foto

Prof. PhD U.H.W. Beuers

Position
Medical Specialist
Main activities
Patient care, Research
Specialisation
Gastroenterology and Hepatology
Focus of research

Pathogenetic and therapeutic aspects of chronic cholestatic and immune-mediated liver diseases

The pathophysiology of chronic cholestatic and immune-mediated liver diseases like primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis and overlap syndromes, IgG4-related cholangitis and various genetic cholestatic disorders is still only partly understood. Although evidence-based therapies are now available for some of these diseases such as primary biliary cholangitis and autoimmune hepatitis, many more efforts are needed to disclose the pathophysiological mechanisms leading to these diseases and their progression as well as the symptoms like pruritus and fatique from which the majority of affected patients suffer. Using the full spectrum of laboratory techniques, ranging from basic biochemistry and in vitro cell biology to mouse models, translational studies and clinical trials with affected patients, we try to gain more insight in the pathophysiology of, and possible novel therapeutic approaches towards cholestatic and immune-mediated liver diseases.

Key publications
  • Maillette de Buy Wenniger Lucas J., Doorenspleet Marieke E., Klarenbeek Paul L., Verheij Joanne, Baas Frank, Elferink Ronald P. Oude, Tak Paul P., de Vries Niek, Beuers Ulrich Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis Hepatology (Baltimore, Md.) 2013;57 (6):2390-2398 [PubMed]
  • Beuers Ulrich, Trauner Michael, Jansen Peter, Poupon Raoul New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond Journal of hepatology 2015;62 (1 Suppl):S25-S37 [PubMed]
  • Kremer Andreas E., van Dijk Remco, Leckie Pamela, Schaap Frank G., Kuiper Edith M. M., Mettang Thomas, Reiners Katrin S., Raap Ulrike, van Buuren Henk R., van Erpecum Karel J., Davies Nathan A., Rust Christian, Engert Andreas, Jalan Rajiv, Oude Elferink Ronald P. J., Beuers Ulrich Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions Hepatology (Baltimore, Md.) 2012;56 (4):1391-1400 [PubMed]
  • Hohenester Simon, Wenniger Lucas Maillette de Buy, Paulusma Coen C., van Vliet Sandra J., Jefferson Douglas M., Elferink Ronald P. Oude, Beuers Ulrich A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes Hepatology (Baltimore, Md.) 2012;55 (1):173-183 [PubMed]
  • Beuers Ulrich, Gershwin M. Eric, Gish Robert G., Invernizzi Pietro, Jones David E. J., Lindor Keith, Ma Xiong, Mackay Ian R., Parés Albert, Tanaka Atsushi, Vierling John M., Poupon Raoul Changing nomenclature for PBC: from 'cirrhosis' to 'cholangitis' Gastroenterology 2015;149 (6):1627-1629 [PubMed]
All Publications
Curriculum Vitae

Curriculum Vitae

Name:                        Ulrich H.W. Beuers             

Place of Birth:           Hagen, Germany

Office address:          Department of Gastroenterology & Hepatology

                              Tytgat Institute for Liver and Intestinal Research

                                    Academic Medical Center, C2-327

                                    Amsterdam Univercity Medical Centers, location AMC, C2-327

                                    Meibergdreef 9

                                    1105 AZ Amsterdam

                              The Netherlands

Phone:                        office:          +31-20-5662422 / -5668278 (Executive Assistant: Priscilla Antersijn)

                                           home:          +31-20-8451158

                                    mobile:         +31-630717950

Fax:                            office:          +31-20-5669582

E-mail:                        u.h.beuers@amsterdamumc.nl

 

Career

2020 -           Head, Hepatology, University Medical Centers Amsterdam

2015     (5-9)  Visiting Professor, Yale University School of Medicine, New Haven, CT, USA

2010 - 2019   Head, Hepatology and Core Professor, Academic Medical Center, University of Amsterdam

2010 - 2018   Program Director Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam

2007 - 2009   Professor, Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam; Gastroenterologist & Hepatologist and Internist

2003 - 2006   Senior Consultant, Department of Medicine II – Grosshadern, Ludwig Maximilians University (LMU) München

2001 - 2008   Professor, Internal Medicine, Ludwig Maximilians University (LMU) München

1996               Board exam for Gastroenterology & Hepatology

1995 - 2002   Consultant, Department of Medicine II – Grosshadern, Ludwig Maximilians University (LMU) München

1995               Board exam for Internal Medicine

1994               Habilitation for Internal Medicine.  Title of the thesis: “On clinical effectiveness, metabolism and mechanisms of action of ursodeoxycholic acid in chronic cholestatic liver diseases".

