Optimization of synchrotron radiation parameters using swarm intelligence and evolutionary algorithms.

Alignment of each optical element at a synchrotron beamline takes days, even weeks, for each experiment costing valuable beam time. Evolutionary algorithms (EAs), efficient heuristic search methods based on Darwinian evolution, can be utilized for multi-objective optimization problems in different application areas. In this study, the flux and spot size of a synchrotron beam are optimized for two different experimental setups including optical elements such as lenses and mirrors. Calculations were carried out with the X-ray Tracer beamline simulator using swarm intelligence (SI) algorithms and for comparison the same setups were optimized with EAs. The EAs and SI algorithms used in this study for two different experimental setups are the Genetic Algorithm (GA), Non-dominated Sorting Genetic Algorithm II (NSGA-II), Particle Swarm Optimization (PSO) and Artificial Bee Colony (ABC). While one of the algorithms optimizes the lens position, the other focuses on optimizing the focal distances of Kirkpatrick-Baez mirrors. First, mono-objective evolutionary algorithms were used and the spot size or flux values checked separately. After comparison of mono-objective algorithms, the multi-objective evolutionary algorithm NSGA-II was run for both objectives - minimum spot size and maximum flux. Every algorithm configuration was run several times for Monte Carlo simulations since these processes generate random solutions and the simulator also produces solutions that are stochastic. The results show that the PSO algorithm gives the best values over all setups.

Thyroid hormone receptor alpha modulates fibrogenesis in hepatic stellate cells.

OBJECTIVE: Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or ß (TRα/ß). Here, we evaluated the influence of TH in hepatic fibrogenesis. DESIGN: Human liver tissue was obtained from explanted livers following transplantation. TRα-deficient (TRα-KO) and wild-type (WT) mice were fed a control or a profibrogenic methionine-choline deficient (MCD) diet. Liver tissue was assessed by qRT-PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFß in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor-specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT-PCR. RESULTS: TRα and TRß expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFß-induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFß signalling, which depended on TRα presence. In vivo, TRα-KO enhanced MCD diet-induced liver fibrogenesis. CONCLUSION: These observations indicate that TH action in non-parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFß signalling pathway. Thus, the TH-TR axis may be a valuable target for future therapy of liver fibrosis.

Liver Stiffness Determined by Transient Elastography Is a Simple and Highly Accurate Predictor for Presence of Liver Cirrhosis in Clinical Routine.

INTRODUCTION: Early detection of patients with advanced chronic liver disease is critical for the prevention of complications and inclusion in surveillance programs for hepatocellular carcinoma. In daily clinical care, it remains challenging to differentiate early cirrhosis from lower fibrosis grades without performing a liver biopsy. The aim of the present study was to assess the performance of different non-invasive detection tools to differentiate cirrhosis from lower fibrosis grades. METHODS: Data of 116 patients (51 male, 65 female) with chronic liver disease of various origins undergoing liver biopsy was analyzed. Routine laboratory values, liver stiffness measurement (LSM) by transient elastography, and histological liver assessment were collected. RESULTS: Robust and significant correlations with the histological fibrosis stage were identified for LSM (r = 0.65), the FAST score (0.64), the FIB-4 (0.48), serum aspartate aminotransferase (AST) concentration (0.41), NFS (0.33), international normalized ratio (INR; 0.30), methacetin breath test results (-0.40), and serum albumin concentration (-0.29) by spearman rank correlation. Receiver operating characteristic curves were built for these parameters to separate patients with cirrhosis from those with any other fibrosis stage. The highest AUC was achieved by LSM (0.9130), followed by the FAST score (0.8842), the FIB-4 (0.8644), the NFS (0.8227), INR (0.8142), serum albumin (0.7710), and serum AST (0.7620). The most promising clinical applicability would be an LSM value of 12.2 kPa, achieving 95.7% sensitivity and 75.3% specificity. CONCLUSION: LSM and FAST score seem to be robust non-invasive measurements for liver fibrosis. LSM and FAST scores may have the potential to reliably detect patients with liver cirrhosis in clinical routine settings.

