Publications by authors named "Frank Lammert"

436 Publications

[Impact of Covid 19 on endoscopy in Germany].

Z Gastroenterol 2021 Oct 22. Epub 2021 Oct 22.

III. Medizinische Klinik - Gastroenterologie und Infektiologie, Universitätsklinikum Augsburg, Augsburg, Germany.

Background: Practices and hospitals are facing great challenges in coping with the COVID-19-pandemic. So far, data on the impact of the pandemic on gastroenterological facilities are lacking, especially on a temporal course. A database is lacking, especially for the outpatient care sector. University Hospital of Augsburg was commissioned to generate data on this as a part of the collaborative project B-FAST of the Network of University Medicine (NUM).

Methods: Gastroenterological institutions nationwide were surveyed by an online questionnaire. Recruitment was carried out via the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and the Professional Association of Gastroenterologists in Private Practice (bng). This manuscript provides an overview of data on the use of protective equipment, pre-interventional testing of patients, staff screening and economic impact over the course of the pandemic.

Results: 429 facilities answered the questionnaire. Practices tested their patients pre-interventionally significantly less often than clinics (7.8% vs. 82.6%). In clinics, inpatients (93.1%) were tested significantly more often than outpatients (72.2%). The use of personal protective equipment (PPE) increased significantly during the pandemic. It was shown that over 70% of facilities screened their staff for SARS-CoV-2 without cause. Clinics cancelled elective procedures significantly more often than practices in quarter 4/2020. Procedures and turnover decreased in 2020 compared to the previous year. However, fewer facilities were affected by a loss of revenue than expected in previous studies.

Conclusion: Our data demonstrate the variable implementation of pre-interventional SARS-CoV-2 testing in outpatient and inpatient care. The use of adequate PPE and staff screening increased during the pandemic.
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http://dx.doi.org/10.1055/a-1649-8184DOI Listing
October 2021

Protective Effects of Statin Therapy in Cirrhosis Are Limited by a Common SLCO1B1 Transporter Variant.

Hepatol Commun 2021 10 28;5(10):1755-1766. Epub 2021 Aug 28.

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.

Complications of cirrhosis and portal hypertension (PH) can be reduced by statin therapy. The common loss-of-function variant p.V174A in the solute carrier organic anion transporter gene 1B1 (SLCO1B1) gene encoding the organic anion transporting polypeptide 1B1 results in decreased hepatic uptake of statins. Our specific aim was to assess the impact of this variant in patients with cirrhosis and statin treatment while controlling for the stage of cirrhosis and other potential confounders with propensity score matching (PSM), availing of a large cohort of genotyped study patients. In total, from 1,088 patients with cirrhosis in two German academic medical centers, PSM yielded 154 patients taking statins and 154 matched controls. The effect on PH was assessed by the liver stiffness-spleen size-to-platelet score (LSPS), and complications of cirrhosis were retrospectively recorded applying consensus criteria. As hypothesized, patients on statin treatment presented less frequently with signs of PH: Esophageal varices (41% vs. 62%; P < 0.001) were less common, and LSPS (4.8 ± 11.5 vs. 5.6 ± 6.4; P = 0.01) was reduced. Correspondingly, decompensation events were also reduced in patients on statins (odds ratio [OR] = 0.54, 95% confidence interval [CI] 0.32-0.90; P = 0.02). When the variant in SLCO1B1 was present in patients on statins, esophageal varices (OR = 2.68, 95% CI 1.24-5.81; P = 0.01) and bacterial infections (OR = 2.50, 95% CI 1.14-5.47; P = 0.02) were more common as compared with wild type carriers on statins. Conclusion: In this cohort, signs and complications of PH were reduced in patients with cirrhosis treated with statins. Notably, this effect was diminished by the common loss-of-function variant in SLCO1B1. Further prospective studies in independent cohorts are warranted to confirm these genotype-specific observations.
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http://dx.doi.org/10.1002/hep4.1753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485882PMC
October 2021

Distinct Patterns of Blood Cytokines Beyond a Cytokine Storm Predict Mortality in COVID-19.

