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.

[When should a liver disease patient be admitted to the intensive care unit?] / Wann soll ein Leberkranker auf die Intensivstation?

Liver diseases are a significant global cause of morbidity and mortality. Liver cirrhosis can result in severe complications such as bleeding, hepatic encephalopathy (HE), and infections. Implementing a clear strategy for intensive care unit (ICU) admission management improves patient outcomes. Hemodynamically significant esophageal/gastric variceal bleeding (E/GVB) and grade 4 HE, when accompanied by the need for renal replacement therapy (RRT), are definitive indications for ICU admission. E/GVB, spontaneous bacterial peritonitis (SBP), and infections with multidrug-resistant organisms (MDRO) require close and stringent critical assessment. Patients with severe hepatorenal syndrome (HRS) or respiratory failure have increased baseline mortality and most likely benefit from early ICU treatment. Rapid identification of sepsis in patients with liver cirrhosis is a crucial criterion for ICU admission. Prioritizing cases based on mortality risk and clinical urgency enables efficient resource utilization and optimizes patient management. In addition, "Liver Units" provide an intermediate care (IMC) level for patients with liver diseases who require close monitoring but do not need immediate intensive care.

Liver Diseases: Science, Fiction and the Foreseeable Future.

This Editorial precedes the Special Issue entitled "Novel Challenges and Therapeutic Options for Liver Diseases". Following a historical outline of the roots of hepatology, we provide a brief insight into our colleagues' contributions in this issue on the current developments in this discipline related to the prevention of liver diseases, the metabolic dysfunction-associated steatotic liver disease (or non-alcoholic fatty liver disease, respectively), liver cirrhosis, chronic viral hepatitides, acute-on-chronic liver failure, liver transplantation, the liver-microbiome axis and microbiome transplantation, and telemedicine. We further add some topics not covered by the contributions herein that will likely impact future hepatology. Clinically, these comprise the predictive potential of organokine crosstalk and treatment options for liver fibrosis. With regard to promising developments in basic research, some current findings on the genetic basis of metabolism-associated chronic liver diseases, chronobiology, metabolic zonation of the liver, aspects of the aging liver against the background of demography, and liver regeneration will be presented. We expect machine learning to thrive as an overarching topic throughout hepatology. The largest study to date on the early detection of liver damage-which has been kicked off on 1 March 2024-is highlighted, too.

MASLD-Related HCC-Update on Pathogenesis and Current Treatment Options.

Hepatocellular carcinoma (HCC) is a common complication of chronic liver diseases and remains a relevant cause of cancer-related mortality worldwide. The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocarcinogenesis is on the rise. Early detection of HCC has been crucial in improving the survival outcomes of patients with metabolic dysfunction-associated steatohepatitis (MASH), even in the absence of cirrhosis. Understanding how hepatocarcinogenesis develops in MASH is increasingly becoming a current research focus. Additive risk factors such as type 2 diabetes mellitus (T2DM), genetic polymorphisms, and intestinal microbiota may have specific impacts. Pathophysiological and epidemiological associations between MASH and HCC will be discussed in this review. We will additionally review the available tumor therapies concerning their efficacy in MASH-associated HCC treatment.

l-Ornithine-l-Aspartate (LOLA) Normalizes Metabolic Parameters in Models of Steatosis, Insulin Resistance and Metabolic Syndrome.

l-Ornithine- l-aspartate (LOLA) reduces toxic ammonium (NH3) plasma levels in hepatic encephalopathy. NH3 detoxification/excretion is achieved by its incorporation into urea and glutamine via activation of carbamoyl phosphate synthetase 1 (CSP1) by l-ornithine and stimulation of arginase by l-aspartate. We aimed at identifying additional molecular targets of LOLA as a potential treatment option for non-alcoholic fatty liver disease (NAFLD). In primary hepatocytes from NAFLD patients, urea cycle enzymes CSP1 and ornithine transcarbamylase (OTC) increase, while the catabolism of branched-chain amino acids (BCAAs) decreases with disease severity. In contrast, LOLA increased the expression rates of the BCAA enzyme transcripts bcat2, bckdha, and bckdk. In untreated HepG2 hepatoblastoma cells and HepG2-based models of steatosis, insulin resistance, and metabolic syndrome (the latter for the first time established herein), LOLA reduced the release of NH3; beneficially modulated the expression of genes related to fatty acid import/transport (cd36, cpt1), synthesis (fasn, scd1, ACC1), and regulation (srbf1); reduced cellular ATP and acetyl-CoA; and favorably modulated the expression of master regulators/genes of energy balance/mitochondrial biogenesis (AMPK-α, pgc1α). Moreover, LOLA reconstituted the depolarized mitochondrial membrane potential, while retaining mitochondrial integrity and avoiding induction of superoxide production. Most effects were concentration-dependent at ≤40 mM LOLA. We demonstrate for l-ornithine-l-aspartate a broad range of reconstituting effects on metabolic carriers and targets of catabolism/energy metabolism impaired in NAFLD. These findings strongly advocate further investigations to establish LOLA as a safe, efficacious, and cost-effective basic medication for preventing and/or alleviating NAFLD.

