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 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. Aim of the present study was to assess 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 origin undergoing liver biopsy was analysed. 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 AST concentration (0.41) NFS (0.33), INR (0.30), methacetin breath test results (-0.40), and serum albumin concentration (-0.29) by spearman rank correlation. ROC 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 score may have 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).

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.

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.

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.

[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.

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.

[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.

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.