Recent advances in the prevention and treatment of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) and the role of biomarkers.

The progression of cirrhosis with clinically significant portal hypertension towards decompensated cirrhosis remains clinically challenging and the evolution towards acute-on-chronic liver failure (ACLF), with one or more extrahepatic organ failures, is associated with very high mortality. In the last decade, significant progress has been made in the understanding of the mechanisms leading to decompensation and ACLF. As portal hypertension advances, bacterial translocation across an impaired gut barrier culminates in endotoxaemia, systemic inflammation and cirrhosis-associated immune dysfunction (CAID). Gut-derived systemic inflammation and CAID have become the logical targets for innovative therapies that prevent hepatic decompensation episodes and the progression to ACLF.Furthermore, classification of disease and biomarker discovery to personalise care have advanced in the field. This review discusses progress in biomarker discovery and personalisation of treatment in decompensated cirrhosis and ACLF.

Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET).

BACKGROUND AND AIMS: Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models. METHODS: Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling. RESULTS: Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality. CONCLUSIONS: Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.

Relapse and Need for Extended Immunosuppression: Novel Features of Drug-Induced Autoimmune Hepatitis.

BACKGROUND: Drug-induced autoimmune hepatitis (DI-AIH) has been proposed as a distinct phenotype of drug-induced liver injury (DILI), and frequently has been associated with specific drugs, such as minocycline and nitrofurantoin. However, no clear definition of DI-AIH has been established thus far. OBJECTIVES: We aimed to identify features distinguishing DI-AIH from DILI and idiopathic autoimmune hepatitis (AIH) in an attempt to further define a DI-AIH phenotype. METHOD: A cohort of 38 previously reported DILI and AIH patients who were prospectively recruited at our tertiary centre and who received corticosteroid was analysed regarding the phenotypical presentation and outcome of DI-AIH, DILI, and AIH. RESULTS: AIH (n = 19), DILI (n = 8), and DI-AIH (n = 11) patients presented with similar clinical features at onset, with the only difference being a higher Roussel Uclaf Causality Assessment Method (RUCAM) score in the DILI and DI-AIH patients. Post-treatment AIH scores were lower and a more rapid decrease of alanine aminotransferase in the first week of corticosteroid treatment was observed in both DILI groups when compared to AIH patients, while no significant differences were observed between DI-AIH and DILI patients. Relapse occurred in DI-AIH but not in DILI patients (36% vs. 0%) with a more frequent need for long-term immunosuppression (27% vs. 13%). CONCLUSIONS: Our data show that relapse after cessation of corticosteroids and need for further immunosuppressive treatment does occur in a substantial proportion of DI-AIH patients. However, no other phenotypical differences between DILI due to agents commonly associated with DI-AIH and DILI due to other drugs were identified.

A Simple Prognostic Scoring System for Hepatocellular Carcinoma Treated with Selective Internal Radiation Therapy.

INTRODUCTION: Selective internal radiation therapy (SIRT) is a local treatment option for patients with hepatocellular carcinoma (HCC). Its exact role next to other HCC therapies has yet to be defined. In order to identify patients most suitable for SIRT, a SIRT-specific prognostic score should be developed. METHODS: A cohort of 72 SIRT patients treated at the University Hospital of Munich was retrospectively analyzed. The prognostic performance of 12 HCC staging systems and prognostic scores was assessed. Cox-regression analysis was used to identify independent prognostic factors, which formed the basis of the Munich-SIRT score (M-SIRT). All scores were ranked by calculating the c-Index and Akaike information criterion (AIC). External validation was performed in a cohort of 128 SIRT patients treated at the University Hospital of Pamplona, Spain. RESULTS: median overall survival was 13 months (95% confidence interval 9.9-21.9). AFP (p = 0.005; hazard ratio [HR] 2.38), albumin (p < 0.001; HR 5.87), and alkaline phosphatase (p < 0.001; HR 8.38) were identified as independent prognostic factors. M-SIRT comprises 3 prognostic groups with a median survival of 38.9, 14.6, and 7.7 months, respectively (I vs. II: p = 0.003, II vs. III: p < 0.001). AIC (318) and concordance index (0.711) ranked M-SIRT superior to the established HCC staging systems, and the score successfully passed external validation in an independent SIRT cohort (I vs. II: p = 0.03; II vs. III: p = 0.007). CONCLUSION: Therapy-specific prognostic scores can facilitate treatment decisions and prognostication for HCC patients. Considering its performance in 200 SIRT patients, M-SIRT is a promising prognostic tool for HCC patients evaluated for SIRT.