J Inflamm Res 2021 15;14:4651-4667. Epub 2021 Sep 15.

Department of Internal Medicine and Pulmonology, SHG-Hospital Völklingen, Saarbrücken, 66333, Germany.

Background: COVID-19 comprises several severity stages ranging from oligosymptomatic disease to multi-organ failure and fatal outcomes. The mechanisms why COVID-19 is a mild disease in some patients and progresses to a severe multi-organ and often fatal disease with respiratory failure are not known. Biomarkers that predict the course of disease are urgently needed. The aim of this study was to evaluate a large spectrum of established laboratory measurements.

Patients And Methods: Patients from the prospective PULMPOHOM and CORSAAR studies were recruited and comprised 35 patients with COVID-19, 23 with conventional pneumonia, and 28 control patients undergoing elective non-pulmonary surgery. Venous blood was used to measure the serum concentrations of 79 proteins by Luminex multiplex immunoassay technology. Distribution of biomarkers between groups and association with disease severity and outcomes were analyzed.

Results: The biomarker profiles between the three groups differed significantly with elevation of specific proteins specific for the respective conditions. Several biomarkers correlated significantly with disease severity and death. Uniform manifold approximation and projection (UMAP) analysis revealed a significant separation of the three disease groups and separated between survivors and deceased patients. Different models were developed to predict mortality based on the baseline measurements of several protein markers. A score combining IL-1ra, IL-8, IL-10, MCP-1, SCF and CA-9 was associated with significantly higher mortality (AUC 0.929).

Discussion: Several newly identified blood markers were significantly increased in patients with severe COVID-19 (AAT, EN-RAGE, myoglobin, SAP, TIMP-1, vWF, decorin) or in patients that died (IL-1ra, IL-8, IL-10, MCP-1, SCF, CA-9). The use of established assay technologies allows for rapid translation into clinical practice.
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http://dx.doi.org/10.2147/JIR.S320685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451220PMC
September 2021

Hypophosphatasia: An Underappreciated Cause of Atraumatic Stress Fractures.

Am J Med 2021 Sep 17. Epub 2021 Sep 17.

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Poland. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2021.08.018DOI Listing
September 2021

Excess Body Weight and Gallstone Disease.

Visc Med 2021 Aug 15;37(4):254-260. Epub 2021 Jun 15.

Department of Medicine II, Saarland University Medical Center, University of Saarland, Homburg, Germany.

Background: Approximately one fifth of adults are diagnosed with gallstones worldwide. Of these, around 25% develop gallstone disease (indicated by the presence of symptoms) and undergo cholecystectomy.

Summary: The risk of gallstones is influenced by a combination of genetic and lifestyle factors, such as excess body weight. In fact, body mass has been demonstrated to be a major risk factor for symptomatic gallstones. Rapid weight loss can also initiate a prolithogenic state and further increase the likelihood of either gallstone formation or existing gallstones becoming symptomatic; however, sensible weight loss strategies can mitigate this risk. This review discusses the role of excess body weight and the risk of gallstone disease, as well as the options available for the prevention of symptomatic gallstones.

Key Messages: Healthy weight loss diets combined with regular physical activity can promote successful weight loss and weight maintenance and reduce the risk of gallstones. Should rapid weight loss be required for health reasons or be expected, e.g., after bariatric surgery, prophylactic ursodeoxycholic acid during the period of weight reduction has been demonstrated to reduce the incidence of gallstones formation or symptomatic gallstone occurrence. The recent German guidelines on gallstones recommend simultaneous cholecystectomy during bariatric surgery but only for those with preexisting symptomatic stones.
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http://dx.doi.org/10.1159/000516418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406364PMC
August 2021

Population screening for liver fibrosis: towards early diagnosis and intervention for chronic liver diseases.

Hepatology 2021 Sep 19. Epub 2021 Sep 19.

Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, and Institute for Clinical Research, University of Southern Denmark Odense, Denmark.

Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy non-invasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using non-invasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate -18 to 27%- in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression.
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http://dx.doi.org/10.1002/hep.32163DOI Listing
September 2021

Intrahepatic cholestasis of pregnancy in conjunction with a frameshift deletion in FGFR4.

Clin Res Hepatol Gastroenterol 2021 Sep 10:101800. Epub 2021 Sep 10.

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by increased serum bile acid levels in the third trimester of pregnancy, and resolves quickly after delivery. We present the case of a 29-year-old woman who developed idiopathic liver damage during puberty, and subsequently ICP and severe pruritus during two pregnancies. DNA sequencing revealed a heterozygous deletion (c.393_delG) in the fibroblast growth factor receptor 4 (FGRF4) gene causing a premature stop codon. The resulting FGFR4 haploinsufficiency is likely to impede the enterohepatic feedback repression of hepatic bile acid synthesis via FXR and FGF19. It represents a new genetic etiology of ICP.
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http://dx.doi.org/10.1016/j.clinre.2021.101800DOI Listing
September 2021

Management of Intrahepatic Cholestasis of Pregnancy: Recommendations of the Working Group on Obstetrics and Prenatal Medicine - Section on Maternal Disorders.

Geburtshilfe Frauenheilkd 2021 Aug 9;81(8):922-939. Epub 2021 Aug 9.

Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Gynäkologie und Geburtshilfe, Kiel, Germany.

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease specific to pregnancy. The cardinal symptom of pruritus and a concomitant elevated level of bile acids in the serum and/or alanine aminotransferase (ALT) are suggestive for the diagnosis. Overall, the maternal prognosis is good. The fetal outcome depends on the bile acid level. ICP is associated with increased risks for adverse perinatal outcomes, including preterm delivery, meconium-stained amniotic fluid, and stillbirth. Acute fetal asphyxia and not chronic uteroplacental dysfunction leads to stillbirth. Therefore, predictive fetal monitoring is not possible. While medication with ursodeoxycholic acid (UDCA) improves pruritus, it has not been shown to affect fetal outcome. The indication for induction of labour depends on bile acid levels and gestational age. There is a high risk of recurrence in subsequent pregnancies.
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http://dx.doi.org/10.1055/a-1386-3912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354365PMC
August 2021

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study).

J Hepatol 2021 Aug 5. Epub 2021 Aug 5.

Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany. Electronic address:

Background & Aims: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF.

Methods: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 μg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period.

Results: Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation.

Conclusions: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS.

Gov Number: NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.
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http://dx.doi.org/10.1016/j.jhep.2021.07.033DOI Listing
August 2021

Fibroblast Growth Factor 21 Response in a Preclinical Alcohol Model of Acute-on-Chronic Liver Injury.

Int J Mol Sci 2021 Jul 23;22(15). Epub 2021 Jul 23.

Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany.

Background And Aims: Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in mice with deficiency of the hepatobiliary phospholipid transporter.

Methods: Total RNA was extracted from wild-type (WT, C57BL/6J) and (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KO-EtOH groups; = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; = 31) and healthy controls ( = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments.

Results: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (), , Farnesoid X-activated receptor (), and Small heterodimer partner () and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ.

Conclusions: The simultaneous upregulation of FGF21 and downregulation of expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic and levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of expressions while circulating FGF15 and hepatic and levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1.
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http://dx.doi.org/10.3390/ijms22157898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348955PMC
July 2021

Effects of blocking chemokine receptor CCR1 with BX471 in two models of fibrosis prevention and rescue in mice.

Biochem Biophys Rep 2021 Sep 15;27:101077. Epub 2021 Jul 15.

Department of Medicine II, Saarland University Medical Center, Homburg, Germany.

Background: The induction, progression and resolution of liver fibrosis are influenced by multiple chemokines. The inhibition of CCR1 signalling by a specific non-peptide inhibitor (BX471) reduces kidney fibrosis after unilateral ureteral obstruction via suppression of leukocyte recruitment in mice. However, it remains unclear whether selective CCR1 inhibition also affects hepatic fibrogenesis. Therefore we aimed to study the effect of this intervention on liver fibrosis in prevention (CCl administration) and rescue (ABCB4-deficient mice) mouse models.