Time-dependent characteristics of analytical measurands.

OBJECTIVES: Biological variation is a relevant component of diagnostic uncertainty. In addition to within-subject and between-subject variation, preanalytical variation also includes components that contribute to biological variability. Among these, daily recurring, i.e., diurnal physiological variation is of particular importance, as it contains both a random and a non-random component if the exact time of blood collection is not known. METHODS: We introduce four time-dependent characteristics (TDC) of diurnal variations for measurands to assess the relevance and extent of time dependence on the evaluation of laboratory results. RESULTS: TDC address (i) a threshold for considering diurnality, (ii) the expected relative changes per time unit, (iii) the permissible time interval between two blood collections at different daytimes within which the expected time dependence does not exceed a defined analytical uncertainty, and (iv) a rhythm-expanded reference change value. TDC and their importance will be exemplified by the measurands aspartate aminotransferase, creatine kinase, glucose, thyroid stimulating hormone, and total bilirubin. TDCs are calculated for four time slots that reflect known blood collection schedules, i.e., 07:00-09:00, 08:00-12:00, 06:00-18:00, and 00:00-24:00. The amplitude and the temporal location of the acrophase are major determinates impacting the diagnostic uncertainty and thus the medical interpretation, especially within the typical blood collection time from 07:00 to 09:00. CONCLUSIONS: We propose to check measurands for the existence of diurnal variations and, if applicable, to specify their time-dependent characteristics as outlined in our concept.

Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Mechanisms and aetiology-dependent treatment of acute liver failure.

This review compiles the mechanisms of acute liver failure (ALF) as well as the current and potential therapeutic approaches, including aetiology-specific treatment, and the issues encountered with such approaches. On a cellular level, ALF is characterized by massive hepatocyte death due to different types of cellular demise. Compensatory hyperplasia and functional recovery are possible when the regenerative capacity is sufficient to sustain hepatic function. ALF has a high mortality of about 30% and can lead to death in a very short time despite maximum therapeutic intervention. Besides aetiology-specific therapy and intensive care, the therapeutic option of emergency liver transplantation has significantly improved the prognosis of patients with ALF. However, due to limiting factors such as organ shortage, many patients die on the waiting list. In addition to graft assessment, machine perfusion may have the potential to recondition marginal organs and thus expand the organ donor pool.

Limited access to liver transplantation and TIPS despite high mortality, healthcare resource use and costs of cirrhosis in Germany.

BACKGROUND AND AIMS: Data on number of patients with cirrhosis in Germany are limited. We therefore aimed to estimate prevalence, comorbidities, mortality, utilization of healthcare resources and costs of patients with cirrhosis and incidence of decompensation of cirrhosis in Germany. METHODS: This longitudinal observational study was based on an anonymized representative claims database including 4.9 million persons insured by a statutory health insurance (SHI) between 2015-2020. Patients with decompensated and compensated cirrhosis were selected via diagnostic ICD codes and followed for 2 years. RESULTS: Prevalence of cirrhosis in 2015 was 250/100 000, resulting in 201 747 (95% CI: 197 540-206 040) patients extrapolated to the German population. Out of all patients with compensated cirrhosis in 2015 who did not deceased, 16.0% developed a decompensation within 3 years. Overall, 978 patients (Ø-age: 68 years; 60% male) were included in the decompensated, and 5135 patients (Ø-age: 66 years; 59% male) in the compensated cirrhosis cohort. Patients with decompensated cirrhosis had a higher burden of comorbidities (Charlson Comorbidity Index 7.3 vs. 4.4) and 3 times higher costs per quarter (7172 € vs. 2213 €) than patients with compensated cirrhosis. 1-year mortality after decompensation was 51% compared to 8% in compensated cirrhosis. Of note, only few patients with decompensated cirrhosis received a liver transplantation or transjugular intrahepatic portosystemic shunts (TIPS) (1% and 5%). CONCLUSION: Patients with cirrhosis have a high healthcare burden in especially decompensated stage. Accordingly, 1-year mortality of decompensated cirrhosis in Germany is high. Despite high health resource utilization, only few patients have access to liver transplantation or TIPS.