Challenges and Future of Drug-Induced Liver Injury Research-Laboratory Tests.

Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes.

Liver function test abnormalities at hospital admission are associated with severe course of SARS-CoV-2 infection: a prospective cohort study.

OBJECTIVE: Liver injury has frequently been reported in COVID-19 patients. The clinical relevance of liver injury related to SARS-CoV-2 infection remains unclear with a need for prospective studies on the impact of liver function test (LFT) abnormalities at baseline. DESIGN: Data of 217 patients without pre-existing liver disease prospectively included in the COVID-19 registry of the LMU university hospital were analysed in order to assess the association of abnormal LFT at admission and course of the disease. Severe course was defined as admission to the intensive care unit (ICU) or as COVID-19-related death. RESULTS: Abnormal LFT at baseline was present in 58% of patients, with a predominant elevation of aspartate aminotransferase (AST) (42%), gamma-glutamyltransferase (GGT) (37%) and alanine aminotransferase (ALT) (27%), hypoalbuminaemia was observed in 33%. Elevation of ALT and GGT, as well as hypoalbuminaemia, was associated with higher proportions of patients requiring ICU treatment and mechanical ventilation. After adjusting for age, gender and comorbidities, hypoalbuminaemia combined with abnormal AST or GGT at hospital admission was a highly significant independent risk factor for ICU admission (OR 46.22 and 38.8, respectively) and for a composite endpoint of ICU admission and/or COVID-19-related death (OR 42.0 and 26.9, respectively). CONCLUSION: Abnormal LFTs at hospital admission, in particular GGT and albumin, are associated with a severe course of SARS-CoV-2 infection.

Kupffer cell activation by different microbial lysates: Toll-like receptor-2 plays pivotal role on thromboxane A2 production in mice and humans.

Thromboxane (TX) A2 has been identified as an important intrahepatic vasoconstrictor upon Kupffer cell (KC) activation during infections such as spontaneous bacterial peritonitis (SBP). The study aimed to investigate the role of TLRs in the TXA2 increase in liver nonparenchymal cells and their related mechanisms. Here, we identified TLR-2 as a common pathway for different microbials: microbial lysates including Gram-positive bacteria, Gram-negative bacteria, and fungi all increased TXA2 secretion via activation of TLR-2 in human KCs, accompanied by increased expression and phosphorylation of Myd88-related pathway. Of all TLR agonists, only TLR-1, -2, and -4 agonists increased TXA2 in human KCs. These results were further confirmed by mouse liver nonparenchymal cells. Comparing the effects of TLR-1, -2, and -4 antagonists, only TLR-2 antagonist showed inhibitory effects with all tested microbial lysates. Pretreatment with TLR-2 antagonist in human KCs blocked the secretion of IL-10, CXCL-10, TNF-α, and IL-6 induced by Gram-positive and Gram-negative bacterial stimulation. IL-23 and IL-1ß were only induced by Gram-negative bacteria. Thus, TLR-2 might be a potential marker and an attractive target for future treatment of patients with SBP. In addition, IL-23 and IL-1ß might distinguish early between Gram-positive and Gram-negative SBP.

Metabolic implication of tigecycline as an efficacious second-line treatment for sorafenib-resistant hepatocellular carcinoma.

Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy-limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation-inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA-encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second-line therapeutic approach for advanced-stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events.

Antimitochondrial Rather than Antinuclear Antibodies Correlate with Severe Drug-Induced Liver Injury.

INTRODUCTION: A proportion of patients with drug-induced liver injury (DILI) present with autoantibodies, which has led to the current concept of autoimmune-like DILI. However, no standardized definition exists and the clinical relevance has not been studied in detail yet. METHODS: 143 patients with DILI enrolled in a prospective study were analyzed. DILI diagnosis was based on the monocyte-derived hepatocyte-like cell test and supported by Roussel Uclaf Causality Assessment Method (RUCAM) and expert adjudication. Testing for antinuclear antibodies (ANA) and antimitochondrial antibodies (AMA) was performed using immunofluorescence. ANA titers ≥1:100 were considered positive and ≥1:400 clinically relevant; AMA positivity was considered at titers ≥1:100. RESULTS: 67% exhibited ANA ≥1:100 and 29% ANA ≥1:400; 10% were AMA positive. There was no significant correlation between the ANA titers and the causative drug, while AMA positive patients had taken nonsteroidal anti-inflammatory drugs more frequently. No difference was seen regarding clinical characteristics or laboratory parameters in patients with ANA ≥1:400, while patients with positive AMA presented with higher aminotransferases, bilirubin, and international normalized ratio. Significantly higher proportions of patients with ANA ≥1:400 or AMA positivity exhibited elevated immunoglobulin G levels. AMA positivity but not elevated ANA titers correlated with a higher proportion of Hy's law positivity. CONCLUSION: A closer look in a causality proven DILI cohort provided no evidence that presence of ANA titers is specific for DILI by a certain medication. AMA rather than ANA positivity was related to a more pronounced liver injury.

