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Prof. dr. U.H.W. Beuers

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

Pathogenetic and therapeutic aspects of chronic cholestatic liver diseases

The pathophysiology of chronic cholestatic and autoimmune liver diseases like primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis and overlap syndromes, IgG4-associated 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 cirrhosis 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 and translational studies, we try to gain more insight in the pathophysiology of, and possible novel therapeutic approaches towards cholestatic and autoimmune liver diseases.

Key publications
  • Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, Verheij J, Baas F, Elferink RPO, 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 2013;57 (6):2390-2398 [PubMed]
  • 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 2015;62 (1 Suppl):S25-S37 [PubMed]
  • Kremer AE, van Dijk R, Leckie P, Schaap FG, Kuiper EMM, Mettang T, Reiners KS, Raap U, van Buuren HR, van Erpecum KJ, Davies NA, Rust C, Engert A, Jalan R, Oude Elferink RPJ, Beuers U, Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions. HEPATOLOGY 2012;56 (4):1391-1400 [PubMed]
  • Hohenester S, Wenniger LMDB, Paulusma CC, van Vliet SJ, Jefferson DM, Elferink RPO, Beuers U, A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. HEPATOLOGY 2012;55 (1):173-183 [PubMed]
  • Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DEJ, Lindor K, Ma X, Mackay IR, Parés A, Tanaka A, Vierling JM, Poupon R, Changing nomenclature for PBC: from 'cirrhosis' to 'cholangitis'. GASTROENTEROLOGY 2015;149 (6):1627-1629 [PubMed]
All Publications
Curriculum Vitae
Curriculum Vitae

NAME Ulrich Beuers
POSITION TITLE Professor of Gastroenterology and Hepatology; Head, Hepatology; Program Director, Gastroenterology & Hepatology
EDUCATION/TRAINING Physician (MD; University of Freiburg, 1983); Dr.med. (University of Freiburg, 1983); Dr.med.habil./’Privatdozent’ (University of Munich, 1994); Internist (Munich, 1995), Gastroenterologist & Hepatologist (Munich, 1996); Professor, Internal Medicine (University of Munich, 2001); Professor, Gastroenterology & Hepatology (University of Amsterdam, 2007)

A. Positions:

I. Positions and employment

1983 Public medical exam and licence as physician (MD) after studies in Ghent/Belgium (1976-79), Berlin (1979-80) and Freiburg (1980-83).
1983 Dissertation (Dr.med.): “The effect of the renin angiotensin system on release of β-lipotropin and β-endorphin immunoreactivity in the conscious rat“ (Department of Pharmacology, University of Freiburg,”summa cum laude")
1984 - 1986 Postdoctoral fellow, Department of Biochemistry, University of Göttingen
1986 - 1991 Resident, Department of Medicine II, University of Munich
1991 - 1993 Fellow, Liver Center, Yale University School of Medicine, New Haven, CT
1993 - 2002 Fellow (1993-1995), Consultant (1995-2002), Department of Medicine II, University of Munich
1994 Habilitation for Internal Medicine (Dr.med.habil./’Privatdozent’). Title of the thesis: “On clinical effectiveness, metabolism and mechanisms of action of ursodeoxycholic acid in chronic cholestatic liver diseases"
2001 - 2008 Professor, Internal Medicine, University of Munich
2003 - 2006 Senior Consultant, Department of Medicine II, University of Munich
2007 - now Professor, Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam
2010 - now Program Director, Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam
2011 - now Head, Hepatology, Academic Medical Center, University of Amsterdam

II. Other relevant experience and professional memberships

● Chairman, Netherlands Society of Hepatology / Netherlands Association for the Study of the Liver (2012-       )
● Chairman, Netherlands Education Committee Gastroenterology & Hepatology (2014-       )
● Chairman, EASL Clinical Practice Guidelines “Management of cholestatic liver diseases” (2008-        )
● Associate Editor: Journal of Hepatology (2014-2019, 2000-2004, 1997-2000 [Assist.E.]), Neth J Med (2009-2013)
● Editorial Boards: Hepatology (since 2007), Gut (since 2009), Journal of Hepatology (since 2005), Digestive and Liver Diseases (since 2009), European Journal of Gastroenterology and Hepatology (since 2009), Gastroenterologie Clinique et Biologique (since 2010), World J Gastroenterol (since 2007).

