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1. Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study

Author: Serra-Burriel, Miquel, Juanola, Adrià, Serra-Burriel, Feliu, Thiele, Maja, Graupera, Isabel, Pose, Elisa, Pera, Guillem, Grgurevic, Ivica, Caballeria, Llorenç, Piano, Salvatore, van Kleef, Laurens, Reichert, Mathias, Roulot, Dominique, Pericàs, Juan M, Schattenberg, Jörn M, Tsochatztis, Emmanuel A, Guha, Indra Neil, Garcia-Retortillo, Montserrat, Hernández, Rosario, Hoyo, Jordi, Fuentes, Matilde, Expósito, Carmen, Martínez, Alba, Such, Patricia, Madir, Anita, Detlefsen, Sönke, Tonon, Marta, Martini, Andrea, Ma, Ann T, Pich, Judith, Bonfill, Eva, Juan, Marta, Soria, Anna, Carol, Marta, Gratacós-Ginès, Jordi, Morillas, Rosa M, Toran, Pere, Navarrete, J M, Torrejón, Antoni, Fournier, Céline, Llorca, Anne, Arslanow, Anita, de Koning, Harry J, Cucchietti, Fernando, Manns, Michael, Newsome, Phillip N, Hernáez, Rubén, Allen, Alina, Angeli, Paolo, de Knegt, Robert J, Karlsen, Tom H, Galle, Peter, Wong, Vincent Wai-Sun, Fabrellas, Núria, Castera, Laurent, Krag, Aleksander, Lammert, Frank, Kamath, Patrick S, Ginès, Pere, Alvarez, Marifé, Andersen, Peter, Angeli, Paolo, Ardèvol, Alba, Arslanow, Anita, Beggiato, Luca, Ben Abdesselam, Zahia, Bennett, Lucy, Boutouria, Bajiha, Brocca, Alessandra, Broquetas, M. Teresa, Caballeria, Llorenç, Calvino, Valeria, Camacho, Judith, Capdevila, Aura, Carol, Marta, Castera, Laurent, Cervera, Marta, Cucchietti, Fernando, de Fuentes, Anna, de Knegt, Rob, de Koning, Harry J, Detlefsen, Sonke, Diaz, Alba, Diéguez Bande, José, Esnault, Vanessa, Fabrellas, Núria, Falcó, Josep Lluis, Fernández, Rosa, Fournier, Céline, Fuentes, Matilde, Galle, Peter, García, Edgar, García-Retortillo, Montserrat, Garrido, Esther, Ginès, Pere, Gordillo Medina, Rosa, Gratacós-Ginès, Jordi, Graupera, Isabel, Grgurevic, Ivica, Guha, Indra Neil, Guix, Eva, Hansen, Johanne Kragh, Harris, Rebecca, Hernández Boluda, Elena, Hernández-Ibañez, Rosario, Hoyo, Jordi, Ikram, Arfan, Incicco, Simone, Israelsen, Mads, Juan, Marta, Juanola, Adrià, Kaiser, Ralf, Kamath, Patrick S, Karlsen, Tom H, Kjærgaard, Maria, Korenjak, Marko, Krag, Aleksander, Krawczyk, Marcin, Laboulaye, Philippe, Lambert, Irina, Lammert, Frank, Langkjær Sørensen, Simon, Laserna-Jiménez, Cristina, Lazaro Pi, Sonia, Ledain, Elsa, Levy, Vincent, Lindvig, Katrine Prier, Llorca, Anne, Londoño, Vanessa, Loyer, Guirec, Ma, Ann T., Madir, Anita, Manns, Michael, Marshall, Denise, Martí, M. Lluïsa, Martínez, Sara, Martínez Sala, Ricard, Masa-Font, Roser, Møller Jensen, Jane, Morillas, Rosa M, Muñoz, Laura, Nadal, Ruth, Napoleone, Laura, Navarrete, JM, Newsome, Phillip N, Nielsen, Vibeke, Pérez, Martina, Pericás-Pulido, Juan Manuel, Piano, Salvatore, Pich, Judit, Pose, Elisa, Presas Escobet, Judit, Reichert, Matthias, Riba, Carlota, Roulot, Dominique, Rubio, Ana Belén, Sánchez-Morata, Maria, Schattenberg, Jörn, Serra-Burriel, Miquel, Serra-Burriel, Feliu, Skovborg Just, Louise, Sonneveld, Milan, Soria, Anna, Stern, Christiane, Such, Patricia, Thiele, Maja, Tonon, Marta, Toran, Pere, Torrejón, Antoni, Tsochatzis, Emmanuel A, van Kleef, Laurens, van Wijngaarden, Paulien, Velázquez, Vanessa, Viu, Ana, Weber, Susanne Nicole, and Wildsmith, Tracey
Abstract: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes.
Published: 2023
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2. Presence of NOD2 mutations is not associated with hepatic or systemic hemodynamic abnormalities of cirrhosis.

Author: Greinert, Robin, Zipprich, Alexander, Casper, Markus, Reichert, Matthias Christian, Lammert, Frank, and Ripoll, Cristina
Abstract: Patients with cirrhosis who carry NOD2 mutations are susceptible to bacterial infections. The aim was to evaluate the association of NOD2 mutations with hepatic and systemic hemodynamics in cirrhosis. This is a secondary analysis of a prospectively collected database in the context of the screening for the I N CA trial (EudraCT 2013-001626-26). This cross-sectional study compared hemodynamic findings according to NOD2 status in 215 patients. Patients were genotyped for NOD2 variants (p.N289S, p.R702W, p.G908R, c.3020insC, rs72796367). Hepatic hemodynamic study and right heart catheterization were performed. Patients had a median age of 59 (IQR 53–66) years, and 144 (67%) were men. Most patients (64%) were Child-Pugh stage B. Sixty-six patients (31%) carried a NOD2 mutation, which was slightly more common among Child-Pugh stage C (p = 0.05), without differences in MELD [wild-type: 13 (10–16); NOD2 variants 13 (10–18)]. No differences in hepatic and systemic hemodynamics were observed according to NOD2 status. If excluding patients on prophylactic or therapeutic antibiotics, again no association between hepatic or systemic hemodynamics and NOD2 status could be observed. NOD2 mutations are not associated with hepatic or systemic hemodynamic abnormalities in patients with decompensated cirrhosis, suggesting that other mechanisms leading to bacterial translocation predominate. [ABSTRACT FROM AUTHOR]
Published: 2023
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3. Diverticular Inflammation and Complication Assessment classification, CODA score and fecal calprotectin in clinical assessment of patients with diverticular disease: A decision curve analysis

Author: Tursi, Antonio, Piovani, Daniele, Brandimarte, Giovanni, Mario, Francesco, Elisei, Walter, Picchio, Marcello, Allegretta, Leonardo, Annunziata, Maria Laura, Bafutto, Mauro, Bassotti, Gabrio, Bianco, Maria Antonia, Colucci, Raffaele, Conigliaro, Rita, Dumitrascu, Dan L., Escalante, Ricardo, Ferrini, Luciano, Forti, Giacomo, Franceschi, Marilisa, Graziani, Maria Giovanna, Lammert, Frank, Latella, Giovanni, Maconi, Giovanni, Compare, Debora, Nardone, Gerardo, Camara De Castro Oliveira, Lucia, Oliveira, Enio Chaves, Papa, Alfredo, Papagrigoriadis, Savvas, Pietrzak, Anna, Pontone, Stefano, Poskus, Tomas, Pranzo, Giuseppe, Reichert, Matthias Christian, Rodinò, Stefano, Regula, Jaroslaw, Scaccianoce, Giuseppe, Scaldaferri, Franco, Vassallo, Roberto, Zampaletta, Costantino, Zullo, Angelo, Spaziani, Erasmo, Bonovas, Stefanos, Danese, Silvio, Astegiano, Marco, Bachetti, Francesco, Baldassarre, Gianluca, Baldi, Fabio, Borsotti, Edoardo, Cassieri, Claudio, Cazzato, Alessia, Chiri, Stefania, Ciccone, Antonio, Damiani, Alberto, Colibus, Patrizia De, Faggiani, Roberto, Finocchiaro, Fabio, Fiorella, Serafina, Foschia, Francesca, Furfaro, Federica, Gallina, Sara, Giorgetti, Gian Marco, Grad, Simona, Grande, Giuseppe, Grandolfo, Antonio, Lai, Maria Antonia, Lecca, Piera Giuseppina, Lisi, Daniele, Lopetuso, Loris Riccardo, Penna, Antonio, Pigò, Flavia, Portincasa, Piero, Rizzatti, Giannenrico, Rizzo, Giovanni Luca, Scanni, Stefania, Schiffino, Luigi, Stundiene, Ieva, Tesoriere, Antonino, Urgesi, Riccardo, and Usai, Paolo
Abstract: The Diverticular Inflammation and Complication Assessment (DICA) classification and the Combined Overview on Diverticular Assessment (CODA) were found to be effective in predicting the outcomes of Diverticular Disease (DD). We ascertain whether fecal calprotectin (FC) can further aid in improving risk stratification. A three‐year international, multicentre, prospective cohort study was conducted involving 43 Gastroenterology and Endoscopy centres. Survival methods for censored observations were used to estimate the risk of acute diverticulitis (AD) in newly diagnosed DD patients according to basal FC, DICA, and CODA. The net benefit of management strategies based on DICA, CODA and FC in addition to CODA was assessed with decision curve analysis, which incorporates the harms and benefits of using a prognostic model for clinical decisions. At the first diagnosis of diverticulosis/DD, 871 participants underwent FC measurement. FC was associated with the risk of AD at 3 years (HR per each base 10 logarithm increase: 3.29; 95% confidence interval, 2.13–5.10) and showed moderate discrimination (c‐statistic: 0.685; 0.614–0.756). DICA and CODA were more accurate predictors of AD than FC. However, FC showed high discrimination capacity to predict AD at 3 months, which was not maintained at longer follow‐up times. The decision curve analysis comparing the combination of FC and CODA with CODA alone did not clearly indicate a larger net benefit of one strategy over the other. FC measurement could be used as a complementary tool to assess the immediate risk of AD. In all other cases, treatment strategies based on the CODA score alone should be recommended.
Published: 2023
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4. Genetic variation in TERTmodifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