Monocyte-Derived Hepatocyte-Like Cell Test: A Novel Tool for in vitro Identification of Drug-Induced Liver Injury in Patients with Herbal or Dietary Supplements.

BACKGROUND: Drug-induced liver injury caused by herbal and dietary supplements (HDS) has been an increasingly important phenomenon in recent years. Diagnosis is the major challenge. Definite causality assessment, especially in patients with concomitant prescription medicine or other potential causes of liver injury, can be impossible. OBJECTIVES: We investigated the usefulness of an in vitro test on the basis of peripheral monocytes of the individual patients in patients with acute liver injury consuming HDS. METHOD: Patients with acute liver injury who had been prospectively recruited by the University Hospital Munich (LMU, Munich) and the Chinese University of Hong Kong (CUHK) and who took at least 1 HDS were selected for this analysis. Diagnosis of drug-induced liver injury (DILI) was based on local expert adjudication, Roussel Uclaf Causality Assessment Method (RUCAM) score, and course of the disease and was supported by the monocyte-derived hepatocyte-like (MH) cell test. RESULTS: We identified 47 patients with liver injury and intake of at least 1 HDS: 32 (68%) were diagnosed with DILI. HDS was determined as the causative agent in 28 out of those 32 patients. The MH cell test could correctly identify 29 out of those 32 DILI cases and showed false positive results in only 2 out of the 15 non-DILI patients. The MH cell test therefore reached a sensitivity and specificity of 90.6 and 86.7%, respectively, in patients with acute liver injury and HDS intake. CONCLUSIONS: Our data provide evidence that the MH cell test can be a useful tool to identify the role of HDS in causing DILI and therefore support causality assessment in patients consuming HDS.

To Protect Fatty Livers from Ischemia Reperfusion Injury: Role of Ischemic Postconditioning.

BACKGROUND: The benefit of ischemic postconditioning (IPostC) might be the throttled inflow following cold ischemia. The current study investigated advantage and mechanisms of IPostC in healthy and fatty rat livers. METHODS: Male SD rats received a high-fat diet to induce fatty livers. Isolated liver perfusion was performed after 24 h ischemia at 4 °C as well as in vivo experiments after 90 min warm ischemia. The so-called follow-up perfusions served to investigate the hypothesis that medium from IPostC experiments is less harmful. Lactate dehydrogenase (LDH), transaminases, different cytokines, and gene expressions, respectively, were measured. RESULTS: Fatty livers showed histologically mild inflammation and moderate to severe fat storage. IPostC reduced LDH and TXB2 in healthy and fatty livers and increased bile flow. LDH, TNF-α, and IL-6 levels in serum decreased after warm ischemia + IPostC. The gene expressions of Tnf, IL-6, Ccl2, and Ripk3 were downregulated in vivo after IPostC. CONCLUSIONS: IPostC showed protective effects after ischemia in situ and in vivo in healthy and fatty livers. Restricted cyclic inflow was an important mechanism and further suggested involvement of necroptosis. IPostC represents a promising and easy intervention to improve outcomes after transplantation.