COVID-19-associated secondary sclerosing cholangitis with liver transplantation.

We report on two cases of orthotopic liver transplantation (OLTX) due to SARS-Cov2-associated secondary sclerosing cholangitis (SSC) following long-term artificial respiration and extra-corporal membrane oxygenation in intensive care. Under these conditions, SSC is a rapidly progredient biliary disease featuring degenerative cholangiopathy, loss of bile ducts, ductular and parenchymal cholestasis, biliary fibrosis, and finally cirrhosis. Reduced perfusion and oxygenation of the peribiliary plexus, severe concurrent infections, and secondary medico-toxic effects appear to play a crucial role in the pathogenesis of the disease. A direct cytopathic effect of SARS-Cov2 on endothelial cells followed by thrombosis and fibrosing obliteration in all parts of the vascular bed of the liver may enhance the virus-associated liver disease and particularly SSC.

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.

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.

Efficacy and safety of biologics in primary sclerosing cholangitis with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an immune-mediated, chronic cholestatic liver disease. Currently, liver transplantation is the only established life-saving treatment. Several studies have evaluated the effect of different biologic therapies on PSC with inconclusive findings. We conducted a systematic review and meta-analysis to assess the effects of biologics in PSC and associated inflammatory bowel disease (IBD). METHODS: MEDLINE, Scopus, and Embase were searched up to July 31, 2023, for studies reporting the effects of biologics in patients with PSC-IBD. Effects of biologic therapy on alkaline phosphatase, total bilirubin, ulcerative colitis response score, and adverse events were calculated and expressed as standardized difference of means (SMD), proportions, and 95% CI using a random-effects model. RESULTS: Six studies, including 411 PSC-IBD patients who received biologics, were included. Biologic treatment was associated with no change in alkaline phosphatase (SMD: 0.1, 95% CI: -0.07 -0.17, p=0.43), but a small and statistically significant increase in total bilirubin (SMD: 0.2, 95% CI: 0.05-0.35, p<0.01). 31.2% (95% CI: 23.8-39.7) of patients with IBD achieved endoscopic response, and there was a significant improvement in ulcerative colitis response score (SMD: -0.6,95% CI: -0.88 to 0.36, p<0.01). Furthermore, 17.6% (95% CI: 13.0-23.5) of patients experienced adverse events severe enough to discontinue therapy, and 29.9% (95% CI: 25.2-34.8) had a loss of response to biologics. CONCLUSIONS: Treatment of patients with PSC-IBD with biologics (vedolizumab, infliximab, and adalimumab) was not associated with improvement of biochemical markers of cholestasis. Biologics are effective in treating the colitis associated with PSC. Vedolizumab was associated with worsening liver enzymes in contrast to other biologics, a finding that warrants further study.

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.

Long-term exposure to air pollution and prevalent nonalcoholic fatty liver disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is a disease characterized by lipid accumulation within hepatocytes, ranging from simple steatosis to steatohepatitis, in the absence of secondary causes of hepatic fat accumulation. Although air pollution (AP) has been associated with several conditions related to NAFLD (e.g., metabolic syndrome, type 2 diabetes mellitus), few studies have explored an association between AP and NAFLD. The aim of the study was to investigate whether exposure to AP is associated with NAFLD prevalence. Methods: We used baseline cross-sectional data (2000-2003) of the Heinz-Nixdorf-Recall cohort study in Germany (baseline n = 4,814), a prospective population-based cohort study in the urbanized Ruhr Area. Mean annual exposure to size-fractioned particulate matter (PM10, PM2.5, PMcoarse, and PM2.5abs), nitrogen dioxide, and particle number was assessed using two different exposure models: a chemistry transport dispersion model, which captures urban background AP exposure on a 1 km2 grid at participant's residential addresses, and a land use regression model, which captures point-specific AP exposure at participant's residential addresses. NAFLD was assessed with the fatty liver index (n = 4,065), with NAFLD defined as fatty liver index ≥60. We estimated ORs of NAFLD per interquartile range of exposure using logistic regression, adjusted for socio-demographic and lifestyle variables. Results: We observed a NAFLD prevalence of 31.7% (n = 1,288). All air pollutants were positively associated with NAFLD prevalence, with an OR per interquartile range for PM2.5 of 1.11 (95% confidence interval [CI] = 1.00, 1.24) using chemistry transport model, and 1.06 (95% CI = 0.94, 1.19) using the land use regression model, respectively. Conclusion: There was a positive association between long-term AP exposure and NAFLD.

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.

Higher pNRF2, SOCS3, IRF3, and RIG1 Tissue Protein Expression in NASH Patients versus NAFL Patients: pNRF2 Expression Is Concomitantly Associated with Elevated Fasting Glucose Levels.