1993 - 1996    Fellow at the Department of Medicine II - Grosshadern of the Ludwig Maximilians University (LMU) München (Prof. Dr. G. Paumgartner)

1991 - 1993    Fellow at the Liver Center, Yale University School of Medicine, New Haven, CT, U.S.A. (Prof. Dr. J. L. Boyer)

1986 - 1991    Residency at the Department of Medicine II - Grosshadern of the Ludwig Maximilians University (LMU) München (Prof. Dr. G. Paumgartner)

1984 - 1986    Postdoctoral fellow, Department of Biochemistry, University of Göttingen (Prof. Dr. K. Jungermann)

1983                Dissertation, (Pharmakological Department, University of Freiburg, Prof. Dr. G. Hertting; „summa cum laude")

                        Title of the thesis:”The effect of the renin angiotensin system on release of b-lipotropin und b-endorphin immunoreactivity in the conscious rat “.

1983                Public medical exam and licence as physician

1982 - 1984     Extended medical clerkships in Flores/Indonesia and Northeastern Brasil

1980 - 1983     Studies of Medicine at the University of Freiburg / Germany

1979 - 1980     Studies of Medicine at the Free University of Berlin / Germany

1976 - 1979     Studies of Medicine at the University of Ghent / Belgium

1975 - 1976     Military service (medical corps), Hamm

1966 - 1975     Albrecht-Dürer-Gymnasium, Hagen

 

Major research lines

2009-2019 (ongoing): Pathogenesis of IgG4-related disease of biliary tree and pancreas

2007-2019 (ongoing): The biliary bicarbonate umbrella in fibrosing cholangiopathies

2003-2019 (ongoing): Pathogenesis and treatment of pruritus in cholestasis

1990-2008: Mechanisms of action of ursodeoxycholic acid in cholestatic liver disease

1987-2019 (ongoing): Pathophysiology and treatment of cholestatic liver diseases

 

 

Publications

h-Index (10-2019): 74 (Google); 60 (web of science)

 

Selection of 10 relevant original papers

Beuers U, Spengler U, Kruis W, Aydemir Ü, Wiebecke B, Heldwein W, Weinzierl M, Pape GR, Sauerbruch T, Paumgartner G. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a double-blind, placebo-controlled trial. Hepatology 16:707-714, 1992

Beuers U, Nathanson MH, Isales CM, Boyer JL. Tauroursodeoxycholic acid stimulates hepatocellular exocytosis by mobilization of extracellular Ca++, a mechanism defective in cholestasis. J Clin Invest 92:2984-2993, 1993

Beuers U, Throckmorton DO, Anderson MS, Isales CM, Thasler W, Kullak-Ublick GA, Sauter G, Koebe HG, Paumgartner G, Boyer JL. Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes. Gastroenterology 110:1553-1563, 1996

Beuers U, Bilzer M, Chittattu A, Kullak-Ublick GA, Keppler D, Paumgartner G, Dombrowski F. Tauroursodexycholic Acid Inserts the Apical Conjugate Export Pump, Mrp2, Into Canalicular Membranes and Stimulates Organic Anion Secretion by Protein Kinase C-Dependent Mechanisms in Cholestatic Rat Liver. Hepatology 33:1206–1216, 2001

Beuers U, Denk G, Soroka C, Wimmer R, Rust Ch, Paumgartner G, Boyer J. Taurolithocholic acid exerts cholestatic effects via phosphatidylinositol-3 kinase-dependent mechanisms in perfused rat livers an rat hepatocyte couplets. J Biol Chem 278:17810-17818, 2003

Hohenester S, Wenniger LM, Paulusma CC, van Vliet SJ, Jefferson DM, Elferink RP, Beuers U. A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology 55:173-83, 2012

Kremer AE, van Dijk R, Leckie P, Schaap FG, Kuiper EM, Mettang T, Reiners KS, Raap U, van Buuren HR, van Erpecum KJ, Davies NA, Rust C, Engert A, Jalan R, Oude Elferink RP, Beuers U, Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions.Hepatology 56:1391-400, 2012

Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, Verheij J, Baas F, Oude Elferink RP, Tak PP, de Vries N, Beuers U. Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis. Hepatology 57:2390-8, 2013

Maroni L, Hohenester SD, van de Graaf SFJ, Tolenaars D, van Lienden K, Verheij J, Marzioni M, Karlsen TH, Oude Elferink RPJ, Beuers U. Knockout of the primary sclerosing cholangitis-risk gene Fut2 causes liver disease in mice. Hepatology 66:542-554, 2017

Hubers LM, Vos H, Schuurman AR, Erken R, Oude Elferink RP, Burgering B, van de Graaf SFJ, Beuers U. Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease. Gut 67:728-735, 2018

 

Selection of 10 relevant reviews, thesis papers, guidelines

Beuers U, Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis: Potential mechanisms of action and therapeutic applications. Hepatology 28:1449-1453, 1998

Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 36:525-31, 2002.