Methods: In the prevention model, hepatic fibrosis was induced by repeated injections of CCl. Additionally, the verum group was treated with subcutaneous injections of BX471, while controls received vehicle only. ABCB4 deficient mice (on the BALB/c-background) with sclerosing cholangitis and biliary fibrosis received BX471 or vehicle, respectively (rescue model). Liver histopathology was assessed after Sirius red staining of collagen, and hepatic collagen contents were measured. In addition, we performed gene expression analyses of fibrosis-related genes.

Results: BX471 injections were tolerated moderately well by all mice, and all mice developed hepatic fibrosis. Significant differences were neither observed in serum aminotransferase activities after 6 weeks of treatment between the two groups in the prevention nor in the rescue model. Interestingly, hepatic collagen contents were significantly higher in mice treated with BX471 in the prevention model as compared to controls but histological stages of liver sections did not differ. Of note, we observed only moderate effects on liver fibrosis in the ABCB4 knock-out model.

Conclusions: Our data indicate that BX471 treatment did neither affect serum and tissue markers of liver injury and fibrosis in the CCl model and only moderately in the model of biliary fibrosis. The animal models indicate that treatment with BX471 alone is unlikely to exert major beneficial effects in chronic liver disease.
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http://dx.doi.org/10.1016/j.bbrep.2021.101077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313839PMC
September 2021

[Quality management in the field of gastroenterology - Proposals of the Quality Commission of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) for Outpatient and Inpatient Quality Assurance].

Z Gastroenterol 2021 Jul 12;59(7):665-676. Epub 2021 Jul 12.

Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten, Berlin.

The quality of the medical care depends on numerous factors that can often be influenced by the doctor itself. It is a great challenge to follow the constant scientific progress in practice. Scientific standards in gastroenterology are defined in DGVS guidelines and regularly revised. The implementation of evidence-based recommendations in practice remains challenging. On the basis of the DGVS guidelines, the Quality Commission has therefore developed a selection of quality indicators with particular relevance using standardized criteria, the broad implementation of which could contribute to improved patient care in gastroenterology.
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http://dx.doi.org/10.1055/a-1451-6350DOI Listing
July 2021

Adiponectin, Leptin, and IGF-1 Are Useful Diagnostic and Stratification Biomarkers of NAFLD.

Front Med (Lausanne) 2021 23;8:683250. Epub 2021 Jun 23.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease where liver biopsy remains the gold standard for diagnosis. Here we aimed to evaluate the role of circulating adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) levels as non-invasive NAFLD biomarkers and assess their correlation with the metabolome. Leptin, adiponectin, and IGF-1 serum levels were measured by ELISA in two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls (discovery: 38 NAFLD, 13 controls; validation: 194 NAFLD, 31 controls) and correlated with clinical data, histology, genetic parameters, and serum metabolomics. In both cohorts, leptin increased in NAFLD vs. controls (discovery: AUROC 0.88; validation: AUROC 0.83; < 0.0001). The leptin levels were similar between obese and non-obese healthy controls, suggesting that obesity is not a confounding factor. In the discovery cohort, adiponectin was lower in non-alcoholic steatohepatitis (NASH) vs. non-alcoholic fatty liver (AUROC 0.87; < 0.0001). For the validation cohort, significance was attained for homozygous for PNPLA3 allele c.444C (AUROC 0.63; < 0.05). Combining adiponectin with specific serum lipids improved the assay performance (AUROC 0.80; < 0.0001). For the validation cohort, IGF-1 was lower with advanced fibrosis (AUROC 0.67, < 0.05), but combination with international normalized ratio (INR) and ferritin increased the assay performance (AUROC 0.81; < 0.01). Serum leptin discriminates NAFLD, and adiponectin combined with specific lipids stratifies NASH. IGF-1, INR, and ferritin distinguish advanced fibrosis.
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http://dx.doi.org/10.3389/fmed.2021.683250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260936PMC
June 2021

Deep learning-based detection of eosinophilic esophagitis.