Comparison of Mortality Prediction Scores in Intermediate-Care Patients with Liver Cirrhosis at a German University Transplant Centre: A Prospective Study.

BACKGROUND AND AIMS: Mortality prediction models help to extract and relate patient data upon admission to intensive or intermediate care units (ImCUs). Considering technical and economic healthcare developments, re-evaluations of score performances are required to warrant their validity. This study validates and compares established scoring systems in cirrhotic ImCU patients. METHODS: Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) 2 and 3, Sepsis Organ Failure Assessment (SOFA), Mortality Probability Model at ICU admission (MPMo) II and III, Model for End stage Liver Disease (MELD), CLIF-Consortium Acute-on-Chronic Liver Failure (CLIF-C ACLF), CLIF-Consortium Acute Decompensation (CLIF-C AD), and Intermediate Care Unit Severity Score (ImCUSS) were calculated in patients with cirrhosis (n = 98) at ImCU admission. Discrimination performances were evaluated by area under the receiver operating characteristic curves (AUROCs), calibration performances with calibration belt plots, and their corresponding p values. RESULTS: Overall, SAPS 3 and CLIF-C ACLF have shown the best 90-day mortality prediction outcomes with AUROCs of 0.825 and 0.783 along with calibration belt p values of 0.128 and 0.061, respectively. In a subgroup analysis of patients with acute-on-chronic liver failure (ACLF), expanded SAPS 2, SOFA, and SAPS 3 reached the best AUROCs, i.e., 0.760, 0.750, and 0.714, but none of the tested scores reached an acceptable calibration. CONCLUSION: Ninety-day mortality risk prediction of the SAPS 3 and CLIF-C ACLF was accurate in our cohort of patients with liver cirrhosis admitted to ImCUs. A particular challenge remains that is the mortality prediction in patients with ACLF requiring ImCU-level care; here, further developments are needed to generate scores with acceptable predictive performances.

Performance of the Liver Maximum Function Capacity Test, Fibrinogen, and Transient Elastography in Patients with Acute Liver Injury.

BACKGROUND: Acute liver failure (ALF) occurs as a rare, sudden, extensive loss of liver function in a previously healthy liver. In advanced cases, ALF may require liver transplantation (LT). Available prognostic parameters have limited accuracy to decide, which patient to consider for LT. The liver maximum function capacity test (LiMAx) can accurately determine liver function and was assessed as predictor of survival, along with coagulation parameters and liver stiffness in nonacetaminophen-induced ALF. METHODS: Various liver function tests, including LiMAx measurements, coagulation factors, and transient elastography (TE), were analyzed retrospectively for associations with clinical outcome in 34 patients with ALF or acute hepatitis (AH). Data were compared between patients with spontaneous recovery (SR) and non-SR (3-month mortality/LT; NSR). RESULTS: The analysis included 34 patients (22 ALF, 12 AH; 19 males, 15 females; age 36.7 ± 14.6 years) with drug-induced liver injury (DILI) (n = 12), autoimmune hepatitis (AIH; n = 13), AIH-DILI overlap (n = 1), viral (n = 9), or cryptogenic liver failure (n = 1). Thirty-one patients recovered spontaneously, 2 patients died, and 1 patient underwent LT. The LiMAx was 197.6 (±68.4) for SR versus 92.33 (±65.0) for NSR (p = 0.0157). Fibrinogen was significantly lower in patients with NSR than in SR patients (209.0 vs. 106.3; p = 0.02). Mean liver stiffness measured by TE was 39.3 for NSR and 17.3 for SR (p = 0.26). KCC was fulfilled in only 4 patients (3 SR, 1 NSR). LiMAx results correlated positively with serum fibrinogen and antithrombin III concentrations and correlated negatively with liver stiffness. No other analyzed factor could differentiate between SR and NSR. CONCLUSION: Decision-making in ALF remains challenging. LiMAx and fibrinogen might predict the prognosis in patients with nonacetaminophen-induced ALF and in combination could be feasible tools to decide if LT is necessary.