● Member of selection committees: EASL, AASLD, APASL, NVGE/NVH, DGVS; AASLD Steering Board “Cholestasis” (2008-2012)

● Professional Memberships:
European Association for the Study of the Liver (EASL)
American Association for the Study of Liver Diseases (AASLD)
Netherlands Association for the Study of the Liver (NVH)
Netherlands Association for Gastroenterology (NVGE)
Netherlands Association for Gastroenterology & Hepatology (NVMDL)
Deutsche Gesellschaft für Innere Medizin (DGIM)
Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (DGVS)
Deutsche Arbeitsgemeinschaft zum Studium der Leber (GASL)

III. Honors and awards
2010 Honorary member, Czechian Society of Hepatology
2005 Honorary member, Slovakian Society of Medicine, Section of Hepatology
1994 German Association for the Study of the Liver Award for the paper “Tauroursodeoxycholic acid translocates alpha-protein kinase C in isolated rat hepatocytes“ (Gastroenterology 1996;110:1553-63)
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 “The effect of the renin angiotensin system on release of β-lipotropin and β-endorphin immunoreactivity in the conscious rat“ (Brit J Pharmacol 1982;76:579-585)

B. Selection of peer-reviewed publications:

I. Selection of eight most contributing publications 2010-2014

1: Beuers U, Kremer AE, Bolier R, OudeElferink RP. Pruritus in cholestasis – facts and fictions. Hepatology 2014;59:in press

2: Maillette de Buy Wenniger LJ, Curver EL, Beuers U. Exposure to occupational antigens might predispose to IgG4-related disease. Hepatology 2014;59:epub ahead of print

3: Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, Verheij J, Baas F, OudeElferink 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 2013;57:2390-8.

4: 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, OudeElferink RP, Beuers U. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions. Hepatology 2012;56:1391-400.

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

6: Denk GU, Maitz S, Wimmer R, Rust C, Invernizzi P, Ferdinandusse S, Kulik W, Fuchsbichler A, Fickert P, Trauner M, Hofmann AF, Beuers U. Conjugation is essential for the anticholestatic effect of norursodeoxycholic acid in taurolithocholic acid-induced cholestasis in rat liver. Hepatology 2010;52:1758-68.

7: Beuers U, Hohenester S, Maillette de Buy Wenniger L, Kremer AE, Jansen PLM, OudeElferink RPJ. The biliary HCO3- umbrella: A unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 2010;52:1489-1496.

8: Kremer AE, Martens J, Kulik W, Ruëff F, Kuiper EMM, van Buren HR, van Erpecum KJ, Kondrackiene J, Prieto J, Rust C, Geenes VL, Williamson C, Moolenaar WH, Beuers U, OudeElferink RPJ. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010;139:1008-1018.

II. Median impact factor of publications: 9.86
(total 327 publications [ISI web of knowledge 03-01-2014], average citations per item: 15.7; h-index 39)

III. Median impact factors for the own field(s): 2.2 (ISI web of knowledge category Gastroenterology & Hepatology)

IV. The top 3 leading Journals in the own field are Gastroenterology: IF 12.8; Hepatology: IF 12.0; Gut: IF 10.7

V. Patents: pending (European Patent Agency, method for diagnosing IgG4 related diseases, originally applied
30/9/2012 under application number EP 12 18 6746)
Research programmes

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
Prof. dr. U.H.W. Beuers
Dr. K.F.J. van de Graaf

Postdocs
Dr. L. Maroni MD

PhD Students
S.J. Aronson
Drs. R. Erken MD
T. Herta
Drs. L.M. Hubers
J.A.G.M. Langedijk
K.N. van Munster
Drs. J.B. van Niekerk
Drs. R.L.P. Roscam Abbing
W.L. Smit
J.J. Witjes
K. de Wit MD

Others
W.D. Tolenaars

Other research related activities
  • Membership of editorial board / Editorship, JOURNAL OF HEPATOLOGY
  • Membership of editorial board / Editorship, HEPATOLOGY
  • Membership of editorial board / Editorship, GUT
  • Membership of editorial board / Editorship, EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY
  • Membership of editorial board / Editorship, DIGESTIVE AND LIVER DISEASE
  • Membership of editorial board / Editorship, GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE
  • Membership of editorial board / Editorship, WORLD JOURNAL OF GASTROENTEROLOGY
  • Membership of advisory board / Consultant, Intercept, San Diego
  • Membership of advisory board / Consultant, Novartis BV
  • Contribution to guidelines and protocols, EASL Clinical Practice Guidelines "Management of cholestatic liver diseases"
Current research funding
  • Accelsiors Ltd.
  • CRO at Covance Caps Ltd.
  • Dr. Falk Pharma GmbH
  • ENYO Pharma SA
  • Europese Unie
  • Généthon
  • Gilead Sciences, Inc.
  • Gilead Sciences Netherlands B.V. NL815897996B01
  • Intercept Pharmaceuticals Inc.
  • Maag-Darm Stichting
  • Maag, Lever, Darm Stichting
  • Medical Research BV
  • Merck Sharp & Dohme BV
  • Nederlandse Vereniging voor Gastro-Enterologie
  • PPD Netherlands BV
  • Stichting AMC Foundation (Vrijgesteld)
  • Stichting Gastrostart
  • ZonMw