Non-alcoholic fatty liver disease (NAFLD) embraces simple steatosis in non-alcoholic fatty liver (NAFL) to advanced non-alcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, and cirrhosis. NAFLD patients often have metabolic syndrome and high risks of cardiovascular and liver-related mortality. Our aim was to clarify which proteins play a role in the progression of NAFL to NASH. The study investigates paraffin-embedded samples of 22 NAFL and 33 NASH patients. To detect potential candidates, samples were analyzed by immunohistochemistry for the proteins involved in innate immune regulation, autophagy, apoptosis, and antioxidant defense: IRF3, RIG-1, SOCS3, pSTAT3, STX17, SGLT2, Ki67, M30, Caspase 3, and pNRF2. The expression of pNRF2 immunopositive nuclei and SOCS3 cytoplasmic staining were higher in NASH than in NAFL (p = 0.001); pNRF2 was associated with elevated fasting glucose levels. SOCS3 immunopositivity correlated positively with RIG1 (r = 0.765; p = 0.001). Further, in NASH bile ducts showed stronger IRF3 immunostaining than in NAFL (p = 0.002); immunopositive RIG1 tissue was higher in NASH than in NAFL (p = 0.01). Our results indicate that pNRF2, SOCS3, IRF3, and RIG1 are involved in hepatic lipid metabolism. We suggest that they may be suitable for further studies to assess their potential as therapeutics.

Influence of the Bile Acid Transporter Genes ABCB4, ABCB8, and ABCB11 and the Farnesoid X Receptor on the Response to Ursodeoxycholic Acid in Patients with Nonalcoholic Steatohepatitis.

The prevalence of NAFLD and NASH is increasing worldwide, and there is no approved medical treatment until now. Evidence has emerged that interfering with bile acid metabolism may lead to improvement in NASH. In this study, 28 patients with elevated cholestatic liver function tests (especially GGT) were screened for bile acid gene polymorphisms and treated with UDCA. All patients had a bile acid gene polymorphism in ABCB4 or ABCB11. Treatment with UDCA for 12 months significantly reduced GGT in all patients and ALT in homozygous patients. No difference in fibrosis was observed using FIb-4, NFS, and transient elastography (TE). PNPLA3 and TM6SF2 were the most common NASH-associated polymorphisms, and patients with TM6SF2 showed a significant reduction in GGT and ALT with the administration of UDCA. In conclusion, NASH patients with elevated GGT should be screened for bile acid gene polymorphisms, as UDCA therapy may improve liver function tests. However, no difference in clinical outcomes, such as progression to cirrhosis, has been observed using non-invasive tests (NITs).

No Differences in Rotational Thromboelastometry Measurements between Portal and Peripheral Circulation in Cirrhotic Patients Undergoing TIPS.

BACKGROUND: In patients with liver cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) is considered a standardized treatment of refractory ascites or variceal bleeding. TIPS thrombosis (TT) and/or portal vein thrombosis (PVT) are possible complications during/after TIPS placement. Previous studies suggested increased clotting activity in portal circulation (PORC). This pilot study aimed to evaluate alterations and differences of coagulation function in PORC and in peripheral circulation (PERC) via rotational thromboelastometry during TIPS. METHODS: Blood samples were collected from cirrhotic patients (n = 13; median Model of End Stage Liver Disease, MELD Score: 12; median age: 60 years) undergoing TIPS (10/13 TIPSs were elective procedures due to refractory ascites) as follows: median cubital vein (MCV; PERC)-confluence of the three hepatic veins to the inferior cava vein (HV/ICV; PORC)-portal vein (PV; PORC)-TIPS (PORC). This research utilized four variables of the extrinsic test EXTEM, i.e., clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and maximum lysis (ML). RESULTS: EXTEM results [mean, M (range) ± standard deviation, SD (range)] showed no significant differences for CT [M (70-73) ± SD (9-13); p = 0.93] or CFT [M (137-155) ± SD (75-112); p = 0.97] or MCF [M (51-54) ± SD (9-10); p = 0.90] or ML [M (9-10) ± SD (4-5); p = 0.89] between the compartments, i.e., MCV vs. HV/ICV vs. PV vs. TIPS. Overall, we detected no differences in coagulation function between PERC and PORC. CONCLUSION: These results are in contrast to previous reports suggesting increased clotting activity in PORC vs. PERC in association with liver cirrhosis. Rotational thromboelastometry-based evaluation of coagulation function in PERC appears to reliably reflect coagulation function in PORC with respect to risk estimation for TT and/or PVT in cirrhotic patients undergoing TIPS.

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.

Clinical and pathophysiological understanding of the hepatorenal syndrome: Still wrong or still not exactly right?

The hepatorenal syndrome (HRS) is one major extrahepatic complication of end-stage liver diseases. While circulatory dysregulation is considered as primary etiology for HRS, cirrhosis-related (systemic) inflammation and/or cardial dysfunction may also play a key pathogenic role in HRS development. Exclusion of other causes of acute kidney injury (AKI) is required for diagnosis of HRS-AKI by the definition of the International Club of Ascites. However, the pathophysiology of HRS is not understood completely and there are still limited therapeutic options. Reversibility of renal dysfunction after liver transplantation indicates that HRS-AKI is a functional disorder caused by altered cellular function. The interplay between systemic inflammation and the onset of kidney-related hypometabolism may have a key role and needs to be studied in depth. This minireview challenges simplified views of the HRS in the context of diagnostics and therapy stressing the need for further evidence to advance the knowledge on this syndrome.

[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.