Pathophysiology, Prevention and Treatement Of End-stage Liver disease

PATHOPHYSIOLOGY, PREVENTION AND TREATMENT OF END-STAGE LIVER DISEASE (PI B. van Hoek)

Most chronic liver diseases lead towards cirrhosis and its complications, and a.o. acute and chronic liver failure can be indications for liver transplantation. The aim of our research is prevention of these end-stages by a better understanding and treatment of the underlying liver diseases, and the complications of advanced liver disease. While we undertake and participate in various, mainly translational and clinical, investigations in different acute and chronic liver diseases, the focus currently is on auto-immune and metabolic liver disease, and shifting away from viral liver disease. Biobanking and clinical databases are part of the basic infrastructure for many of these studies. In our clinical trial bureau several study nurses lead various -mostly phase 2 and 3- clinical studies in liver diseases. In vitro studies to understand pathophysiology are done..

LUMC is one of the founders of the Dutch Autoimmune Hepatitis Group, which started in 2005 and is a national cooperation of all academic and larger other hospitals. It is part of the worldwide International Autoimmune Hepatitis Group, and joint clinical investigations on presentation, treatment and outcome are being performed. Especially B-cell auto-immunity, genetics,  inflammation and fibrogenesis is investigated in cooperation with the immunohematology department of the LUMC. We participate in the national Cholestasis Working Group for joint investigations on cholestatic liver disease and overlap syndromes (e.g. genotype-phenotype studies in PSC and clinical studies with new drugs and on outcome in PSC and PBC). For viral hepatitis LUMC is  part of HepNed, a cooperation of Dutch hepatitis treatment centers, for joint clinical investigation, e.g. with the new direct antivirals and as part of the CELINE initiative aiming at elimination of hepatitis C from our country. LUMC is a reference center for alpha-1-antitrypsin deficiency (A1ATD); the focus has been on lung disease, but now is also on liver disease from A1ATD as part of a cooperation from the European Association for the Study of the Liver (EASL). Investigations in acute and acute-on-chronic liver failure are ongoing, and recently we joined a European group aiming at bringing bioartificial liver support to the clinic.

LIVER FIBROSIS

Hepatitis and cholestasis lead to liver fibrosis, which leads to cirrhosis and liver failure. Fibrosis is a bad prognosticator in many liver disease. An important aim for current treatments is prevention of development of liver fibrosis and cirrhosis. This is investigated clinically, with non-invasive monitoring liver diseases and its treatment with e.g.  Fibroscan and blood tests, but also in vitro and in vivo in our lab, where novel models have been developed. The influence of novel drugs and mesenchymal stem cells on several pathways and matrix proteins is investigated.


LIVER TRANSPLANTATION

After having perfomed the first liver transplantation (LT) in our country in 1966 (one of the first worldwide), since 1992 the LUMC is one of the three liver transplant programs in the Netherlands. While clinical results are above the European average and quite reasonable compared to the early days (90% patient survival at 1 year and 85% at 5 years), improvements are still being made on a continuous basis. Our studies focus on pathophysiology, treatment and prevention of LT complications. This includes studies on immunosuppression, prevention of its side-effects like renal insufficiency, infections, biliary strictures, bone disease, and nutrition before and after LT. Within the RADIcAL2 study the cost-effectiveness and accuracy of noninvasive diagnostics with MRI of a.o. biliary disorders after liver transplantation is investigated, within a European consortium. LUMC participates in (inter)national machine liver preservation trials in order to improve outcomes. Side-studies of these trials allow better insight into ischemia-reperfusion injury. Improving quality of life after LT is an important aim. Extending LT indications for malignancy combined with locoregional and systemic treatments in order to maintain acceptable outcomes currently also is a focus. Bridging therapies to transplantation are investigated.


Ongoing PhD projects

Akin Inderson, M.D. – Immunosuppression and complications in liver transplantation (expected 2019)

Martine Baven-Pronk, M.D. – Autoimmune Hepatitis. (expected 2019), Leiden University. 

Bert-Jan de Rooij, M.D., M.Sc. – The lectin pathway of complement activation in liver transplantation. (expected 2019).

Danny van der Helm, M.Sc. – Liver fibrosis and mesenchymal stem cells (2013- expected 2019)

Lars Pietersen, M.D. – Surgical aspects of liver transplantation (expected 2019)

Jelte Schaapman, M.D. – Chronic liver disease, ACLF and MRI (expected 2010)

Maaike Biewenga, M.D. -AIH and overlap syndromes (expected 2020)

Gabrielle Alblas, M.D.– NAFLD (expected 2021)


Biosketch Bart van Hoek

Bart van Hoek, M.D., Ph.D. is gastroenterologist –hepatologist since 1993 at the Leiden University Medical Center, Leiden, The Netherlands. After graduating as medical doctor (Groningen, 1982 and USA VQE, London 1984), he completed his specialization in Internal Medicine (Groningen, 1988), and obtained a PhD with a thesis on auto-immune hepatitis (Groningen, 1989). He worked at Mayo Clinic, Rochester MN, U.S.A. for two years during a research fellowship followed by a clinical fellowship in advanced clinical hepatology (1989-1991). In 1991-1992 he finished his specialization in Gastroenterology and Hepatology, at the same time working as a hepatologist in Maastricht UMC, Netherlands.  Since January 1993 he was cofounder of the Hepatology and Liver transplantation unit at LUMC Leiden, where he is Medical Director of this program. Since 2009 he is also Professor of Hepatology at Leiden University. His clinical focus is on auto-immune hepatitis, cholestatic and viral liver disease, end-stage liver disease, liver failure  and liver transplantation.