Endoscopy 2021 May 31. Epub 2021 May 31.

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.

Background:  For eosinophilic esophagitis (EoE), a substantial diagnostic delay is still a clinically relevant phenomenon. Deep learning-based algorithms have demonstrated potential in medical image analysis. Here we establish a convolutional neuronal network (CNN)-based approach that can distinguish the appearance of EoE from normal findings and candida esophagitis.

Methods:  We trained and tested a CNN using 484 real-world endoscopic images from 134 subjects consisting of three classes (normal, EoE, and candidiasis). Images were split into two completely independent datasets. The proposed approach was evaluated against three trainee endoscopists using the test set. Model-explainability was enhanced by deep Taylor decomposition.

Results:  Global accuracy (0.915 [95 % confidence interval (CI) 0.880-0.940]), sensitivity (0.871 [95 %CI 0.819-0.910]), and specificity (0.936 [95 %CI 0.910-0.955]) were significantly higher than for the endoscopists on the test set. Global area under the receiver operating characteristic curve was 0.966 [95 %CI 0.954-0.975]. Results were highly reproducible. Explainability analysis found that the algorithm identified the characteristic signs also used by endoscopists.

Conclusions:  Complex endoscopic classification tasks including more than two classes can be solved by CNN-based algorithms. Therefore, our algorithm may assist clinicians in making the diagnosis of EoE.
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http://dx.doi.org/10.1055/a-1520-8116DOI Listing
May 2021

and Expression in Hepatocellular Carcinoma and Tumor-Surrounding Liver Tissue.

Visc Med 2021 Mar 12;37(2):110-115. Epub 2021 Jan 12.

Department of Medicine II, Saarland University Medical Center, Homburg, Germany.

Introduction: The endoplasmic reticulum transmembrane proteins Sec61, Sec62, and Sec63 are responsible for the intracellular trafficking of precursor proteins and affect intracellular signaling. overexpression has been linked to various human cancers. Our aim was to investigate and expression in hepatocellular carcinoma (HCC) and surrounding liver tissue.

Patients And Methods: Primary liver tissue was collected from 11 consecutive patients (70 ± 9 years; 10 men) who underwent HCC resection. In the HCC and the tumor-surrounding liver tissue we investigated und mRNA expression using quantitative real-time PCR. For Sec62, immunohistochemistry was performed.

Results: and total mRNA contents were significantly ( = 0.001) higher in HCCs (C 22.5 ± 0.4 and 22.6 ± 0.3) when compared to the surrounding tissue (C 24.6 ± 0.6 and 25.1 ± 0.9). Using the comparative Cmethod, and expression in HCC was increased 5- and 8.1-fold, respectively, in comparison to surrounding tissue. For Sec62 immunohistochemistry, the mean immunoreactive scores (IRS) were 7.9 ± 2.9 for HCC and 4.8 ± 1.2 for non-tumorous liver ( = 0.027). The mean IRS in HCC were 5.7 ± 3.5 and 8.9 ± 2.3 for patients without ( = 3) and with tumor recurrence ( = 8), respectively.

Conclusions: Overexpression of and is a common feature of HCC. The role of Sec62 as a prognostic marker for tumor recurrence after surgery and its potential role in treatment stratification must be addressed in future studies.
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http://dx.doi.org/10.1159/000513293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077548PMC
March 2021

[Intrahepatic cholestasis of pregnancy].

Gynakologe 2021 Apr 20:1-16. Epub 2021 Apr 20.

Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universität Düsseldorf, Düsseldorf, Deutschland.