Beuers U: Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nature Clin Pract Gastroenterol Hepatol 3:318-328, 2006

Beuers U, Boberg K, Chapman R, et al. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 51:237-67, 2009

Beuers U, Hohenester S, de Buy Wenniger LJ, Kremer AE, Jansen PL, Oude Elferink RP. The biliary HCO3- umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 52:1489-96, 2010

Beuers U, Kremer AE, Bolier R, Oude Elferink RP. Pruritus in cholestasis: facts and fiction. Hepatology 60(1):399-407, 2014

Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K, Ma X, Mackay IR, Parés A, Tanaka A, Vierling JM, Poupon R. Changing nomenclature for PBC: from 'cirrhosis' to 'cholangitis'. Gastroenterology 149:1627-9, 2015; J Hepatol 63: 1285-87, 2015; Hepatology 62: 1620-22, 2015; Gut 64:1671-2, 2015

Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol 62(1 Suppl):S25-37, 2015

Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet 391(10139):2547-2559, 2018

De Vries, Beuers U. Ursodeoxycholic acid in pregnancy. J Hepatol 71:1237-1245, 2019

 

Editorial activities since 1997

2014 - 2019            Associate Editor                   Journal of Hepatology (IF 18.9)

2009 - 2013            Associate Editor                   Neth J Medicine

2000 - 2004            Associate Editor                   Journal of Hepatology

1997 - 1999            Assistant/Associate Editor   Journal of Hepatology

 

2019 – 2024            Editorial Board                  Journal of Hepatology

2010 -                      Editorial Board                  Gastroenterologie Clinique et Biologique

2009 -                      Editorial Board                  Gut

2009 -                      Editorial Board                  Digestive and Liver Diseases

2007 - 2017             Editorial Board                  Hepatology

2007 -                      Editorial Board                  World Journal of Gastroenterology

2005 - 2014             Editorial Board                  Journal of Hepatology

 

International administrative activities since 2008

2019 - 2022   Educational Councilor, European Association for the Study of the Liver (EASL)

2020 - 2022   Clinical Research Committee American Association for the Study of Liver Diseases (AASLD)

2019 - 2021   United European Gastroenterology (UEG) Educational Committee

2019 – 2020   Co-chairman, UEG Guidelines “IgG4-related diseases of the digestive tract”

2018 - 2022   Governing Board, European Association for the Study of the Liver (EASL)

2017 - 2021   Secretary, International PSC Study Group (IPSCSG; with C.Ponsioen)

2016 - 2020   EASL Committees Clinical Practice Guidelines “Primary biliary cholangitis” , “Sclerosing cholangitis”, “Pregnancy-related liver diseases”

2013 - 2017   Chairman, Netherlands Education Committee Gastroenterol. & Hepatology

2012 - 2018   Chairman, Netherlands Association for the Study of the Liver (NASL/NVH)

2008 - 2009   Chairman, EASL Clinical Practice Guidelines “Management of cholestatic liver disease”

 

Reviewer activities

International scientific journals:

New England Journal of Medicine, Lancet, Nature Medicine, Journal of Clinical Investigation, Gastroenterology, Gut, Hepatology, Journal of Hepatology, Nature Communications, Nature Reviews Gastroenterology & Hepatology, Transplantation, Liver Transplantation, Clinical Gastroenterology  & Hepatology, Biochimica et Biophysica Acta, Scientific Reports, European Journal of Clinical Investigation, Liver International, European Journal of Gatroenterology & Hepatology, Scandinavian Journal of Gastroenterology, Digestion, Zeischrift für Gastroenterologie etc.

 

Awards and Honours

2018   Lucie-Bolte-Award (‘lifetime achievements’ on the field of liver cirrhosis)

2010   Honorary Member, Czechian Society of Hepatology

2005   Honorary Member, Slovakian Society of Internal Medicine (Hepatology)          

1994   GASL-Award, German Association for the Study of the Liver, for the paper “Tauroursodeoxycholic acid translocates a-protein kinase C in isolated rat hepatocytes“ (Gastroenterology                                                                                                                                                    1996;110:1553-1563)

1994   Adolf-Kußmaul-Award, Southwest-German Society of Gastroenterology, for the paper “Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++,                                                                                                                                                                mechanisms defective in cholestasis“ (J Clin Invest 1993;92:2984-2993)

1984   Fritz-Külz-Award, German Pharmacological Society, for the dissertation “Die Wirkung des Renin-Angiotensin-Systems auf die Freisetzung von b-Lipotropin und b-Endorphin-                                                                                                                                                         Immunreaktivität in der wachen Ratte ” (Brit J Pharmacol 1982;76: 579-585)

 

 

 

Research programmes

Prof. PhD U.H.W. Beuers (Pathogenetic and therapeutic aspects of chronic cholestatic liver diseases)