Author: Buch, Stephan, Innes, Hamish, Lutz, Philipp Ludwig, Nischalke, Hans Dieter, Marquardt, Jens U, Fischer, Janett, Weiss, Karl Heinz, Rosendahl, Jonas, Marot, Astrid, Krawczyk, Marcin, Casper, Markus, Lammert, Frank, Eyer, Florian, Vogel, Arndt, Marhenke, Silke, von Felden, Johann, Sharma, Rohini, Atkinson, Stephen Rahul, McQuillin, Andrew, Nattermann, Jacob, Schafmayer, Clemens, Franke, Andre, Strassburg, Christian, Rietschel, Marcella, Altmann, Heidi, Sulk, Stefan, Thangapandi, Veera Raghavan, Brosch, Mario, Lackner, Carolin, Stauber, Rudolf E, Canbay, Ali, Link, Alexander, Reiberger, Thomas, Mandorfer, Mattias, Semmler, Georg, Scheiner, Bernhard, Datz, Christian, Romeo, Stefano, Ginanni Corradini, Stefano, Irving, William Lucien, Morling, Joanne R, Guha, Indra Neil, Barnes, Eleanor, Ansari, M Azim, Quistrebert, Jocelyn, Valenti, Luca, Mu¨ller, Sascha A, Morgan, Marsha Yvonne, Dufour, Jean-Francois, Trebicka, Jonel, Berg, Thomas, Deltenre, Pierre, Mueller, Sebastian, Hampe, Jochen, and Stickel, Felix
Abstract: ObjectiveHepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis.DesignPatients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina).ResultsAssociations with variants rs738409 in PNPLA3and rs58542926 in TM6SF2previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT(telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10−9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10−5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERTwas associated with an increased leucocyte telomere length (p=2.12×10−44).ConclusionThis study identifies rs2242652 in TERTas a novel protective factor for HCC in patients with alcohol-related cirrhosis.
Published: 2023
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5. Neglected geriatric assessment and overtreatment of older patients with pancreatic cancer - Results from a prospective phase IV clinical trial.

Author: Betge, Johannes, Schulte, Nadine, Belle, Sebastian, Zhan, Tianzuo, Krammer-Steiner, Beate, Moulin, Jean-Charles, Kleiß, Matthias, Lammert, Frank, Wedding, Ulrich, Räth, Sebastian, Maenz, Martin, Hegele, Lisa, Larcher-Senn, Julian, Jesenofsky, Ralf, Ebert, Matthias P., and Härtel, Nicolai
Abstract: Older patients with metastatic pancreatic cancer may suffer increased toxicity from intensive chemotherapy. Treatment individualization by geriatric assessment (GA) might improve functional outcome. We performed a multicenter, phase IV, open label trial in patients ≥70 years with metastatic pancreatic adenocarcinoma. Patients underwent GA and were assigned to one of three categories based on their scores: Go-Go, Slow-Go, or Frail. These categories were intended to guide physician's treatment decisions when choosing to treat patients with nab-paclitaxel/gemcitabine (arm A), gemcitabine (arm B), or best supportive care (arm C). Primary objective was a stable (loss of five points or less) Barthel's Activities of Daily Living (ADL) score during chemotherapy; secondary endpoints included GA scores during therapy, safety, quality of life, response and survival rates. Thirty-two patients were enrolled in the trial in six centers in Germany (out of 135 planned), resulting in termination due to low recruitment. Fifteen patients were allocated to nab-paclitaxel/gemcitabine, fifteen to gemcitabine, and two to best supportive care by their physicians, although according to their GA scores 29 patients (91%) were categorized as Slow-Go and three (9%) as Go-Go. Thus, fifteen of 32 (47%) patients were misclassified and given a course of treatment inconsistent with their GA scores. Median progression-free survival (PFS) were 3.3 months and 9.1 months and median time to quality-of-life deterioration 13 days and 29 days in the nab-paclitaxel/gemcitabine and gemcitabine monotherapy arms, respectively. Serious adverse events were reported in 11 (78.6%) patients in the nab-paclitaxel/gemcitabine and 8 (53.3%) patients in the gemcitabine arm. Clinical evaluations by investigators differed markedly from geriatric assessments, leading to potential overtreatment. In our modest sample size study, those patients undergoing more intensive therapy had a less favorable course. [ABSTRACT FROM AUTHOR]
Published: 2022
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6. The rs12532734 Polymorphism Near the Solute Carrier 26A3Gene Locus Is Associated With Gallstone Disease in Children

Author: Krawczyk, Marcin, Niewiadomska, Olga, Jankowska, Irena, Jankowski, Krzysztof, Świderska, Jolanta, Lebensztejn, Dariusz, Więcek, Sabina, Gozdowska, Jolanta, Kułaga, Zbigniew, Weber, Susanne N., Lammert, Frank, and Socha, Piotr
Abstract: Gallstones are increasingly frequent in children. In this candidate gene study, we genotyped 5 gene variants (ANO1, SPTLC3, TMEM147, TNRC6B, rs12532734) from a recent gallstone genome-wide association study (GWAS) in a cohort of 214 children with gallstones and 172 gallstone-free adult controls. In total, 138 genotyped children presented with symptomatic gallstone disease, 47 underwent cholecystectomy, and 126 received ursodeoxycholic acid (UDCA) as therapy for stones. Among 5 tested variants, the rs12532734 polymorphism modulated the gallstone risk in the studied cohort. Its genotype distribution significantly (P= 0.025) departed from the Hardy-Weinberg equilibrium among cases, and the common allele was associated with increased odds of developing gallstones at young age (OR = 1.69, P= 0.014). SLC26A3is the nearest gene to rs12532734 and is involved in the transepithelial bicarbonate and chloride transport. The association of rs12532734 with pediatric gallstones is a novel finding warranting further investigations also with regard to biliary bicarbonate flux and bile composition.
Published: 2022
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7. The rs12532734 Polymorphism Near the Solute Carrier 26A3Gene Locus Is Associated With Gallstone Disease in Children

Author: Krawczyk, Marcin, Niewiadomska, Olga, Jankowska, Irena, Jankowski, Krzysztof, Swiderska, Jolanta, Lebensztejn, Dariusz, Wiecek, Sabina, Gozdowska, Jolanta, Kulaga, Zbigniew, Weber, Susanne N., Lammert, Frank, and Socha, Piotr
Abstract: Gallstones are increasingly frequent in children. In this candidate gene study, we genotyped 5 gene variants (ANO1, SPTLC3, TMEM147, TNRC6B, rs12532734) from a recent gallstone genome-wide association study (GWAS) in a cohort of 214 children with gallstones and 172 gallstone-free adult controls. In total, 138 genotyped children presented with symptomatic gallstone disease, 47 underwent cholecystectomy, and 126 received ursodeoxycholic acid (UDCA) as therapy for stones. Among 5 tested variants, the rs12532734 polymorphism modulated the gallstone risk in the studied cohort. Its genotype distribution significantly (P= 0.025) departed from the Hardy-Weinberg equilibrium among cases, and the common allele was associated with increased odds of developing gallstones at young age (OR = 1.69, P= 0.014). SLC26A3is the nearest gene to rs12532734 and is involved in the transepithelial bicarbonate and chloride transport. The association of rs12532734 with pediatric gallstones is a novel finding warranting further investigations also with regard to biliary bicarbonate flux and bile composition.
Published: 2022
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8. Prognostic performance of the ‘DICA’ endoscopic classification and the ‘CODA’ score in predicting clinical outcomes of diverticular disease: an international, multicentre, prospective cohort study

Author: Tursi, Antonio, Brandimarte, Giovanni, Di Mario, Francesco, Elisei, Walter, Picchio, Marcello, Allegretta, Leonardo, Annunziata, Maria Laura, Bafutto, Mauro, Bassotti, Gabrio, Bianco, Maria Antonietta, Colucci, Raffaele, Conigliaro, Rita, Dumitrascu, Dan, Escalante, Ricardo, Ferrini, Luciano, Forti, Giacomo, Franceschi, Marilisa, Graziani, Maria Giovanna, Lammert, Frank, Latella, Giovanni, Maconi, Giovanni, Nardone, Gerardo, Camara de Castro Oliveira, Lucia, Chaves Oliveira, Enio, Papa, Alfredo, Papagrigoriadis, Savvas, Pietrzak, Anna, Pontone, Stefano, Poskus, Tomas, Pranzo, Giuseppe, Reichert, Matthias Christian, Rodinò, Stefano, Regula, Jaroslaw, Scaccianoce, Giuseppe, Scaldaferri, Franco, Vassallo, Roberto, Zampaletta, Costantino, Zullo, Angelo, Piovani, Daniele, Bonovas, Stefanos, and Danese, Silvio
Abstract: ObjectiveTo investigate the predictive value of the Diverticular Inflammation and Complication Assessment (DICA) classification and to develop and validate a combined endoscopic-clinical score predicting clinical outcomes of diverticulosis, named Combined Overview on Diverticular Assessment (CODA).DesignA multicentre, prospective, international cohort study.Setting43 gastroenterology and endoscopy centres located in Europe and South America.Participants2215 patients (2198 completing the study) at the first diagnosis of diverticulosis/diverticular disease were enrolled. Patients were scored according to DICA classifications.InterventionsA 3-year follow-up was performed.Main outcome measuresTo predict the acute diverticulitis and the surgery according to DICA classification. Survival methods for censored observation were used to develop and validate a novel combined endoscopic-clinical score for predicting diverticulitis and surgery (CODA score).ResultsThe 3-year cumulative probability of diverticulitis and surgery was of 3.3% (95% CI 2.5% to 4.5%) in DICA 1, 11.6% (95% CI 9.2% to 14.5%) in DICA 2 and 22.0% (95% CI 17.2% to 28.0%) in DICA 3 (p<0.001), and 0.15% (95% CI 0.04% to 0.59%) in DICA 1, 3.0% (95% CI 1.9% to 4.7%) in DICA 2 and 11.0% (95% CI 7.5% to 16.0%) in DICA 3 (p<0.001), respectively. The 3-year cumulative probability of diverticulitis and surgery was ≤4%, and ≤0.7% in CODA A; <10% and <2.5% in CODA B; >10% and >2.5% in CODA C, respectively. The CODA score showed optimal discrimination capacity in predicting the risk of surgery in the development (c-statistic: 0.829; 95% CI 0.811 to 0.846) and validation cohort (c-statistic: 0.943; 95% CI 0.905 to 0.981).ConclusionsDICA classification has a significant role in predicting the risk of diverticulitis and surgery in patients with diverticulosis, which is significantly enhanced by the CODA score.Trial registration numberNCT02758860.
Published: 2022
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9. Drug adherence and psychosocial characteristics of patients presenting with hypertensive urgency at the emergency department

Author: Lauder, Lucas, Ewen, Sebastian, Glasmacher, Julius, Lammert, Frank, Reith, Wolfgang, Schreiber, Naemi, Kaddu-Mulindwa, Dominic, Ukena, Christian, Böhm, Michael, Meyer, Markus R., and Mahfoud, Felix
Abstract: Supplemental Digital Content is available in the text
Published: 2021
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10. The Treatment of Gallstone Disease.