Age independent survival benefit for patients with hepatocellular carcinoma (HCC) without metastases at diagnosis: a population-based study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a major cause of death worldwide and its incidence is expected to increase globally. Aim of this study was to assess whether the implementation of screening policies and the improvement of treatment options translated into a real-world survival benefit in HCC patients. DESIGN: 4078 patients diagnosed with HCC between 1998 and 2016 from the Munich Cancer Registry were analysed. Tumour characteristics and outcome were analysed by time period and according to age and presence of metastases at diagnosis. Overall survival (OS) was analysed using Kaplan-Meier method and relative survival (RS) was computed for cancer-specific survival. Cox proportional hazard models were conducted to control for prognostic variables. RESULTS: While incidence of HCC remained substantially stable, tumours were diagnosed at increasingly earlier stages, although the median age at diagnosis increased. The 3 years RS in HCC improved from 19.8% in 1998-2002, 22.4% in 2003-2007, 30.6% in 2008-2012 up to 31.0% in 2013-2016. Median OS increased from 6 months in 1998-2002 to 12 months in 2008-2016. However, analysis according to the metastatic status showed that survival improved only in patients without metastases at diagnosis whereas the prognosis of patients with metastatic disease remained unchanged. CONCLUSION: These real-world data show that, in contrast to the current assumptions, the incidence of HCC did not increase in a representative German region. Earlier diagnosis, likely related to the implementation of screening programmes, translated into an increasing employment of effective therapeutic options and a clear survival benefit in patients without metastases at diagnosis, irrespective of age.

Albumin in decompensated cirrhosis: new concepts and perspectives.

The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.

Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting.

Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.

IL-18 but Not IL-1 Signaling Is Pivotal for the Initiation of Liver Injury in Murine Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life "American lifestyle-induced obesity syndrome" (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r-/-- but not Il-1r-/- mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.

Antifibrotic effects of hypocalcemic vitamin D analogs in murine and human hepatic stellate cells and in the CCl4 mouse model.

Liver cirrhosis is a life-threatening consequence of liver fibrosis. The aim of this study was to investigate the antifibrotic potential of clinically available vitamin D analogs compared to that of calcitriol in vitro and in vivo. Murine hepatic stellate cells, Kupffer cells, and human LX-2 cells were treated with vitamin D analogs, and the profibrotic behavior of these cells was studied. In vivo liver fibrosis was induced using CCl4 until measurable fibrosis was established. Animals were then treated with calcitriol and paricalcitol. Vitamin D and its analogs showed antifibrotic effects in vitro. Treatment with active vitamin D (calcitriol, CAL) and its analogs reduced the protein expression of α-smooth muscle actin (α-SMA) in mHSC. In human LX-2 cells alfacalcidol reduced transforming growth factor-ß (TGF-ß) induced platelet-derived growth factor receptor-ß protein expression and contractility while paricalcitol (PCT), in its equipotent dose to CAL, reduced TGF-ß induced α-SMA protein expression, and ACTA2 and TGF-ß mRNA expression. No effects of a treatment with vitamin D and its analogs were observed in Kupffer cells. In vivo, PCT-treated mice had significantly lower calcium levels than CAL-treated mice. CAL and PCT reduced the hepatic infiltration of CD11b-positive cells and alanine transaminase levels, while PCT but not CAL significantly inhibited fibrosis progression, with a favorable side effect profile in the CCl4 model. We conclude that hypocalcemic vitamin D analogs should be considered in future studies investigating vitamin D for the treatment of liver fibrosis.

Cell death markers in patients with cirrhosis and acute decompensation.

The aims of this study were to determine the role of cell death in patients with cirrhosis and acute decompensation (AD) and acute on chronic liver failure (ACLF) using plasma-based biomarkers. The patients studied were part of the CANONIC (CLIF Acute-on-Chronic Liver Failure in Cirrhosis) study (N = 337; AD, 258; ACLF, 79); additional cohorts included healthy volunteers, stable patients with cirrhosis, and a group of 16 AD patients for histological studies. Caspase-cleaved keratin 18 (cK18) and keratin 18 (K18), which reflect apoptotic and total cell death, respectively, and cK18:K18 ratio (apoptotic index) were measured in plasma by enzyme-linked immunosorbent assay. The concentrations of cK18 and K18 increased and the cK18:K18 ratio decreased with increasing severity of AD and ACLF (P < 0.001, respectively). Alcohol etiology, no previous decompensation, and alcohol abuse were associated with increased cell death markers whereas underlying infection was not. Close correlation was observed between the cell death markers and, markers of systemic inflammation, hepatic failure, alanine aminotransferase, and bilirubin, but not with markers of extrahepatic organ injury. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining confirmed evidence of greater hepatic cell death in patients with ACLF as opposed to AD. Inclusion of cK18 and K18 improved the performance of the CLIF-C AD score in prediction of progression from AD to ACLF (P < 0.05). CONCLUSION: Cell death, likely hepatic, is an important feature of AD and ACLF and its magnitude correlates with clinical severity. Nonapoptotic forms of cell death predominate with increasing severity of AD and ACLF. The data suggests that ACLF is a heterogeneous entity and shows that the importance of cell death in its pathophysiology is dependent on predisposing factors, precipitating illness, response to injury, and type of organ failure. (Hepatology 2018;67:989-1002).