The biliary bicarbonate umbrella: We hypothesized that biliary bicarbonate secretion is essential for protection of human biliary epithelia against uncontrolled influx of nonpolarized glycine-conjugated bile acids (Beuers et al., Hepatology 2010; Hohenester et al. Hepatology 2012). Genetic polymorphisms may contribute to weakening of the biliary bicarbonate umbrella leading to chronic cholangiopathies like primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis-associated liver disease or posttransplant biliary strictures. Pharmacological stabilization of the bicarbonate umbrella with bile salts (e.g., ursodeoxycholate, norursodeoxycholate) or nuclear receptor agonists (e.g., obeticholate) represents a potential therapeutic strategy for these disorders.

Itch in cholestasis: Itch is a major burden for patients with cholestatic disorders. Its pathogenesis is unknown. We recently identified autotaxin (ATX) and its product, lysophosphatidic acid (LPA), a pruritogen in rodents, in serum of patients with cholestatic itch at higher concentrations than in controls and found a striking association with itch intensity (Kremer et al., Gastroenterology 2010) and treatment response (Kremer et al., Hepatology 2012). We also found that the most potent antipruritic agent, the pregnane-X receptor (PXR) agonist rifampicine, impairs ATX expression by PXR-dependent mechanisms possibly explaining its beneficial effect in patients at least in part (Kremer, van Dijk et al. Hepatology 2012). Further understanding of the role of ATX/LPA in cholestatic itch may allow development of novel therapeutic strategies for management of itch (for review: Beuers et al. Hepatology 2014, epub).

IgG4-associated cholangitis (IAC) and IgG4-related systemic disease: IAC is a recently defined autoimmune bile duct disorder which is often associated with autoimmune pancreatitis or other systemic manifestations of IgG4-related systemic disease. IAC has a good prognosis when adequately diagnosed and treated. The pathogenesis of this corticosteroid-responsive disorder is completely unknown. In clinical practice, it is challenging to differentiate IAC, cholangiocarcinoma (CCA) or primary sclerosing cholangitis (PSC) as these disorders may show comparable features in serum biochemistry and cholangiography. Bile duct cytology / histology is often of limited reliability for the diagnosis. IgG4 serum levels may be elevated in all these disorders. We recently succeeded by use of a novel next generation sequencing technique in unraveling highly abundant IgG4+ B cell receptor (BCR) clones in blood and tissue of patients with active IAC (but not PSC or CCA), which disappear upon corticosteroid treatment (Maillette de Buy Wenniger, Doorenspleet et al. Hepatology 2013). Our data strongly suggest that specific B cell responses are pivotal to the pathogenesis of IAC. In support of our concept, we most recently identified "blue collar work" as a potential risk factor for development of IgG4-related disease in two independent cohorts of patients with IgG4-related systemic disease (Maillette de Buy Wenniger, Curver, Beuers, Hepatology 2014, epub). Our next aims are to define the antigens against which IgG4 are directed in IAC and to better understand the pathophysiological role of IgG4 in IgG4-related systemic disease.

Severe persistent hepatocellular secretory failure (PHSF): We recently identified the pregnane X receptor (PXR) agonist rifampicin as a potent drug to effectively treat severe persistent hepatocellular secretory failure, a rare disorder induced by drugs, toxins or transient bile duct obstruction and associated with severe progressive jaundice (bilrubine > 255 umol/l) after removal of the trigger. We try to elucidate the molecular mechanisms involved in PHSF and its reversal induced by the PXR agonist rifampicin (van Dijk et al. submitted).

Clinical therapeutic trials 2014:

- Obeticholate in primary biliary cirrhosis,

- Budesonide in primary biliary cirrhosis,

- Norursodeoxycholate in primary sclerosing cholangitis,

- Diagnosis and treatment of IgG4-associated cholangitis,

- Rifampicin in severe persistent hepatocellular secretory failure,

- A PPAR alpha/delta agonist in nonalcoholic steatohepatitis (NASH)

Faculty
PhD K.F.J. van de Graaf

Postdocs
MD PhD L. Maroni

Others
W.D. Tolenaars

Current research funding
  • Accelsiors Ltd.
  • CRO at Covance Caps Ltd.
  • Dr. Falk Pharma GmbH
  • ENYO Pharma SA
  • Europese Unie
  • Gilead Sciences, Inc.
  • Gйnйthon
  • ICON Clinical Research Ltd.
  • Intercept Pharmaceuticals Inc.
  • Maag, Lever, Darm Stichting
  • Maag-Darm Stichting
  • Medical Research BV
  • Nederlandse Vereniging voor Gastro-Enterologie
  • Norgine Limited
  • PPD Netherlands BV
  • Stichting AMC Foundation (Vrijgesteld)
  • ZonMw