Intrahepatic cholestasis of pregnancy (ICP) is the most frequent pregnancy-specific liver disease. It is characterized by pruritus and an accompanying elevation of serum bile acid concentrations and/or alanine aminotransferase (ALT), which are the key parameters in the diagnosis. Despite good maternal prognosis, elevated bile acid concentration in maternal blood is an influencing factor to advers fetal outcome. The ICP is associated with increased rates of preterm birth, neonatal unit admission and stillbirth. This is the result of acute fetal asphyxia as opposed to a chronic uteroplacental insufficiency. Reliable monitoring or predictive tools (e.g. cardiotocography (CTG) or ultrasound) that help to prevent advers events are yet to be explored. Medicinal treatment with ursodeoxycholic acid (UDCA) does not demonstrably reduce adverse perinatal outcomes but does improve pruritus and liver function test results. Bile acid concentrations and gestational age should be used as indications to determine delivery. There is a high risk of recurrence in subsequent pregnancies.
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http://dx.doi.org/10.1007/s00129-021-04787-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056200PMC
April 2021

Combined analysis of gut microbiota, diet and PNPLA3 polymorphism in biopsy-proven non-alcoholic fatty liver disease.

Liver Int 2021 07 7;41(7):1576-1591. Epub 2021 May 7.

Department of Hepatology and Gastroenterology, Charité University Medicine, Campus Virchow Clinic and Campus Charité Mitte, Berlin, Germany.

Background And Aims: Non-alcoholic fatty liver disease (NAFLD) is a global health burden. Risk factors for disease severity include older age, increased body mass index (BMI), diabetes, genetic variants, dietary factors and gut microbiota alterations. However, the interdependence of these factors and their individual impact on disease severity remain unknown.

Methods: In this cross-sectional study, we performed 16S gene sequencing using fecal samples, collected dietary intake, PNPLA3 gene variants and clinical and liver histology parameters in a well-described cohort of 180 NAFLD patients. Principal component analyses were used for dimensionality reduction of dietary and microbiota data. Simple and multiple stepwise ordinal regression analyses were performed.

Results: Complete data were available for 57 NAFLD patients. In the simple regression analysis, features associated with the metabolic syndrome had the highest importance regarding liver disease severity. In the multiple regression analysis, BMI was the most important factor associated with the fibrosis stage (OR per kg/m : 1.23, 95% CI 1.10-1.37, P < .001). The PNPLA3 risk allele had the strongest association with the histological grade of steatosis (OR 5.32, 95% CI 1.56-18.11, P = .007), followed by specific dietary patterns. Low abundances of Faecalibacterium, Bacteroides and Prevotella and high abundances of Gemmiger were associated with the degree of inflammation, ballooning and stages of fibrosis, even after taking other cofactors into account.

Conclusions: BMI had the strongest association with histological fibrosis, but PNPLA3 gene variants, gut bacterial features and dietary factors were all associated with different histology features, which underscore the multifactorial pathogenesis of NAFLD.
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http://dx.doi.org/10.1111/liv.14899DOI Listing
July 2021

Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine.

Gastroenterology 2021 07 2;161(1):301-317.e16. Epub 2021 Apr 2.

Department of Neurology, Duke University, Durham, North Carolina; Center for Translational Pain Medicine, Department of Anesthesiology, Duke University, Durham, North Carolina; Department of Neurobiology, Duke University, Durham, North Carolina; Neurology Clinics for Headache, Head-Pain and Trigeminal Sensory Disorders, Duke University, Durham, North Carolina; Clinics for Innovative Pain Therapy, Department of Anesthesiology, Duke University, Raleigh, North Carolina. Electronic address:

Background & Aims: Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus.

Methods: Pruritogenicity of lysophosphatidylcholine (LPC), LPA's precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC's pruritogenicity involving keratinocyte TRPV4 was studied using genetic and pharmacologic approaches, cultured keratinocytes, ion channel physiology, and structural computational modeling. Activation of pruriceptor sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in vitro and ex vivo Ca imaging assays. Sera from patients with primary biliary cholangitis were used for measuring the levels of LPC and miR-146a.

Results: LPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. Three-dimensional structural modeling, site-directed mutagenesis, and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4 activation by LPC induced extracellular release of miR-146a, which activated TRPV1 sensory neurons to cause itch. LPC and miR-146a levels were both elevated in sera of patients with primary biliary cholangitis with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates.