Author: Gutt, Carsten, Schläfer, Simon, and Lammert, Frank
Abstract: Background: Gallstone disease affects up to 20% of the European population, and cholelithiasis is the most common reason for hospitalization in gastroenterology. Methods: This review is based on pertinent publications retrieved by a selective search of the literature, including the German clinical practice guidelines on the diagnosis and treatment of gallstones and corresponding guidelines from abroad. Results: Regular physical activity and an appropriate diet are the most important measures for the prevention of gallstone disease. Transcutaneous ultrasonography is the paramount method of diagnosing gallstones. Endoscopic retrograde cholangiography should only be carried out as part of a planned therapeutic intervention; endosonography beforehand lessens the number of endoscopic retrograde cholangiographies that need to be performed. Cholecystectomy is indicated for patients with symptomatic gallstones or sludge. This should be performed laparoscopically with a four-trocar technique, if possible. Routine perioperative antibiotic prophylaxis is not necessary. Cholecystectomy can be performed in any trimester of pregnancy, if urgently indicated. Acute cholecystitis is an indication for early laparoscopic cholecystectomy within 24 hours of admission to hospital. After successful endoscopic clearance of the biliary pathway, patients who also have cholelithiasis should undergo laparoscopic cholecystectomy within 72 hours. Conclusion: The timing of treatment for gallstone disease is an essential determinant of therapeutic success. [ABSTRACT FROM AUTHOR]
Published: 2020
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11. Risk of chemotherapy-associated liver injury (CALI) in PNPLA3 p.148M allele carriers: Preliminary results of a transient elastography-based study.

Author: Casper, Markus, Zimmermann, Simone, Weber, Susanne N., Arslanow, Anita, Lammert, Frank, and Krawczyk, Marcin
Abstract: Liver steatosis is one of the side effects of chemotherapy. The PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 p.G17E variants represent genetic determinants for progressive liver diseases. Here, we investigate their association with chemotherapy-associated steatosis. Prospectively, we recruited 87 patients undergoing systemic chemotherapy for gastrointestinal cancers. Hepatic fat (controlled attenuation parameter, CAP) and liver stiffness (LSM) were measured non-invasively before the initiation of chemotherapy (T0) and after at least two (T1) and four cycles (T2). Genetic variants were genotyped using allelic discrimination assays. In the final dataset (n = 60) patients demonstrated the following CAP values: T0 – 215.0 ± 55.7 dB/m, T1 – 223.3 ± 53.6 dB/m, T2 – 223.4 ± 56.7 dB/m, consistent with mild steatosis. Initial CAP correlated with BMI (P < 0.01) and serum triglyceride concentrations (P = 0.03). Whereas at T0 none of the variants was associated with CAP or LSM, carriers of the prosteatotic PNPLA3 p.148M allele showed significantly (P = 0.008) higher steatosis at T1 as compared to patients carrying the homozygous wild-type genotype [II]. Our preliminary results show that patients carrying the PNPLA3 p.I148 M risk allele might be prone to hepatic fat accumulation during chemotherapy. Further studies are be needed to validate the clinical value of these findings. [ABSTRACT FROM AUTHOR]
Published: 2020
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12. Global multi-stakeholder endorsement of the MAFLD definition

Author: Méndez-Sánchez, Nahum, Bugianesi, Elisabetta, Gish, Robert G, Lammert, Frank, Tilg, Herbert, Nguyen, Mindie H, Sarin, Shiv K, Fabrellas, Núria, Zelber-Sagi, Shira, Fan, Jian-Gao, Shiha, Gamal, Targher, Giovanni, Zheng, Ming-Hua, Chan, Wah-Kheong, Vinker, Shlomo, Kawaguchi, Takumi, Castera, Laurent, Yilmaz, Yusuf, Korenjak, Marko, Spearman, C Wendy, Ungan, Mehmet, Palmer, Melissa, El-Shabrawi, Mortada, Gruss, Hans-Juergen, Dufour, Jean-François, Dhawan, Anil, Wedemeyer, Heiner, George, Jacob, Valenti, Luca, Fouad, Yasser, Romero‐Gomez, Manuel, Eslam, Mohammed, Abate, Maria Lorena, Abbas, Bahaa, Abbassy, Ahmed Amr, Abd El Ghany, Waleed, Abd Elkhalek, Amira, Abd ElMajeed, Emad, Abdalgaber, Mohammad, AbdAllah, Mohamed, Abdallah, Marwa, Abdallah, Nourhan, Abdelaleem, Shereen, Abdelghani, Yasser, Abdelghany, Wael, Abdelhalim, Safaa Mohamed, Abdelhamid, Wafaa, Abdelhamid, Nehal, Abdelkader, Nadia A., Abdelkreem, Elsayed, Abdelmohsen, Aly Mohamed, Abdelrahman, Awny Ali, Abd-elsalam, Sherief M, Abdeltawab, Doaa, Abduh, Abdulbaset, Abdulhakam, Nada, Abdulla, Maheeba, Abedpoor, Navid, Abenavoli, Ludovico, Åberg, Fredrik, Ablack, Omala, Abo elftouh, Mostafa, Abo-Amer, Yousry Esam-Eldin, Aboubkr, Ashraf, Aboud, Alaa, Abouelnaga, Amr M., Aboufarrag, Galal A., Aboutaleb, Ashraf, Abundis, Leticia, Adalı, Gupse, Adames, Enrique, Adams, Leon, Adda, Danjuma, Adel, Noor, Adel, Nada, Adel Sayed, Muhammad, Afaa, Taiba Jibril, Afredj, Nawal, Aghayeva, Gulnara, Aghemo, Alessio, Aguilar-Salinas, Carlos A., Ahlenstiel, Golo, Ahmady, Walid, Ahmed, Wafaa, Ahmed, Amira, Ahmed, Samah Nasser, Ahmed, Heba Mostafa, Ahmed, Rasha, Aigner, Elmar, Akarsu, Mesut, Akroush, Maisam, Akyuz, Umit, Al Mahtab, Mamun, Al Qadiri, Tahani, Al Rawahi, Yusriya, AL rubaee, Razzaq, Al Saffar, Muna, Alam, Shahinul, Al-Ani, Zaid, Albillos, Agustín, Alboraie, Mohamed, Al-Busafi, Said, Al-Emam, Mohamed, Alharthi, Jawaher, Ali, Kareem, Ali, Basma Abdelmoez, Ali, Mohammad, Ali, Raja Affendi Raja, Alisi, Anna, AL-Khafaji, Ali Raad, Alkhatry, Maryam, Aller, Rocio, Almansoury, Yahya, Al-Naamani, Khalid, Alnakeeb, Alaa, Alonso, Anna, Alqahtani, Saleh A., Alrabadi, Leina, Alswat, Khalid, Altaher, Mahir, Altamimi, Turki, Altamirano, Jose, Alvares-da-Silva, Mario R., Aly, Elsragy Adel M., Alzahaby, Amgad, Alzamzamy, Ahmed, Amano, Keisuke, Amer, Maysa A., Amin, Mona A., Amin, Sayed A., Amir, Ashraf A., Ampuero, Javier, Anas, Noha, Andreone, Pietro, Andriamandimby, Soa Fy, Anees, Mahmoud, Angela, Peltec, Antonios, Manal, Arafat, Wael, Araya, Jose Moreno, Armendariz-Borunda, Juan, Armstrong, Matthew J., Ashktorab, Hassan, Aspichueta, Patricia, Assal, Fathia, Atef, Mira, Attia, Dina, Atwa, Hoda, Awad, Reham, Awad, Mohyeldeen Abd Elaziz, Awny, Sally, Awolowo, Obafemi, Awuku, Yaw Asante, Ayada, Ibrahim, Aye, Than Than, Ayman, Sherif, Ayman, Hedy, Ayoub, Hesham, Azmy, Hosny M., Babaran, Romiro P., Badreldin, Omneya, Badry, Ahmed, Bahçecioğlu, İbrahim Halil, Bahour, Amira, Bai, Jiajia, Balaban, Yasemin, 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Marchesini, Giulio, Marcus, Claude, Marinho, Rui António Rocha Tato, Martinez-Chantar, Maria L, Martins, Antonieta A. Soares, Marwan, Rana, Mason, Karen Frances, Masoud, Ghadeer, Massoud, Mohamed Naguib, Matamoros, Maria Amalia, Mateos, Rosa Martín, Mawed, Asmaa, Mbanya, Jean Claude, Mbendi, Charles, McColaugh, Lone, McLeod, Duncan, Medina, Juan Francisco Rivera, Megahed, Ahmed, Mehrez, Mai, Memon, Iqbal, Merat, Shahin, Mercado, Randy, Mesbah, Ahmed, Meskini, Taoufik, Metwally, Mayada, Metwaly, Rasha, Miao, Lei, Micah, Eileen, Miele, Luca, Milivojevic, Vladimir, Milovanovic, Tamara, Mina, Yvonne L., Mishkovik, Milan, Mishriki, Amal, Mitchell, Tim, Mohamed, Alshaimaa, Mohamed, Mona, Mohamed, Sofain, Mohammed, Shady, Mohammed, Ahmed, Mohan, Viswanathan, Mohie, Sara, Mokhtar, Aalaa, Moniem, Reham, Montilla, Mabel Segura, Morales, Jose Antonio Orozco, Morata, María María Sánchez, Moreno-Planas, Jose Maria, Morise, Silvia, Mosaad, Sherif, Moselhy, Mohamed, Mostafa, Alaa Mohamed, Mostafa, Ebraheem, Mouane, Nezha, Mousa, Nasser, Moustafa, Hamdy Mahfouz, Msherif, Abeer, Muller, Kate, Munoz, Christopher, Muñoz-Urribarri, Ana Beatriz, Murillo, Omar Alfaro, Mustapha, Feisul Idzwan, Muzurović, Emir, Nabil, Yehia, Nafady, Shaymaa, Nagamatsu, Ayu, Nakajima, Atsushi, Nakano, Dan, Nan, Yuemin, Nascimbeni, Fabio, Naseef, Mirella S., Nashat, Nagwa, Natalia, Taran, Negro, Francesco, Nersesov, Alexander V., Neuman, Manuela, Ng'wanasayi, Masolwa, Ni, Yan, Nicoll, Amanda, Niizeki, Takashi, Nikolova, Dafina, Ningning, Wang, Niriella, Madunil, Nogoibaeva, K.A, Nordien, Rozeena, O Sullivan, Catherine, O'Beirne, James, Obekpa, Solomon, Ocama, Ponsiano, Ochwoto, Missiani, Ogolodom, Michael Promise, Ojo, Olusegun, Okrostsvaridze, Nana, Oliveira, Claudia P., Omaña, Raul Contreras, Omar, Omneya M., Omar, Hanaa, Omar, Mabroka, Omran, Salma, Omran, Reham, Osman, Marian Muse, Owise, Nevin, Owusu-Ansah, Theobald, Padilla- Machaca, P. 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Pablo, Robles, Jorge Alberto Prado, Rockey, Don, Rodríguez, Manuel, Rodríguez Hernández, Heriberto, Román, Eva, Romeiro, Fernando Gomes, Romeo, Stefano, Rosales-Zabal, Jose Miguel, Roshdi, Georgina R., Rosso, Natalia, Ruf, Andres, Ruiz, Patricia Cordero, Runes, Nelia R., Ruzzenente, Andrea, Ryan, Marno, Saad, Ahmed, Sabbagh, Eman BE, Sabbah, Meriam, Saber, Shimaa, Sabrey, Reham, Sabry, Ramy, Saeed, Maysaa Abdallah, Said, Dina, Said, Ebada M, Sakr, Mohammad Amin, Salah, Yara, Salama, Rabab Maamoun, Salama, Asmaa, Saleh, Hussein, Saleh, Ahmed, Salem, Ahmed, Salem, Ahmed Thabet, Salifou, Alkassoum, Salih, Aso Faeq, Salman, Abdallah, Samouda, Hanen, Sanai, Faisal, Sánchez-Ávila, Juan Francisco, Sanker, Lakshumanan, Sano, Tomoya, Sanz, Miquel, Saparbu, Tobokalova, Sawhney, Rohit, Sayed, Fatma, Sayed, Sayed A., Sayed, Ashraf Othman, Sayed, Manar, Sebastiani, Giada, Secadas, Laura, Sediqi, Khawaja Qamaruddin, Seif, Sameh, Semida, Nady, Şenateş, Ebubekir, Serban, Elena Daniela, Serfaty, 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Mohammed, Xia, Hongping, Xiao, Jian, Xiao, Xiao, Xiaofeng, Wang, Xiong, Wanyuan, Xu, Liang, Xu, Jie, Xu, Weiguo, Xu, Jing-Hang, Xu, Keshu, Xu, Yumin, Xu, Shi-Hao, Xu, Meng, Xu, Aimin, Xu, Chengfu, Yan, Hongmei, Yang, Jingyi, Yang, Rui-Xu, Yang, Yating, Yang, Qinhe, Yang, Naibin, Yao, Jia, Yara, Justine, Yaraş, Serkan, Yılmaz, Nimet, Younes, Ramy, younes, Huda, Young, Sona, Youssef, Farah, Yu, Yanyan, Yu, Ming-Lung, Yuan, Jing, Yue, Zhang, Yuen, Man-Fung, Yun, Wang, Yurukova, Nonka, Zakaria, Serag, Zaky, Samy, Zaldastanishvili, Maia, Zapata, Rodrigo, Zare, Nazanin, Zerem, Enver, Zeriban, Nema, Zeshuai, Xu, Zhang, Huijie, Zhang, Xuemei, Zhang, Yupei, Zhang, Wen-Hua, Zhang, Xuchen, Zhang, Yon-ping, Zhang, Yuexin, Zhang, Zhan-qing, Zhao, Jingmin, Zhao, Rong-Rong, Zhao, Hongwei, Zheng, Chao, Zheng, Yijie, Zheng, Ruidan, Zheng, Tian-Lei, Zheng, Kenneth, Zhou, Xi Qiao, Zhou, Yongjian, Zhou, Yu-Jie, Zhou, Hong, Zhou, Ling, Zhou, Yongning, Zhu, Long dong, Zhu, Yong Fen, Zhu, Yueyong, Zhu, Pei-Wu, Ziada, Ebtesam, Ziring, David, Ziyi, Li, Zou, Shanshan, Zou, Zhengsheng, Zou, Huaibin, and Zuart Ruiz, Roberto
Published: 2022
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13. Excess Body Weight and Gallstone Disease