[Health economic evaluation of an internal medicine intermediate care unit (IMC) with gastroenterological focus at a maximum care university hospital - Evaluating the Profitability of Intermediate Care (IMC) in modern University Hospital Gastroenterology]. / Gesundheitsökonomische Bewertung einer internistischen Intermediate Care (IMC)-Station mit gastroenterologischem Schwerpunkt an einem universitären Klinikum der medizinischen Maximalversorgung ­ Wertung der Rentabilität einer Intermediate Care (IMC)-Station für die moderne universitäre Gastroenterologie.

Intermediate care (IMC) units meet the complex treatment needs of patients with specific diseases and/or those requiring advanced nursing care and can help turning the occupancy management of intensive care unit (ICU) beds more efficient. Despite the exclusion of nursing staff costs from the Diagnosis-Related-Groups (DRG) reimbursement system, prolonged periods of below-average monthly revenues due to loss of complex DRGs and/or misallocation/blocking of IMC beds can lead to a fixed cost refinancing problem; this again brings to the fore the question of the profitability of an IMC unit. Thus, the aim of this work has been to evaluate the profitability of a gastroenterological IMC, as part of an interdisciplinary medical IMC (MIMC) at the University Hospital Essen, for the period 01.01.2014-31.12.2016. Retrospectively, 1015 cases of the MIMC ward of the Department of Gastroenterology and Hepatology (Med.G./MIMC; N=12 beds) were examined with regard to length of stay (LoS), admission/main diagnosis, procedures provided as well as secondary diagnoses, revenues, age, and sex (median patient age 57 years; ♂ 61%, ♀ 39%). Overall, 85% of DRG reimbursements comes from treatment cases within the top 20 base DRGs; these highlight the hepatology focus of Med.G./MIMC. The case-mix (CM) monthly average is 65; the CM index (CMI), which has significant seasonal variation (analogous to CM), monthly average is 10.891 (2014-2016). The average LoS on the Med.G./MIMC is 12.3 days, which is significantly higher than the average LoS in German hospitals (7.2 days). Concrete economic assessment of Med.G./MIMC reveals that the inpatient revenues increase from € 2.90 million to € 3.72 million (2014-2016). Thus, there is a positive development of primary revenues from € 2.98 million (2014) to € 3.56 million (2015) to € 3.81 million (2016), with largely constant expenses in the area of primary costs and of claimed secondary services. Empirically, taking into account the potential interdisciplinary synergy effects, this can be considered as an exceptionally good health economic development/outcome.

The Aging Human Liver: The Weal and Woe of Evolutionary Legacy.

Aging is characterized by the progressive decline of biological integrity and its compensatory mechanisms as well as immunological dysregulation. This goes along with an increasing risk of frailty and disease. Against this background, we here specifically focus on the aging of the human liver. For the first time, we shed light on the intertwining evolutionary underpinnings of the liver's declining regenerative capacity, the phenomenon of inflammaging, and the biotransformation capacity in the process of aging. In addition, we discuss how aging influences the risk for developing nonalcoholic fatty liver disease, hepatocellular carcinoma, and/or autoimmune hepatitis, and we describe chronic diseases as accelerators of biological aging.

Comparison of age- and sex-dependent reference limits derived from distinct sources for metabolic measurands in basic liver diagnostics.