Conclusions: We identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron cross talk, whereby it directly activates skin keratinocyte TRPV4, which rapidly releases miR-146a to activate skin-innervating TRPV1 pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons, and central neural pathways supporting pruriception.
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http://dx.doi.org/10.1053/j.gastro.2021.03.049DOI Listing
July 2021

Increased B-cell activity with consumption of activated monocytes in severe COVID-19 patients.

Eur J Immunol 2021 06 19;51(6):1449-1460. Epub 2021 Apr 19.

Internal Medicine I, Saarland University Medical Center, Homburg, Germany.

The pathogenesis of autoimmune complications triggered by SARS-CoV2 has not been completely elucidated. Here, we performed an analysis of the cellular immune status, cell ratios, and monocyte populations of patients with COVID-19 treated in the intensive care unit (ICU) (cohort 1, N = 23) and normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated in ICU for noninfectious reasons (cohort 3, n = 30) and patients treated in NCU for infections other than COVID-19 (cohort 4, n = 21). Patients in cohort 1 presented significant differences in comparison with the other cohorts, including reduced frequencies of lymphocytes, reduced CD8+T-cell count, reduced percentage of activated and intermediate monocytes and an increased B/T8 cell ratio. Over time, patients in cohort 1 who died presented with lower counts of B, T, CD4 T, CD8 T-lymphocytes, NK cells, and activated monocytes. The B/T8 ratio was significantly lower in the group of survivors. In cohort 1, significantly higher levels of IgG1 and IgG3 were found, whereas cohort 3 presented higher levels of IgG3 compared to controls. Among many immune changes, an elevated B/T8-cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID-19. Both parameters were associated with death in cohort 1.
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http://dx.doi.org/10.1002/eji.202049163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250224PMC
June 2021

Complement in Acute Liver Failure: The Right Timing to Give a Sincere Compliment.

Cell Mol Gastroenterol Hepatol 2021 20;11(5):1546-1547. Epub 2021 Mar 20.

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.

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http://dx.doi.org/10.1016/j.jcmgh.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099675PMC
March 2021

Cholesterol crystals in biliary cast syndrome related to sclerosing cholangitis in critically ill patients.

Clin Res Hepatol Gastroenterol 2021 May 15;45(3):101485. Epub 2021 Mar 15.

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.clinre.2020.06.011DOI Listing
May 2021

Drug adherence and psychosocial characteristics of patients presenting with hypertensive urgency at the emergency department.

J Hypertens 2021 08;39(8):1697-1704

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Saarland University.

Objective: To identify potentially targetable psychosocial factors associated with nonadherence to prescribed antihypertensive medications in patients presenting with hypertensive urgencies at an emergency department.

Methods: This prospective study included patients treated with antihypertensive drugs who presented with hypertensive urgencies (SBP ≥180 mmHg and/or DBP ≥110 mmHg) at the emergency department of a tertiary referral clinic between April 2018 and April 2019. Health literacy was assessed using the Newest Vital Sign test. The Hospital Anxiety and Depression Scale (HADS) was used to quantify symptoms of anxiety and depression. Patients were classified nonadherent if less than 80% of the prescribed antihypertensive drugs were detectable in urine or plasma using liquid chromatography-high-resolution mass spectrometry.

Results: A total of 104 patients (62% women) presenting with hypertensive urgencies with a median SBP of 200 mmHg (IQR 190-212) and DBP of 97.5 mmHg (IQR 87-104) were included. Twenty-five patients (24%) were nonadherent to their antihypertensive medication. Nonadherent patients were more often men (66 versus 23%, P = 0.039), prescribed higher numbers of antihypertensive drugs (median 3, IQR 3-4 versus 2, IQR 1-3; P < 0.001), and more often treated with calcium channel blockers (76 versus 25%; P < 0.001) and/or diuretics (64 versus 40%; P = 0.030). There was no difference in health literacy (P = 0.904) or the scores on the HADS subscales for depression (P = 0.319) and anxiety (P = 0.529) between adherent and nonadherent patients.