Author: Stokes, Caroline Sarah and Lammert, Frank
Abstract: 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.
Published: 2021
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14. SEC62and SEC63Expression in Hepatocellular Carcinoma and Tumor-Surrounding Liver Tissue

Author: Casper, Markus, Linxweiler, Maximilian, Linxweiler, Johannes, Zimmermann, Richard, Glanemann, Matthias, Lammert, Frank, and Weber, Susanne N.
Abstract: Introduction:The endoplasmic reticulum transmembrane proteins Sec61, Sec62, and Sec63 are responsible for the intracellular trafficking of precursor proteins and affect intracellular signaling. SEC62overexpression has been linked to various human cancers. Our aim was to investigate SEC62and SEC63expression 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 SEC62und SEC63mRNA expression using quantitative real-time PCR. For Sec62, immunohistochemistry was performed. Results:SEC62andSEC63total mRNA contents were significantly (p= 0.001) higher in HCCs (CT 22.5 ± 0.4 and 22.6 ± 0.3) when compared to the surrounding tissue (CT 24.6 ± 0.6 and 25.1 ± 0.9). Using the comparative CTmethod, SEC62and SEC63expression 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 (p= 0.027). The mean IRS in HCC were 5.7 ± 3.5 and 8.9 ± 2.3 for patients without (n= 3) and with tumor recurrence (n= 8), respectively. Conclusions:Overexpression of SEC62and SEC63is 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.
Published: 2021
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15. European Guideline on IgG4-related digestive disease – UEG and SGF evidence-based recommendations

Author: Löhr, J-Matthias, Beuers, Ulrich, Vujasinovic, Miroslav, Alvaro, Domenico, Frøkjær, Jens Brøndum, Buttgereit, Frank, Capurso, Gabriele, Culver, Emma L, de-Madaria, Enrique, Della-Torre, Emanuel, Detlefsen, Sönke, Dominguez-Muñoz, Enrique, Czubkowski, Piotr, Ewald, Nils, Frulloni, Luca, Gubergrits, Natalya, Duman, Deniz Guney, Hackert, Thilo, Iglesias-Garcia, Julio, Kartalis, Nikolaos, Laghi, Andrea, Lammert, Frank, Lindgren, Fredrik, Okhlobystin, Alexey, Oracz, Grzegorz, Parniczky, Andrea, Mucelli, Raffaella Maria Pozzi, Rebours, Vinciane, Rosendahl, Jonas, Schleinitz, Nicolas, Schneider, Alexander, van Bommel, Eric FH, Verbeke, Caroline Sophie, Vullierme, Marie Pierre, and Witt, Heiko
Abstract: The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6–0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2–4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.
Published: 2020
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16. European Guideline on IgG4-related digestive disease – UEG and SGF evidence-based recommendations

Author: Löhr, J-Matthias, Beuers, Ulrich, Vujasinovic, Miroslav, Alvaro, Domenico, Frøkjær, Jens Brøndum, Buttgereit, Frank, Capurso, Gabriele, Culver, Emma L, de-Madaria, Enrique, Della-Torre, Emanuel, Detlefsen, Sönke, Dominguez-Muñoz, Enrique, Czubkowski, Piotr, Ewald, Nils, Frulloni, Luca, Gubergrits, Natalya, Duman, Deniz Guney, Hackert, Thilo, Iglesias-Garcia, Julio, Kartalis, Nikolaos, Laghi, Andrea, Lammert, Frank, Lindgren, Fredrik, Okhlobystin, Alexey, Oracz, Grzegorz, Parniczky, Andrea, Mucelli, Raffaella Maria Pozzi, Rebours, Vinciane, Rosendahl, Jonas, Schleinitz, Nicolas, Schneider, Alexander, Bommel, Eric FH, Verbeke, Caroline Sophie, Vullierme, Marie Pierre, and Witt, Heiko
Abstract: The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6–0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2–4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.
Published: 2020
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17. miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease.

