grade in liver diseases. Since this laborious, costly, and invasive procedure is associated with possible complications, non-invasive methods and biomarkers, which allow for an easy, reliable, and repeatable assessment of liver disease are warranted. Cytokeratin (CK) 18 is an intermediary filament protein, expressed in hepatocytes, which is proteolytically cleaved during liver damage. The resultant CK-18 fragments are released by hepatocytes and can be detected in serum. METHODS: A selective literature search in PubMed for original publications about the detection of CK-18 cell death markers in liver diseases was undertaken. RESULTS: Assessment of CK-18 cell death biomarkers allows for the early detection of liver damage in acute and chronic liver diseases. This is even feasible when transaminases are in the normal ranges. Detection of CK-18 biomarkers can also hint at disease activity and severity. For example, patients with non-alcoholic steatohepatitis exhibit elevated serum cell-death markers compared to those with simple steatosis. Furthermore, in patients with relevant fibrosis higher CK-18 values are found as compared to those with low fibrosis. In acute liver failure, cell death biomarkers may assist decision finding for the necessity of liver transplantation. DISCUSSION: Due to promising results of various studies, CK-18 cell death markers could be applied in clinical routine soon.

Adiponectin attenuates osteolysis in aseptic loosening of total hip replacements.

Joint replacements have a longer durability in patients with high serum levels of adiponectin (APN) than in patients with low levels. We aimed to characterize the unknown pathophysiological effects of APN on wear particle-induced inflammation, apoptosis and osteolysis. Immunohistochemistry was performed to detect APN, its receptors and apoptosis in patients with and without aseptic loosening. Additionally, APN knockout mouse studies and pharmacological intervention of APN were performed in an established calvarial mouse model. Osteolysis and inflammation were quantified by histomorphometry and microcomputed tomography, apoptosis by immunohistochemistry and TUNEL assay. In a cell culture model, human monocyte-derived macrophages were incubated with or without metal wear debris particles and partially treated with APN. Expression of APN, AdipoR1 and calreticulin in specimens from patients with aseptic loosening were significantly higher than in patients without aseptic loosening. Administration of APN in mice significantly reduced wear particle-induced inflammation, osteolysis and the number of caspase-3-positive macrophages. The cell culture model showed that APN leads to significantly lower values of TNF-α. These findings support a prominent role of APN in the development of particle-induced osteolysis and APN may be therapeutically useful in patients with aseptic loosening.