BACKGROUND: Reference intervals for basic liver laboratory diagnostic rely on manufacturers' information, remaining unchanged for more than 20 years. This ignores known age and sex dependencies. METHODS: We performed a retrospective cross-sectional study to compare the age-dependent distribution of flagged and non-flagged laboratory findings between reference limits from 3 distinct sources: manufacturer, published reference study, and the truncated maximum likelihood method applied on a cohort of inpatients aged 18-100 years. Discordance rates adjusted for the permissible analytical uncertainty are reported for serum levels of albumin (n= 150,550), alkaline phosphatase (n= 433,721), gamma-GT (n=580,012), AST (n= 510,620), and ALT (n= 704,546). RESULTS: The number of flagged findings differed notably between reference intervals compared, except for alkaline phosphatase. AST and alkaline phosphatase increased with age in women. Overall discordance for AP, AST, and ALT remained below 10%, respectively, in both sexes. Albumin decreased with age which led to discordant flags in up to 22% in patients ≥70 years. GGT and ALT peaked in 50-59-year-old men with up to 23.5% and 22.8% discordant flags, respectively. CONCLUSION: We assessed the impact of different reference limits on liver related laboratory results and found up to 25 % discordant flags. We suggest to further analyse the diagnostic and economic effects of reference limits adapted to the population of interest even for well-established basic liver diagnostics.

Whipple's Disease - delay of diagnosis by immunosuppressive therapy; a case-series report.

BACKGROUND: Risk factors for the development of Whipple's disease (WD) are largely unknown. Case reports, case series, and reviews suggest immunosuppressive therapy as a potential triggering factor in WD. The low incidence of WD and non-specific symptoms at disease onset contribute to the frequent delay of diagnosis. We describe our centre´s experience on differences in the clinical presentation of patients with classic WD compared to patients with "masked" WD because of immunosuppressive therapy. METHODS: In this retrospective case series, 8 patients were included. Diagnosis of WD was confirmed by histological staining of duodenal biopsies revealing T. whipplei within foamy macrophages or by PCR- based detection of specific T. whipplei DNA. Clinical manifestations, laboratory data, and medication have been recorded over a period of 19 years. Subgroup analyses for the two different variants of WD were performed. RESULTS: Seven of eight patients were initially diagnosed with rheumatic disease (polyarthritis, polymyalgia rheumatica). One patient was correctly diagnosed at the beginning without any medication. Three patients were on immunosuppressive therapy and being treated with disease-modifying drugs (DMARDs), three patients were receiving low-dose cortisone in combination with non-steroidal anti- inflammatory drugs (NSAIDs), and one patient was receiving NSAIDs only. All patients presented with increased parameters of inflammation and with clinical and/or laboratory signs of a malabsorption. From the onset of first symptoms, diagnosis of WD took a median of 36 months (range: 6-120 months). The time between onset of joint complaints and onset of gastrointestinal symptoms was 36 months (range: 0-117 months). WD patients receiving immunosuppressive therapy, compared to those not receiving it, had a longer duration of gastrointestinal symptoms (12 months versus 6 months) and reported a greater weight loss (20,3 kg versus 7,8 kg) up to diagnosis of WD. CONCLUSIONS: Immunosuppressive drugs may delay the diagnosis of WD and prolong the course of T. whipplei infection with deterioration of clinical symptoms. If a patient with rheumatic complaints develops gastrointestinal symptoms, diagnosis of WD should be considered and proper diagnostic investigation carried out.

Patients with NAFLD exhibit more advanced fibrosis in liver biopsy than patients with other chronic liver diseases.