Conclusion: Male sex, higher numbers of antihypertensive drugs, and treatment with diuretics and/or calcium channel blockers were associated with nonadherence. We did not identify a specific psychosocial characteristic associated with nonadherence.
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http://dx.doi.org/10.1097/HJH.0000000000002842DOI Listing
August 2021

Environmental and Dietary Risk Factors for Colonic Diverticulosis and Diverticulitis.

J Gastrointestin Liver Dis 2021 Mar 13;30(1):66-72. Epub 2021 Mar 13.

Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Background And Aims: Colonic diverticulosis (CD) is among the most common conditions of the large bowel. Several factors have been associated with an increased risk of CD and its complications, including advanced age, obesity, physical inactivity, and a low-fiber diet. Available data is conflicting and a comprehensive analysis of different bowel, dietary and environmental habits linked with CD is lacking. We aimed to investigate the relationship between potential risk factors and CD prevalence using full data from a colonoscopy-based cross-sectional study in Europe.

Methods: The study was conducted at three tertiary referral centers in Germany and Lithuania. It included consecutive adult patients referred for routine colonoscopy who completed a detailed questionnaire on our considered multiple risk factors for diverticulosis and diverticulitis, including dietary and environmental factors, and bowel habits.

Results: The study included 1,333 patients, 696 women and 635 men. Colonic diverticulosis was diagnosed in 858 (64%) of patients. Multivariate analysis revealed that age (OR: 1.08, 95%CI: 1.06-1.10, p<0.001) and obesity (OR: 1.05, 95%CI: 1.02-1.09, p=0.004) were associated with CD. We also revealed new risk factors for CD: increased frequency of bowel movements (OR: 0.10, 95%CI: 0.03-0.33, p<0.001) and feeling of incomplete bowel emptying (OR: 2.05, 95%CI: 1.47-2.87, p<0.001). Older participants had reduced odds (OR: 0.921, 95 CI: 0.89-0.95, p<0.05) of diverticulitis compared to younger subjects. Feeling of incomplete bowel emptying after defecation was associated with increased odds (OR: 2.769, 95% CI 1.35-5.7, p<0.006) for diverticulitis. Moreover, participants with a higher educational status had increased odds (OR: 2.453, 95%CI: 1.31-4.59, p=0.005) for diverticulitis compared to the lower education group.

Conclusions:  Study shows that older age, obesity, frequency of bowel movements, and feeling of incomplete bowel emptying are associated with the risk of CD. Furthermore, older age, feeling of incomplete bowel emptying, and higher education were associated with the risk of diverticulitis among CD patients.
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http://dx.doi.org/10.15403/jgld-3208DOI Listing
March 2021

Direct cystic remnant ductoscopy.

Clin Res Hepatol Gastroenterol 2021 Mar 5;45(2):101476. Epub 2021 Mar 5.

Department of Medicine II, Saarland University Medical Centre, Saarland University, Homburg, Germany.

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http://dx.doi.org/10.1016/j.clinre.2020.05.022DOI Listing
March 2021

Isolated bacterial infection without decompensation has no impact on survival of compensated patients with cirrhosis.

Liver Int 2021 06 14;41(6):1370-1378. Epub 2021 Mar 14.

Department of Medicine I, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany.

Background & Aims: Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was to evaluate the impact of BI on the natural history of compensated cirrhosis.

Methods: We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI.

Results: About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline.

Conclusions: In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.
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http://dx.doi.org/10.1111/liv.14842DOI Listing
June 2021

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

Gut 2021 Feb 25. Epub 2021 Feb 25.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.

Objective: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.

Design: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.

Results: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.

Conclusion: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.
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http://dx.doi.org/10.1136/gutjnl-2020-323729DOI Listing
February 2021

Amiodarone and hypothyroidism.

Lancet 2021 02;397(10275):704

Department of Medicine II, Saarland University Medical Centre, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)00204-XDOI Listing
February 2021

Small Bowel Polypoid Lesions: Similar But Different!

Gastroenterology 2021 04 18;160(5):1481-1482. Epub 2020 Dec 18.

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1053/j.gastro.2020.12.021DOI Listing
April 2021
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