Author: Fernández-Tussy, Pablo, Fernández-Ramos, David, Lopitz-Otsoa, Fernando, Simón, Jorge, Barbier-Torres, Lucía, Gomez-Santos, Beatriz, Nuñez-Garcia, Maitane, Azkargorta, Mikel, Gutiérrez-de Juan, Virginia, Serrano-Macia, Marina, Rodríguez-Agudo, Rubén, Iruzubieta, Paula, Anguita, Juan, Castro, Rui E., Champagne, Devin, Rincón, Mercedes, Elortza, Felix, Arslanow, Anita, Krawczyk, Marcin, and Lammert, Frank
Abstract: Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolic pathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation and fibrosis. The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, is downregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression. miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Different in vitro and in vivo NAFLD murine models were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy. We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria. In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondrial functionality in a preclinical murine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating with hepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation and fibrosis by enhancing fatty acid β-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment. GNMT participates in the regulation of metabolic pathways and mitochondrial functionality through the regulation of Complex II activity in the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment. Image 1 • The microRNA miR-873-5p is upregulated in human and murine NAFLD/NASH livers. • miR-873-5p upregulation downregulates GNMT in the liver. • miR-873-5p inhibition reduces liver steatosis, inflammation and fibrosis in in vivo NAFLD mouse models. • GNMT is a hepatic metabolic hub with mitochondria activity through the regulation of Complex II of the ETC. • Mitochondrial GNMT deficiency compromises ETC functionality and metabolism. [ABSTRACT FROM AUTHOR]
Published: 2019
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18. Screening for fibrosis to diagnose liver diseases early: the LIVERSCREEN project

Author: Ginès, Pere, Thiele, Maja, Graupera, Isabel, Serra-Burriel, Miquel, de Knegt, Robert J., Lammert, Frank, Castera, Laurent, Korenjak, Marko, Kamath, Patrick S., Grgurević, Ivica, Piano, Salvatore, Fabrellas, Núria, Arslanow, Anita, and Krag, Aleksander
Published: 2023
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19. Non-Alcoholic Fatty Liver Disease in Non-Obese Individuals: Prevalence, Pathogenesis and Treatment

Author: Molina-Molina, Emilio, Krawczyk, Marcin, Stachowska, Ewa, Lammert, Frank, and Portincasa, Piero
Abstract: Non-alcoholic fatty liver disease (NAFLD) parallels comorbidities such as metabolic syndrome, dyslipidaemia or diabetes. Although NAFLD is very prevalent in overweight-obese individuals (i.e. body mass index ≥25 kg/m2), recent studies point to the presence of NAFLD in non-obese individuals, for both the Asian (<25 kg/m2) and Caucasian (<30 kg/m2) populations. This paper discusses the pathogenic pathways and current treatment options of NAFLD in non-obese populations. In this respect, non-obese subjects also need to undergo the medical screening for NAFLD. Across the scientific community, we aim to promote the advancement of knowledge in this emerging field.
Published: 2019
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20. SOP Aszitespunktion – Diagnostik, Indikation und Durchführung

Author: Appenrodt, Beate and Lammert, Frank
Published: 2019
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21. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial

Author: Traussnigg, Stefan, Schattenberg, Jörn M, Demir, Münevver, Wiegand, Johannes, Geier, Andreas, Teuber, Gerlinde, Hofmann, Wolf Peter, Kremer, Andreas E, Spreda, Frank, Kluwe, Johannes, Petersen, Jörg, Boettler, Tobias, Rainer, Florian, Halilbasic, Emina, Greinwald, Roland, Pröls, Markus, Manns, Michael P, Fickert, Peter, Trauner, Michael, Vogel, Wolfgang, Aigner, Elmar, Datz, Christian, Tilg, Herbert, Gerken, Guido, Rust, Christian, Cordes, Hans-Jörg, Steib, Christian, Pathil-Warth, Anita, Prinz, Christian, Lammert, Frank, Antoni, Christoph, Klausmann, Gerhard, Häussinger, Dieter, and Zipprich, Alexander
Abstract: Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease.
Published: 2019
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22. Neuroendokrine Neoplasien im deutschen NET-Register

Author: Maasberg, Sebastian, Pape, Ulrich-Frank, Fottner, Christian, Goretzki, Peter E., Anlauf, Martin, Hörsch, Dieter, Cremer, Birgit, Schulte, Dominik M., Quietzsch, Detlef, Scheerer, Frank, Pöpperl, Gabriele, Poeppel, Thorsten D., Begum, Nehara, Grohé, Christian, Rinke, Anja, Plöckinger, Ursula, Wiedenmann, Betram, Arnold, Rudolf, Neuhaus, Peter, Knapp, Wolfram H., Lehnert, Hendrick, Auernhammer, Christoph, Pavel, Marianne, Weikersthal, Ludwig Fischer von, Schmidt, Bernd, Klein, Harald H., Essler, Markus, Neumann, Jörg-Dietrich, Hamann, Susanne, Steffens, Frank, Demtröder, Frank, Kröcher, Anke, Zoicas, Flavius, Lahner, Harald, Weber, Frank, Geißler, Michael, Raffel, Andreas, Krausch, Markus, Zimmermann, Patrick, Lerch, Markus M., Wirth, Thomas, Lang, Matthias, Ezziddin, Samer, Lammert, Frank, Bischoff, Marina, Altendorf-Hofmann, Annelore, Müller, Lothar, Hoffmeister, Albrecht, Klose, Silke, Musholt, Thomas J., Post, Stefan, Gertler, Ralf, Scheuerlein, Hubert, Bergmann, Tanja, Bisping, Guido, Knauerhase, Andreas, Rendenbach, Bernhard, Groß, Volker, Scheurlen, Michael, Mönig, Heiner, Kudlich, Theodor, Grabowski, Patricia, Musholt, Thomas J., Watza, Felix, Scheidhauer, Klemens, and Möbius, Elke
Published: 2019
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23. Short-term Dietary Interventions for the Management of Nonalcoholic Fatty Liver

Author: Stokes, Caroline S., Lammert, Frank, and Krawczyk, Marcin
Abstract: Background: Non-alcoholic fatty liver disease (NAFLD) affects millions of individuals on a global scale and currently no gold standard treatment exists. The risk of developing NAFLD is considerably higher with increasing body mass index. Consequently, weight loss should be recommended to all overweight patients with fatty liver. However, lifestyle interventions, irrespective of weight status, may also influence the condition. The aim herein is to present examples of short-term interventions which assess direct effects of dietary-related components on hepatic steatosis. Methods: This review includes studies with short-term dietary-related interventions of up to 16 weeks that evaluate their efficacy in reducing intrahepatic lipid contents (hepatic steatosis). This review primarily focuses on the three main macronutrients: dietary carbohydrates, fats and proteins. Results: High saturated fat intake and high consumption of carbohydrates, particularly from simple sugars such as fructose are reported as risk factors for hepatic steatosis. Overall, shortterm hypocaloric diets have shown beneficial effects in reducing intrahepatic lipid contents. Macronutrient manipulations such as carbohydrate restriction as well as the consumption of unsaturated fatty acids are also reported to have efficacious effects. Conclusion: This review highlights the different dietary interventions that can influence hepatic steatosis in the short term, illustrating both pro and anti-steatotic effects.
Published: 2019
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24. Medicinal Diets: From Molecules to Nutrients to Foods: Basic and Clinical Implications

Author: Portincasa, Piero, De Angelis, Maria, Lammert, Frank, and Stokes, Caroline S.
Published: 2019
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25. The Role of Diet in the Pathogenesis of Cholesterol Gallstones

Author: Di Ciaula, Agostino, Garruti, Gabriella, Frühbeck, Gema, De Angelis, Maria, de Bari, Ornella, Wang, David Q.-H., Lammert, Frank, and Portincasa, Piero
Abstract: Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans. There is a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation.
Published: 2019
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26. Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Author: Schafmayer, Clemens, Harrison, James William, Buch, Stephan, Lange, Christina, Reichert, Matthias C, Hofer, Philipp, Cossais, Francois, Kupcinskas, Juozas, von Scho¨nfels, Witigo, Schniewind, Bodo, Kruis, Wolfgang, Tepel, Ju¨rgen, Zobel, Myrko, Rosendahl, Jonas, Jacobi, Thorsten, Walther-Berends, Andreas, Schroeder, Michael, Vogel, Ilka, Sergeev, Petr, Boedeker, Hans, Hinrichsen, Holger, Volk, Andreas, Erk, Jens-Uwe, Burmeister, Greta, Hendricks, Alexander, Hinz, Sebastian, Wolff, Sebastian, Bo¨ttner, Martina, Wood, Andrew R, Tyrrell, Jessica, Beaumont, Robin N, Langheinrich, Melanie, Kucharzik, Torsten, Brezina, Stefanie, Huber-Scho¨nauer, Ursula, Pietsch, Leonora, Noack, Laura Sophie, Brosch, Mario, Herrmann, Alexander, Thangapandi, Raghavan Veera, Schimming, Hans Wolfgang, Zeissig, Sebastian, Palm, Stefan, Focke, Gerd, Andreasson, Anna, Schmidt, Peter T, Weitz, Juergen, Krawczak, Michael, Vo¨lzke, Henry, Leeb, Gernot, Michl, Patrick, Lieb, Wolfgang, Gru¨tzmann, Robert, Franke, Andre, Lammert, Frank, Becker, Thomas, Kupcinskas, Limas, D’Amato, Mauro, Wedel, Thilo, Datz, Christian, Gsur, Andrea, Weedon, Michael N, and Hampe, Jochen
Abstract: ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1with a p value of 2.3×10−10and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1(OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2(OR 1.21, 95% CI 1.04 to 1.42), CALCB(OR 1.17, 95% CI 1.03 to 1.33) and S100A10(OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
Published: 2019
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27. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Author: Strnad, Pavel, Buch, Stephan, Hamesch, Karim, Fischer, Janett, Rosendahl, Jonas, Schmelz, Renate, Brueckner, Stefan, Brosch, Mario, Heimes, Carolin V, Woditsch, Vivien, Scholten, David, Nischalke, Hans Dieter, Janciauskiene, Sabina, Mandorfer, Mattias, Trauner, Michael, Way, Michael J, McQuillin, Andrew, Reichert, Matthias C, Krawczyk, Marcin, Casper, Markus, Lammert, Frank, Braun, Felix, von Scho¨nfels, Witigo, Hinz, Sebastian, Burmeister, Greta, Hellerbrand, Claus, Teufel, Andreas, Feldman, Alexandra, Schattenberg, Joern M, Bantel, Heike, Pathil, Anita, Demir, Muenevver, Kluwe, Johannes, Boettler, Tobias, Ridinger, Monika, Wodarz, Norbert, Soyka, Michael, Rietschel, Marcella, Kiefer, Falk, Weber, Thomas, Marhenke, Silke, Vogel, Arndt, Hinrichsen, Holger, Canbay, Ali, Schlattjan, Martin, Sosnowsky, Katharina, Sarrazin, Christoph, von Felden, Johann, Geier, Andreas, Deltenre, Pierre, Sipos, Bence, Schafmayer, Clemens, Nothnagel, Michael, Aigner, Elmar, Datz, Christian, Stickel, Felix, Morgan, Marsha Yvonne, Hampe, Jochen, Berg, Thomas, and Trautwein, Christian
Abstract: ObjectiveHomozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.DesignWe analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.ResultsThe Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).ConclusionThe Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
Published: 2019
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28. Preservation of hormonal function by identifying pituitary gland at endoscopic surgery.