Early ALT response to corticosteroid treatment distinguishes idiosyncratic drug-induced liver injury from autoimmune hepatitis.

BACKGROUND: Drug-induced liver injury (DILI) and idiopathic autoimmune hepatitis (AIH) are competing diagnoses in patients with acute liver injury (ALI) and drug intake. In absence of unequivocal markers, scores like RUCAM and AIH are used to distinguish both entities. However, in some cases the diagnosis remains ambiguous. Our aim was to identify a simple parameter to discriminate DILI and AIH shortly after starting corticosteroid treatment. METHODS: For the current analysis, 44 patients with ALI who took at least one drug and who received corticosteroids were included and comprised 22 DILI and 22 AIH cases. Scores of AIH and RUCAM were calculated at initial presentation, the final diagnosis was made from analysing the course of disease. Changes in the serum alanine aminotransferase (ALT) concentrations after starting corticosteroid treatment were determined and compared between the DILI and AIH groups. RESULTS: Fifty-nine per cent of patients (n = 26) were correctly classified at presentation by AIH score and RUCAM respectively. However, in one-third (n = 13) of the 44 patients, results were inconclusive and five other patients were misclassified. The decrease in ALT levels 1 week after the initiation of steroid therapy was significantly more pronounced in patients with the final diagnosis of DILI than in AIH patients (accuracy 77%). This difference was also observed in the 18 initially misclassified or inconclusive cases (accuracy 83%). CONCLUSION: Short-term response of ALT to corticosteroid therapy helps to differentiate DILI and AIH. This finding may be helpful in treatment decision for patients with inconclusive diagnostic scores.

The Munich-Transarterial Chemoembolisation Score Holds Superior Prognostic Capacities Compared to TACE-Tailored Modifications of 9 Established Staging Systems for Hepatocellular Carcinoma.

BACKGROUND/AIMS: The recently proposed Munich-transarterial chemoembolisation-score (M-TACE) was tailored to suit hepatocellular Carcinoma (HCC) patients evaluated for TACE. M-TACE outperformed the established HCC-staging-systems and successfully passed external validation. Modifications of staging-systems through the rearrangement of stages or by adding prognostic factors are methods of improving prognostic power. M-TACEs performance compared to scores modified this way should be tested. METHODS: Seven well-known HCC staging-systems (including Cancer of the Liver Italian Program-score [CLIP] and Barcelona Clinic liver cancer [BCLC]) and 2 TACE-specific scores (Selection for Transarterial Chemoembolisation Treatment [STATE] and Hepatoma Arterial embolisation Prognostic [HAP]) were rearranged in a cohort of 186 TACE-patients through score-point-analysis and subsequent linking of non-significant adjacent score-points. Additionally, a new score was constructed by combining the top established staging-system in TACE patients (CLIP-TACE) and the prognostic parameter with the highest hazard ratio for death in the TACE-cohort [C-reactive protein (CRP)]. Additionally, the TACE-tailored-scores were applied to an external TACE-cohort (n = 71). -Results: Rearrangement resulted in optimal stratification and monotonicity. CLIP-TACE demonstrated the best prognostic capability of all rearranged scores (c-index 0.668, AIC 1294) and the addition of CRP yielded further prognostic improvement (c-index 0.680, AIC 1289). However, superiority over M-TACE could not be achieved by any of the new scores in the internal and external cohort. CONCLUSION: M-TACE outperforms TACE-tailored modifications of all relevant HCC-staging-systems. Prospective validation of M-TACE to promote its role as the preferred staging-system for TACE-patients is therefore justified.

[Updated S2k-Guideline "Complications of liver cirrhosis". German Society of Gastroenterology (DGVS)]. / Aktualisierte S2k-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) "Komplikationen der Leberzirrhose".

This guideline provides evidence-based key recommendations for diagnosis and therapy of complications of liver cirrhosis and upgrades the 2011 version. An interdisciplinary team of medical experts and patient support groups developed the guideline following the AWMF recommendations for evidence based consensus guidelines. New chapters concerning diagnosis and therapy of hepatic encephalopathy were added.