INTRODUCTION: Despite extremely high and seemingly rising prevalence of non-alcoholic fatty liver disease (NAFLD), awareness for this health condition is still low. In the present study we analyzed, if this is reflected in clinical routine for advanced diagnostic measures. METHODS: Retrospective data of 93 patients with histologically determined fibrosis stage and confirmed etiology was analyzed. Patients were grouped according to chronic liver disease alone (n=40), concomitant chronic liver disease and NAFLD (n=29), or NAFLD alone (n=24). Fibrosis stage and presence of cirrhosis were main outcome measures. RESULTS: Patients with NAFLD were significantly older and had significantly higher body mass index and CAP-values than patients with chronic liver disease. Significantly higher fibrosis stages were observed in patients with NAFLD than in those with chronic liver disease alone (p=0.003). Presence of cirrhosis was significantly higher in patients with NAFLD than in patients with chronic liver disease (p=0.01). This was not associated with a significantly different age distribution over fibrosis stages between chronic liver disease and NAFLD. Undergoing liver biopsy 10 years earlier could have possibly prevented progression to cirrhosis in up to 7 patients with NAFLD. This could have potentially saved 35,000 € yearly health care resources. CONCLUSION: These findings suggest that the time course for development of liver fibrosis and cirrhosis is not fundamentally different between patients with NAFLD or with other chronic liver diseases. Higher rates of cirrhosis observed in patients with NAFLD could potentially be ameliorated by earlier diagnostic work-up and improved monitoring.

Validation of the German Inflammatory Bowel Disease Fatigue (IBD-F) Questionnaire.

INTRODUCTION: Fatigue is a common symptom in patients with inflammatory bowel diseases (IBD). To date, there is no instrument to assess IBD-specific fatigue in German. The aim of this study was to translate the IBD Fatigue (IBD-F) scale and to test its psychometric properties in a German IBD population. METHODS: After completing the translation process, 20 IBD patients participated in a pilot testing phase. For further analyses, 180 IBD patients with fatigue answered the IBD-F (Sections I, II, III) and the IBD Questionnaire (IBDQ-D). Reliability was tested by using Cronbach's alpha and corrected item-total correlation. Exploratory factor analyses (EFA) were carried out. Spearman's correlation was calculated between the IBD-F and IBDQ-D . 78 patients could be included to calculate the test-retest reliability. RESULTS: The German version of the IBD-F shows high face and content validity. Internal consistency was excellent, with a Cronbach's alpha of 0.93-0.98. Corrected item-total correlations ranged from 0.51 to 0.89. The correlation between the IBD-F and the IBDQ-D was statistically significant for Section I (rs=-0.59; p<0.01) and Section II (rs=-0.76; p<0.01) of the IBD-F. The EFA identified one relevant factor for each section. Test-retest reliability was acceptable for Section I (intraclass correlation coefficient (ICC)=0.73) and Section II (ICC=0.84). CONCLUSION: The German version of the IBD-F is a reliable and valid tool to assess fatigue in IBD.

[Use of Thrombopoetin-Receptor-Agonists (TPO-RA) in patients with liver cirrhosis before invasive procedures]. / Einsatz von Thrombopoetin-Rezeptor-Agonisten (TPO-RA) vor invasiven Eingriffen bei Patienten mit Leberzirrhose.

Advanced chronic liver disease is accompanied with relevant changes in the corpuscular and plasmatic coagulation system. Due to thrombocytopenia that is regularly observed in these patients, platelet transfusions are often performed prior invasive procedures to prevent possible bleeding complications. However, platelet transfusions are associated with clinically significant adverse events and economically relevant health care costs. Thus, avoiding unnecessary platelet transfusions remains pivotal in daily clinical practice. The first step is to carefully check if increasing platelet counts prior to a planned invasive procedure is really necessary. Nowadays, two well-tolerated thrombopoetin-receptor agonists (TPO-RAs), Avatrombopaq and Lusutrombopaq, to treat thrombocytopenia preemptively before an invasive procedure in patients with liver cirrhosis are available. This review provides a guide for clinician when to increase platelet counts prior an invasive procedure in patients with liver cirrhosis and helps to identify situations in which the use of TPO-RA may be reasonable.

[Intersectoral management of patients with abnormal liver enzymes and non-alcoholic fatty liver disease (NAFLD)]. / Intersektorales Management von Patienten mit unklarer Leberwerterhöhung und nichtalkoholischer Fettlebererkrankung (NAFLD).