Author: Linsler, Stefan, Hero-Gross, Renate, Friesenhahn-Ochs, Bettina, Sharif, Salman, Lammert, Frank, and Oertel, Joachim
Abstract: Objective The endonasal endoscopic approach has been established for perisellar tumor surgery with a higher resection rate and reduced complications. We analyzed the potential to identify the pituitary gland under endoscopic view, at surgery and see its relation to postoperative hormonal insufficiency in endonasal endoscopic procedures. Methods Between January 2011 and January 2014, 70 cases of pituitary adenomas with preoperative intact pituitary function underwent endoscopic endonasal transsphenoidal procedures for intrasellar pathologies. Endocrinologists and neurosurgeons followed these patients prospectively. Special attention was paid to intraoperative identification of gland tissue, surgical complications, degree of resection and postoperative hormonal insufficiency. Results The pituitary gland was identified in 57 out of 70 procedures (81.4%). Eleven percent (8 of 70 patients) had persistent pituitary insufficiency. Two of these 8 patients belonged to the group with pituitary gland identification (2 out of 57); thus, when the pituitary gland was identified during the procedure postoperative hormonal insufficiency was seen in 3.5% of cases. Failure of pituitary gland identification presented with hormonal insufficiency of 46.2%. In analysis with Fisher’s exact test, there was a high significant correlation between the identification of the pituitary gland intraoperatively and normal pituitary function postoperatively (p < 0.005). On follow up radical tumor resection was seen in 88% (62 of 70 patients). Conclusions This study indicates that identification and preservation of pituitary gland tissue and function is possible in endoscopic transsphenoidal surgery. This preservation of gland tissue is a positive predictor of postoperative normal pituitary function. [ABSTRACT FROM AUTHOR]
Published: 2017
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29. PNPLA3 p.I148M variant is associated with greater reduction of liver fat content after bariatric surgery.

Author: Krawczyk, Marcin, Jiménez-Agüero, Raúl, Alustiza, José M., Emparanza, José I., Perugorria, María J., Bujanda, Luis, Lammert, Frank, and Banales, Jesús M.
Abstract: Background Obesity is the major trigger of nonalcoholic fatty liver disease (NAFLD). NAFLD is further favored by the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, transmembrane 6 superfamily member 2 (TM6SF2) p.E167K, and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 variants. Objectives To investigate the relationship between the PNPLA3, TM6SF2, and MBOAT7 genotypes and the outcomes of bariatric surgery. Setting University hospital. Methods Prospectively we monitored 84 obese individuals (body mass index 35–64 kg/m 2 ) scheduled for bariatric surgery. The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants were genotyped using restriction fragment length polymorphism analysis and TaqMan assays. Hepatic steatosis was determined before surgery using analysis of liver biopsy samples and a novel magnetic resonance imaging–based equation. One year later, steatosis was reevaluated by magnetic resonance imaging. Results The presence of the PNPLA3 allle [M] was associated with increased hepatic triglyceride content ( P = .03), steatosis detected by magnetic resonance imaging ( P = 0.04), and decreased serum glucose concentrations ( P = .04). Neither variant TM6SF2 nor MBOAT7 increased hepatic steatosis (all P >.05); however, the MBOAT7 polymorphism was associated with increased triglyceride, total cholesterol, low density lipoprotein, and serum glucose levels (all P <.05). Patients carrying the prosteatotic PNPLA3 allele [M] lost more weight ( P <.01) and liver fat ( P = .04) one year after surgery, as compared to individuals having the common genotype. The PNPLA3 genotype and initial grade of steatosis, but not the TM6SF2 or MBOAT7 variants, were independent predictors of NAFLD improvement ( P = .03 and P <.01, respectively). Conclusion In obese patients, the presence of the PNPLA3 p.I148M allele might be associated with greater improvement of hepatic steatosis after bariatric surgery in comparison to carriers of PNPLA3 wild-type alleles. [ABSTRACT FROM AUTHOR]
Published: 2016
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30. Acute Pancreatitis in the Setting of Hepatitis E Virus (Genotype 3) Infection and Compound CLDN2-PRSS1Risk Variants

Author: Lehmann, Johannes, Muresan, Simina, Weber, Susanne N., Lammert, Frank, and Krawczyk, Marcin
Published: 2020
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31. Deep-learning based detection of gastric precancerous conditions

Author: Guimarães, Pedro, Keller, Andreas, Fehlmann, Tobias, Lammert, Frank, and Casper, Markus
Published: 2020
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32. Cytokine‐mediated modulation of the hepatic miRNome: miR‐146b‐5p is an IL‐6‐inducible miRNA with multiple targets

Author: Kirchmeyer, Mélanie, Servais, Florence A., Hamdorf, Matthias, Nazarov, Petr V., Ginolhac, Aurélien, Halder, Rashi, Vallar, Laurent, Glanemann, Matthias, Rubie, Claudia, Lammert, Frank, Kreis, Stephanie, and Behrmann, Iris
Abstract: Interleukin‐6 (IL‐6)‐type cytokines play important roles in liver (patho‐)biology. For instance, they regulate the acute phase response to inflammatory signals and are involved in hepatocarcinogenesis. Much is known about the regulation of protein‐coding genes by cytokines whereas their effects on the miRNome is less well understood. We performed a microarray screen to identify microRNAs (miRNAs) in human hepatocytes which are modulated by IL‐6‐type cytokines. Using samples of 2 donors, 27 and 68 miRNAs (out of 1,733) were found to be differentially expressed upon stimulation with hyper‐IL‐6 (HIL‐6) for up to 72 h, with an overlap of 15 commonly regulated miRNAs. qPCR validation revealed that miR‐146b‐5p was also consistently up‐regulated in hepatocytes derived from 2 other donors. Interestingly, miR‐146b‐5p (but not miR‐146a‐5p) was induced by IL‐6‐type cytokines (HIL‐6 and OSM) in non‐transformed liver‐derived PH5CH8 and THLE2 cells and in Huh‐7 hepatoma cells, but not in HepG2 or Hep3B hepatoma cells. We did not find evidence for a differential regulation of miR‐146b‐5p expression by promoter methylation, also when analyzing the TCGA data set on liver cancer samples. Inducible overexpression of miR‐146b‐5p in PH5CH8 cells followed by RNA‐Seq analysis revealed effects on multiple mRNAs, including those encoding IRAK1 and TRAF6 crucial for Toll‐like receptor signaling. Indeed, LPS‐mediated signaling was attenuated upon overexpression of miR‐146b‐5p, suggesting a regulatory loop to modulate inflammatory signaling in hepatocytes. Further validation experiments suggest DNAJC6, MAGEE1, MPHOSPH6, PPP2R1B, SLC10A3, SNRNP27, and TIMM17B to be novel targets for miR‐146b‐5p (and miR‐146a‐5p). IL‐6‐type cytokines up‐regulate miR‐146b‐5p expression in liver cells, an anti‐inflammatory miRNA with multiple targets shared with miR‐146a‐5p.
Published: 2018
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33. Renal Failure in Patients with Liver Cirrhosis: Novel Classifications, Biomarkers, Treatment

Author: Appenrodt, Beate and Lammert, Frank
Published: 2018
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34. Could inherited predisposition drive non-obese fatty liver disease? Results from German tertiary referral centers

Author: Krawczyk, Marcin, Bantel, Heike, Rau, Monika, Schattenberg, Jörn M., Grünhage, Frank, Pathil, Anita, Demir, Münevver, Kluwe, Johannes, Boettler, Tobias, Weber, Susanne N., Geier, Andreas, and Lammert, Frank
Abstract: Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3p.I148M, TM6SF2p.E167K and MBOAT7rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20–72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2and MBOAT7polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n= 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3p.I148M allele (74.6%), but not of the TM6SF2or MBOAT7polymorphisms, was significantly (P< 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P< 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P< 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3mutation was absent. The MBOAT7polymorphism was more frequent (P= 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.
Published: 2018
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35. Complement C5a receptors C5L2 and C5aR in renal fibrosis

Author: Martin, Ina V., Bohner, Annika, Boor, Peter, Shagdarsuren, Erdenechimeg, Raffetseder, Ute, Lammert, Frank, Floege, Jürgen, Ostendorf, Tammo, and Weber, Susanne N.
Abstract: Complement factor C5a has two known receptors, C5aR, which mediates proinflammatory effects, and C5L2, a potential C5a decoy receptor. We previously identified C5a/C5aR signaling as a potent profibrotic pathway in the kidney. Here we tested for the first time the role of C5L2 in renal fibrosis. In unilateral ureteral obstruction (UUO)-induced kidney fibrosis, the expression of C5aR and C5L2 increased similarly and gradually as fibrosis progressed and was particularly prominent in injured dilated tubules. Genetic deficiency of either C5aR or C5L2 significantly reduced UUO-induced tubular injury. Expression of key proinflammatory mediators, however, significantly increased in C5L2- compared with C5aR-deficient mice, but this had no effect on the number of renal infiltrating macrophages or T cells. Moreover, in C5L2−/−mice, the cytokine and matrix metalloproteinase-inhibitor tissue inhibitor of matrix metalloproteinase-1 was specifically enhanced. Consequently, in C5L2−/−mice the degree of renal fibrosis was similar to wild type (WT), albeit with reduced mRNA expression of some fibrosis-related genes. In contrast, C5aR−/−mice had significantly reduced renal fibrosis compared with WT and C5L2−/−mice in UUO. In vitro experiments with primary tubular cells demonstrated that deficiency for either C5aR or C5L2 led to a significantly reduced expression of tubular injury and fibrosis markers. Vice versa, stimulation of WT tubular cells with C5a significantly induced the expression of these markers, whereas the absence of either receptor abolished this induction. In conclusion, in experimental renal fibrosis C5L2 and C5aR both contribute to tubular injury, and, while C5aR acts profibrotic, C5L2 does not play a role in extracellular matrix accumulation, arguing against C5L2 functioning simply as a decoy receptor.
Published: 2018
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36. Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease.