The prevalence of fatty liver disease has increased significantly in Germany in recent years. With an estimated 18 million German citizens being affected, it is now among the most prevalent diseases. Furthermore, it is also considered a relevant and independent risk factor for other common cardiovascular diseases such as heart attack or stroke. Finally, diabetes mellitus promotes the development of and an unfavorable course of fatty liver disease. Given the high prevalence and complications, the German healthcare system is reaching its limits.Therefore, close coordination of all healthcare providers and specialists involved in the treatment of these patients is essential. In an expert consensus involving private practice and hospital doctors from the fields of gastroenterology, endocrinology, cardiology, general practitioners and laboratory physicians, as well as in close coordination with patient representatives, we have designed a concept for the care of these patients in the German healthcare system. Necessary developments are also addressed. In addition to being useful as a practical guideline, this should also support health policy work, especially in the development of practical care solutions at the medical level.

Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity. METHODS: We performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes. RESULTS: Prior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed 'futile cycling' of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity. CONCLUSIONS: APAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication. LAY SUMMARY: Only one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.

Creld2 function during unfolded protein response is essential for liver metabolism homeostasis.

The unfolded protein response (UPR) is associated with hepatic metabolic function, yet it is not well understood how endoplasmic reticulum (ER) disturbance might influence metabolic homeostasis. Here, we describe the physiological function of Cysteine-rich with EGF-like domains 2 (Creld2), previously characterized as a downstream target of the ER-stress signal transducer Atf6. To this end, we generated Creld2-deficient mice and induced UPR by injection of tunicamycin. Creld2 augments protein folding and creates an interlink between the UPR axes through its interaction with proteins involved in the cellular stress response. Thereby, Creld2 promotes tolerance to ER stress and recovery from acute stress. Creld2-deficiency leads to a dysregulated UPR and causes the development of hepatic steatosis during ER stress conditions. Moreover, Creld2-dependent enhancement of the UPR assists in the regulation of energy expenditure. Furthermore, we observed a sex dimorphism in human and mouse livers with only male patients showing an accumulation of CRELD2 protein during the progression from non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and only male Creld2-deficient mice developing hepatic steatosis upon aging. These results reveal a Creld2 function at the intersection between UPR and metabolic homeostasis and suggest a mechanism in which chronic ER stress underlies fatty liver disease in males.

Transaminase Concentrations Cannot Separate Non-Alcoholic Fatty Liver and Non-Alcoholic Steatohepatitis in Morbidly Obese Patients Irrespective of Histological Algorithm.

BACKGROUND: In current general practice, elevated serum concentrations of liver enzymes are still regarded as an indicator of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In this study, we analyzed if an adjustment of the upper limit of normal (ULN) for serum liver enzymes can improve their diagnostic accuracy. METHODS: Data from 363 morbidly obese patients (42.5 ± 10.3 years old; mean BMI: 52 ± 8.5 kg/m2), who underwent bariatric surgery, was retrospectively analyzed. NAFL and NASH were defined histologically according to non-alcoholic fatty liver activity score (NAS) and according to steatosis activity fibrosis (SAF) score for 2 separate analyses, respectively. RESULTS: In 121 women (45%) and 45 men (46%), elevated values for at least one serum parameter (ALT, AST, γGT) were present. The serum concentrations of ALT (p < 0.0001), AST (p < 0.0001) and γGT (p = 0.0023) differed significantly between NAFL and NASH, irrespective of the applied histological classification method. Concentrations of all 3 serum parameters correlated significantly positively with the NAS and the SAF score, with correlation coefficients between 0.33 (ALT/NAS) and 0.40 (γGT/SAF). The area under the curves to separate NAFL and NASH by liver enzymes achieved a maximum of 0.70 (ALT applied to NAS-based classification). For 95% specificity, the ULN for ALT would be 47.5 U/L; for 95% sensitivity, the ULN for ALT would be 17.5 U/L, resulting in 62% uncategorized patients. CONCLUSION: ALT, AST, and γGT are unsuitable for non-invasive screening or diagnosis of NAFL or NASH. Utilizing liver enzymes as an indicator for NAFLD or NASH should generally be questioned.