Author: Stokes, Caroline S., Grünhage, Frank, Baus, Crystal, Volmer, Dietrich A., Wagenpfeil, Stefan, Riemenschneider, Matthias, and Lammert, Frank
Abstract: Summary Background and aims Vitamin D deficiency and depression frequently occur in patients with chronic liver diseases (CLD). Depression has recently been inversely associated with vitamin D in a meta-analysis, and vitamin D receptor is expressed in brain. This pilot study investigates whether vitamin D replacement ameliorates depressive symptoms in CLD patients and consists of a cross-sectional and an interventional analysis. Methods Overall, 111 patients with CLD were included in the cross-sectional analysis. The Beck Depression Inventory II (BDI-II) was used to assess depression. Chemiluminescence immunoassay and LC-MS/MS quantified serum 25-hydroxyvitamin D levels. For the interventional analysis, 77 patients with inadequate vitamin D concentrations received 20,000 IU vitamin D per week for six months. The final follow-up was carried out six months post supplementation. Results In the cross-sectional analysis, 81% of patients (median age 55 years, 47% women) had inadequate baseline vitamin D levels (<30 ng/ml), and 31% presented with depressive symptoms (BDI-II score ≥14). Depression severity correlated inversely with vitamin D level in depressed patients (β = −0.483, P = 0.004). Depression scores improved significantly from baseline in depressed patients after three and six months (P = 0.003 and P = 0.004, respectively) of supplementation, with vitamin D levels increasing to normal (P < 0.0001). Subgroup analyses revealed this anti-depressant effect of vitamin D to occur predominantly in women. The final follow-up showed increases in median BDI-II scores in the setting of decreased vitamin D levels. Conclusions Vitamin D levels correlated with BDI-II scores, and vitamin D replacement significantly improved depressive symptoms in women with CLD. Adjuvant vitamin D may be considered in these patients. Registration No DRKS00007782 German Clinical Trials Registry (DRKS) [ABSTRACT FROM AUTHOR]
Published: 2016
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37. A variant in the nuclear dot protein 52 kDa gene increases the risk for spontaneous bacterial peritonitis in patients with alcoholic liver cirrhosis.

Author: Lutz, Philipp, Krämer, Benjamin, Kaczmarek, Dominik J., Hübner, Marc P., Langhans, Bettina, Appenrodt, Beate, Lammert, Frank, Nattermann, Jacob, Hoerauf, Achim, Strassburg, Christian P., Spengler, Ulrich, and Nischalke, Hans Dieter
Abstract: Background Spontaneous bacterial peritonitis is frequently a fatal infection in patients with liver cirrhosis. We investigated if nuclear dot protein 52 kDa ( NDP52 ), a negative regulator of toll-like receptor (TLR) signalling and autophagy adaptor protein, might be involved. Methods Two cohorts comprising 152 (derivation cohort) and 198 patients (validation cohort) with decompensated liver cirrhosis and 168 healthy controls were genotyped for the rs2303015 polymorphism in the NDP52 gene and prospectively followed-up for spontaneous bacterial peritonitis. Results Overall, 57 (38%) patients in the derivation cohort and 77 (39%) in the validation cohort had spontaneous bacterial peritonitis. Cirrhosis was due to alcohol abuse in 57% of the derivation and 66% of the validation cohort. In patients with alcoholic cirrhosis, patients with spontaneous bacterial peritonitis had an increased frequency of the NDP52 rs2303015 minor variant in the derivation ( p = 0.04) and in the validation cohort ( p = 0.01). Multivariate analysis confirmed this minor variant (odds ratio 4.7, p = 0.002) and the TLR2 −16934 TT variant (odds ratio 2.5, p = 0.008) as risk factors for spontaneous bacterial peritonitis. In addition, presence of the NDP52 minor variant affected survival negatively. Conclusion Presence of the NDP52 rs2303015 minor variant increases the risk for spontaneous bacterial peritonitis in patients with alcoholic cirrhosis. [ABSTRACT FROM AUTHOR]
Published: 2016
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38. Direct cholangioscopic visualization of pure "stento-mechanical" lithotripsy.

Author: Zimmer, Vincent and Lammert, Frank
Published: 2022
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39. Combined effects of the PNPLA3rs738409, TM6SF2rs58542926, and MBOAT7rs641738 variants on NAFLD severity: a multicenter biopsy-based study1

Author: Krawczyk, Marcin, Rau, Monika, Schattenberg, Jörn M., Bantel, Heike, Pathil, Anita, Demir, Münevver, Kluwe, Johannes, Boettler, Tobias, Lammert, Frank, and Geier, Andreas
Abstract: The PNPLA3p.I148M, TM6SF2p.E167K, and MBOAT7rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16–88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7variants. Carriers of the PNPLA3and TM6SF2risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P< 0.05). The PNPLA3genotype was associated with steatosis grades S2–S3 (P< 0.001) and fibrosis stages F2–F4 (P< 0.001). The TM6SF2genotype was associated with steatosis (P= 0.003) but not with fibrosis (P> 0.05). The MBOAT7variant was solely associated with increased fibrosis (P= 0.046). In the multivariate model, variants PNPLA3(P= 0.004) and TM6SF2(P= 0.038) were associated with steatosis. Fibrosis stages were affected by the PNPLA3(P= 0.042) and MBOAT7(P= 0.021) but not by the TM6SF2polymorphism (P> 0.05). The PNPLA3, TM6SF2, and MBOAT7variants are associated with increased liver injury. The TM6SF2variant seems to modulate predominantly hepatic fat accumulation, whereas the MBOAT7polymorphism is linked to fibrosis. The PNPLA3polymorphism confers risk of both increased steatosis and fibrosis.
Published: 2017
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40. Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population.

Author: Graupera, Isabel, Thiele, Maja, Serra-Burriel, Miquel, Caballeria, Llorenç, Roulot, Dominique, Wong, Grace Lai-Hung, Fabrellas, Núria, Guha, Indra Neil, Arslanow, Anita, Expósito, Carmen, Hernández, Rosario, Aithal, Guruprasad Padur, Galle, Peter R., Pera, Guillem, Wong, Vincent Wai-Sun, Lammert, Frank, Ginès, Pere, Castera, Laurent, and Krag, Aleksander
Abstract: Fibrosis-4 (FIB-4) and the nonalcoholic fatty liver disease fibrosis score (NFS) are the 2 most popular noninvasive blood-based serum tests proposed for widespread fibrosis screening. We therefore aimed to describe the accuracy of FIB-4 and NFS to detect elevated liver stiffness as an indicator of hepatic fibrosis in low-prevalence populations. This study included a total of 5129 patients with concomitant measurement of FIB-4, NFS, and liver stiffness measurement (LSM) by Fibroscan (Echosens, France) from 5 independent population-based cohorts from Spain, Hong Kong, Denmark, England, and France; 3979 participants from the general population and 1150 from at-risk cohorts due to alcohol, diabetes, or obesity. We correlated LSM with FIB-4 and NFS, and calculated pre- and post-test predictive values of FIB-4 and NFS to detect elevated LSM at 8 kPa and 12 kPa cutoffs. The mean age was 53 ± 12 years, the mean body mass index was 27 ± 5 kg/m2, and 2439 (57%) were women. One in 10 patients (552; 11%) had liver stiffness ≥8 kPa, but 239 of those (43%) had a normal FIB-4, and 171 (31%) had normal NFS. The proportion of false-negatives was higher in at-risk patients than the general population. FIB-4 was false-negative in 11% of diabetic subjects, compared with 2.5% false-negatives with NFS. Waist circumference outperformed FIB-4 and NFS for detecting LSM ≥8 kPa in the general population. Almost one-third (28%–29%) of elevated FIB-4/NFS were false-positive in both the general population and at-risk cohorts. FIB-4 and NFS are suboptimal for screening purposes due to a high risk of overdiagnosis and a non-negligible percentage of false-negatives, especially in patients with risk factors for chronic liver disease. Waist circumference emerged as a potential first step to identify patients at risk for liver fibrosis in the general population. [ABSTRACT FROM AUTHOR]
Published: 2022
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41. C-kit+ resident cardiac stem cells improve left ventricular fibrosis in pressure overload.

Author: Kazakov, Andrey, Meier, Timo, Werner, Christian, Hall, Rabea, Klemmer, Birgit, Körbel, Christina, Lammert, Frank, Maack, Christoph, Böhm, Michael, and Laufs, Ulrich
Abstract: Copyright of Stem Cell Research is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Published: 2015
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42. Screening for liver fibrosis in the general population: a call for action

Author: Ginès, Pere, Graupera, Isabel, Lammert, Frank, Angeli, Paolo, Caballeria, Llorenç, Krag, Aleksander, Guha, I Neil, Murad, S Darwish, and Castera, Laurent
Abstract: Liver cirrhosis is one of the main causes of death and disability-adjusted life-years worldwide. Generally, cirrhosis develops after a long period of liver-cell injury that leads to the deposition of collagen, leading to progressive fibrosis and nodule formation in the liver tissue. Most patients are diagnosed in late stages when liver decompensation or liver cancer develops. The diagnosis is rarely made in early stages—when liver fibrosis is mild to moderate but cirrhosis is not yet established—because the disease is asymptomatic. No strategies for detection of liver fibrosis at these early stages have been developed, but therapies are more effective in early stages than late stages of chronic liver diseases, so enabling early detection is an important research topic. Non-invasive methods for assessing liver fibrosis have been developed, of which the most commonly used are transient elastography—which estimates liver fibrosis by measuring liver stiffness—and serum biomarkers of fibrosis. Studies have shown that 6–7% of the adult population without known liver disease have liver fibrosis, mostly associated with non-alcoholic fatty liver disease. These data suggest that programmes of screening for liver fibrosis in the general population should be assessed.
Published: 2016
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43. Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression

Author: Shen, Zhe, Liu, Yan, Dewidar, Bedair, Hu, Junhao, Park, Ogyi, Feng, Teng, Xu, Chengfu, Yu, Chaohui, Li, Qi, Meyer, Christoph, Ilkavets, Iryna, Müller, Alexandra, Stump-Guthier, Carolin, Munker, Stefan, Liebe, Roman, Zimmer, Vincent, Lammert, Frank, Mertens, Peter R., Li, Hai, ten Dijke, Peter, Augustin, Hellmut G., Li, Jun, Gao, Bin, Ebert, Matthias P., Dooley, Steven, Li, Youming, and Weng, Hong-Lei
Abstract: Disrupting Notch signaling ameliorates experimental liver fibrosis. However, the role of individual Notch ligands in liver damage is unknown. We investigated the effects of Delta-like ligand 4 (Dll4) in liver disease. DLL4 expression was measured in 31 human liver tissues by immunohistochemistry. Dll4 function was examined in carbon tetrachloride– and bile duct ligation–challenged mouse models in vivoand evaluated in hepatic stellate cells, hepatocytes, and Kupffer cells in vitro. DLL4 was expressed in patients' Kupffer and liver sinusoidal endothelial cells. Recombinant Dll4 protein (rDll4) ameliorated hepatocyte apoptosis, inflammation, and fibrosis in mice after carbon tetrachloride challenge. In vitro, rDll4 significantly decreased lipopolysaccharide-dependent chemokine expression in both Kupffer and hepatic stellate cells. In bile duct ligation mice, rDll4 induced massive hepatic necrosis, resulting in the death of all animals within 1 week. Inflammatory cell infiltration and chemokine ligand 2 (Ccl2) expression were significantly reduced in rDll4-receiving bile duct ligation mice. Recombinant Ccl2 rescued bile duct ligation mice from rDll4-mediated death. In patients with acute-on-chronic liver failure, DLL4 expression was inversely associated with CCL2 abundance. Mechanistically, Dll4 regulated Ccl2 expression via NF-κB. Taken together, Dll4 modulates liver inflammatory response by down-regulating chemokine expression. rDll4 application results in opposing outcomes in two models of liver damage. Loss of DLL4 may be associated with CCL2-mediated cytokine storm in patients with acute-on-chronic liver failure.
Published: 2016
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44. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

Author: Buch, Stephan, Stickel, Felix, Trépo, Eric, Way, Michael, Herrmann, Alexander, Nischalke, Hans Dieter, Brosch, Mario, Rosendahl, Jonas, Berg, Thomas, Ridinger, Monika, Rietschel, Marcella, McQuillin, Andrew, Frank, Josef, Kiefer, Falk, Schreiber, Stefan, Lieb, Wolfgang, Soyka, Michael, Semmo, Nasser, Aigner, Elmar, Datz, Christian, Schmelz, Renate, Brückner, Stefan, Zeissig, Sebastian, Stephan, Anna-Magdalena, Wodarz, Norbert, Devière, Jacques, Clumeck, Nicolas, Sarrazin, Christoph, Lammert, Frank, Gustot, Thierry, Deltenre, Pierre, Völzke, Henry, Lerch, Markus M, Mayerle, Julia, Eyer, Florian, Schafmayer, Clemens, Cichon, Sven, Nöthen, Markus M, Nothnagel, Michael, Ellinghaus, David, Huse, Klaus, Franke, Andre, Zopf, Steffen, Hellerbrand, Claus, Moreno, Christophe, Franchimont, Denis, Morgan, Marsha Y, and Hampe, Jochen
Abstract: Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10−9) and TM6SF2 (P = 7.89 × 10−10) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10−48) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.
Published: 2015
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45. A farnesoid X receptor polymorphism predisposes to spontaneous bacterial peritonitis.

Author: Lutz, Philipp, Berger, Cordula, Langhans, Bettina, Grünhage, Frank, Appenrodt, Beate, Nattermann, Jacob, Lammert, Frank, Hoerauf, Achim, Sauerbruch, Tilman, Strassburg, Christian P., Spengler, Ulrich, and Nischalke, Hans Dieter
Abstract: Background In mice, the farnesoid X receptor is involved in bacterial translocation, which can result in spontaneous bacterial peritonitis in patients with cirrhosis. We investigated if polymorphisms in the farnesoid X receptor gene influence the risk for spontaneous bacterial peritonitis. Methods Laboratory and clinical data of 293 cirrhotic patients with ascites and 226 healthy controls were prospectively collected. The rs56163822, rs11110390 and rs12313471 polymorphisms of the farnesoid X receptor were determined. Results 115 (39%) patients had spontaneous bacterial peritonitis. Distribution of all farnesoid X receptor genotypes matched the Hardy–Weinberg equilibrium. Patients with spontaneous bacterial peritonitis had a higher frequency of the rs56163822 GT genotype (7.0%) than patients without (1.7%, OR = 4.4, p = 0.02). This genotype was confirmed as predictor of spontaneous bacterial peritonitis by binary logistic regression analysis (OR = 6.8, p = 0.018). Conclusion The farnesoid X receptor rs56163822 GT genotype increases the risk for spontaneous bacterial peritonitis in cirrhotic patients with ascites. [ABSTRACT FROM AUTHOR]
Published: 2014
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46. Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: A randomized, double-blind, placebo-controlled study.

Author: Beigel, Florian, Teich, Niels, Howaldt, Stefanie, Lammert, Frank, Maul, Jochen, Breiteneicher, Simone, Rust, Christian, Göke, Burkhard, Brand, Stephan, and Ochsenkühn, Thomas
Abstract: Background and Aims Bile acid malabsorption (BAM)-associated diarrhea is an important clinical issue in patients with Crohn's disease (CD). We analyzed the efficacy and safety of the bile acid sequestrant colesevelam for treatment of BAM-associated diarrhea in CD patients in a randomized, double-blind, placebo-controlled study. Methods The primary endpoint was the proportion of patients with > 30% reduction of liquid stools/day from baseline to termination visit at week 4. Secondary endpoints were reduction of the number of liquid stools/day, improvement of stool consistency and quality of life. Results 26 patients were analyzed in the intention-to-treat (ITT) analysis. The primary endpoint was reached by 10 patients (69.7%) in the colesevelam group compared to 3 patients (27.3%) in the placebo group (risk difference RD = .394, 95%CI:[− 0.012; 0.706]; P = .0566). In the per-protocol analysis (n = 22), the risk difference was statistically significant (RD = .470, 95%CI:[0.018; 0.788], P(H 0 : RD = 0) = 0.0364; 95% CI:[1.3;54.7]). Regarding secondary endpoints, in the ITT population colesevelam-treated patients had a significant reduction of liquid stools/day at week 4 (median 5.0 to 2.0; P = 0.01), while patients treated with placebo had no significant reduction (median 4.0 to 3.0; P = 0.42). Significantly more patients in the colesevelam group had improvement of stool consistency of at least one level in the Bristol stool chart, as compared to the placebo group (P = 0.003). Conclusions We found significant differences in favor for colesevelam treatment compared to placebo treatment for CD patients with BAM regarding the reduction of the number of liquid stools/day and stool consistency. ClinicalTrials.gov number: NCT01203254 . [ABSTRACT FROM AUTHOR]
Published: 2014
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47. Phenotypic Variability of MUTYH-Associated Polyposis in Monozygotic Twins and Endoscopic Resection of A Giant Polyp in Pregnancy

Author: Casper, Markus, Spier, Isabel, Holz, Robert, Aretz, Stefan, and Lammert, Frank
Published: 2018
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48. The genetic epidemiology of diverticulosis and diverticular disease: Emerging evidence

Author: Reichert, Matthias C and Lammert, Frank
Abstract: Diverticular disease (DD) is one of the most prevalent gastrointestinal disorders. The pathogenesis of diverticulosis and DD is controversially discussed. Current studies call the traditional concept of a fibre-deficient diet causing the development of diverticula into question. Data from two recent twin studies have provided conclusive evidence for a strong genetic component to diverticulosis. Although genomewide association studies have provided new insights into the polygenic architecture of human diseases, genomic research in diverticulosis and DD has just been started. This is an astonishing fact given the high morbidity and mortality of the disease, as well as the substantial economic burden on health care systems. For this review, we provide an update of the molecular pathobiology and summarise recent evidence supporting the hypothesis that distinct, yet unidentified genetic variants contribute to the development of diverticulosis and DD.
Published: 2015
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49. The genetic epidemiology of diverticulosis and diverticular disease: Emerging evidence

Author: Reichert, Matthias C and Lammert, Frank
Abstract: Diverticular disease (DD) is one of the most prevalent gastrointestinal disorders. The pathogenesis of diverticulosis and DD is controversially discussed. Current studies call the traditional concept of a fibre-deficient diet causing the development of diverticula into question. Data from two recent twin studies have provided conclusive evidence for a strong genetic component to diverticulosis. Although genomewide association studies have provided new insights into the polygenic architecture of human diseases, genomic research in diverticulosis and DD has just been started. This is an astonishing fact given the high morbidity and mortality of the disease, as well as the substantial economic burden on health care systems. For this review, we provide an update of the molecular pathobiology and summarise recent evidence supporting the hypothesis that distinct, yet unidentified genetic variants contribute to the development of diverticulosis and DD.
Published: 2015
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50. Macrophage stimulating protein variation enhances the risk of sporadic extrahepatic cholangiocarcinoma.

Author: Krawczyk, Marcin, Höblinger, Aksana, Mihalache, Florentina, Grünhage, Frank, Acalovschi, Monica, Lammert, Frank, and Zimmer, Vincent
Abstract: Abstract: Background: Primary sclerosing cholangitis confers risk of cholangiocarcinoma. Here, we assessed the primary sclerosing cholangitis-associated variant rs3197999 in the MST1 gene, coding for RON receptor tyrosine kinase ligand macrophage stimulating protein, in a large European cholangiocarcinoma cohort. Materials and methods: 223 cholangiocarcinoma patients including three primary sclerosing cholangitis individuals and 355 cancer- and primary sclerosing cholangitis-free controls were genotyped for MST1 rs3197999. Results: The cancer group departed from Hardy–Weinberg equilibrium (p =0.022) and exhibited a trend for rs3197999 [A] overrepresentation (31% vs. 26%: p =0.10). Homozygous rs3197999 [AA] carrier status significantly increased overall (OR=1.97; p =0.023) and primary sclerosing cholangitis-unrelated biliary tract cancer risk (OR=1.84; p =0.044), relative to homozygous common allele carriers. The association was most pronounced in patients with extrahepatic tumours. This finding was robust to multivariate analysis (p <0.05), validating the [AA] genotype as an independent cholangiocarcinoma risk factor. Conclusions: These results suggest that the [AA] genotype of the common MST1 variant rs3197999 enhances genetic risk of sporadic extrahepatic cholangiocarcinoma irrespective of primary sclerosing cholangitis status, presumably by modulating inflammatory responses and/or altered MSP/RON signalling. [Copyright &y& Elsevier]
Published: 2013
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