He is actively involved in scientific research in the field of complications and treatment of auto-immune and viral liver disease, fibrosis, alfa-1-antitrypsin deficiency (A1ATD), liver failure and complications, and liver transplantation. His main focus in AIH is on immunology, fibrogenesis, genetics and co-factors, non-invasive diagnosis/monitoring and outcome. In liver transplantation reduction of side-effects of immunosuppression, complications of ischemia-reperfusion injury, waitlist management, transplantation for malignancy and bridging to transplant are important fields of interest. 

Next to clinical work and research he is involved in training specialists in gastroenterology and hepatology, in internal medicine, and the training for physician assistants and nurse specialists, and he is educator at the medical school of Leiden University.

Prof. van Hoek currently is as board member of the Eurotransplant Liver and Intestinal Advisory Commission, is chair of the cooperation between the three Dutch liver transplant centers, and is member of the management team of the LUMC Transplant Unit. He is member of several medical societies, a.o.: International Liver Transplant Society (ILTS), European Society for Organ Transplantation (ESOT), European Liver Intestinal Transplant Association (ELITA), European Association for the Study of the Liver (EASL), American Association for the Study of Liver Disease (AASLD), and the Dutch Societies for Gastroenterology and Hepatology (past treasurer).



Selected publications van Hoek

(H-index: 32, Number of publications: 241, Sum of the times cited: 5175 (without self-citation 5054)

van Vugt JLA, Alferink LJM, Buettner S, Gaspersz MP, Bot D, Darwish Murad S, Feshtali S, van Ooijen PMA, Polak WG, Porte RJ, van Hoek B, van den Berg AP, Metselaar HJ, IJzermans JNM. A model including sarcopenia surpasses the MELD score in predicting waiting list mortality in cirrhotic liver transplant candidates: a competing risk analysis in a national cohort. J Hepatol. 2017 Dec 6. pii: S0168-8278(17)32474-1. doi: 10.1016/j.jhep.2017.11.030. [Epub ahead of print] PubMed PMID: 29221886.


Liberal R, de Boer YS, Andrade RJ, Bouma G, Dalekos GN, Floreani A, Gleeson D, Hirschfield GM, Invernizzi P, Lenzi M, Lohse AW, Macedo G, Milkiewicz P, Terziroli B, van Hoek B, Vierling JM, Heneghan MA; International Autoimmune Hepatitis Group (IAIHG). Expert clinical management of autoimmune hepatitis in the real world. Aliment Pharmacol Ther. 2017 Mar;45(5):723-732. doi: 10.1111/apt.13907. Epub 2016 Dec 22. PubMed PMID: 28004405.


Blok JJ, Detry O, Putter H, Rogiers X, Porte RJ, van Hoek B, Pirenne J, Metselaar HJ, Lerut JP, Ysebaert DK, Lucidi V, Troisi RI, Samuel U, den Dulk AC, Ringers J, Braat AE; Eurotransplant Liver Intestine Advisory Committee. Longterm results of liver transplantation from donation after circulatory death. Liver Transpl. 2016 Aug;22(8):1107-14. doi: 10.1002/lt.24449. PubMed PMID: 27028896.


Manns M, Samuel D, Gane EJ, Mutimer D, McCaughan G, Buti M, Prieto M, Calleja JL, Peck-Radosavljevic M, Müllhaupt B, Agarwal K, Angus P, Yoshida EM, Colombo M, Rizzetto M, Dvory-Sobol H, Denning J, Arterburn S, Pang PS, Brainard D, McHutchison JG, Dufour JF, Van Vlierberghe H, van Hoek B, Forns X; SOLAR-2 investigators. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis. 2016 Jun;16(6):685-697. doi: 10.1016/S1473- 099(16)00052-9. Epub 2016 Feb 18. Erratum in: Lancet Infect Dis. 2016 Jun;16(6):636. PubMed PMID: 26907736.


Geissler EK, Schnitzbauer AA, Zülke C, Lamby PE, Proneth A, Duvoux C, Burra P, Jauch KW, Rentsch M, Ganten TM, Schmidt J, Settmacher U, Heise M, Rossi G, Cillo U, Kneteman N, Adam R, van Hoek B, Bachellier P, Wolf P, Rostaing L, Bechstein WO, Rizell M, Powell J, Hidalgo E, Gugenheim J, Wolters H, Brockmann J, Roy A, Mutzbauer I, Schlitt A, Beckebaum S, Graeb C, Nadalin S, Valente U, Turrión VS, Jamieson N, Scholz T, Colledan M, Fändrich F, Becker T, Söderdahl G, Chazouillères O, Mäkisalo H, Pageaux GP, Steininger R, Soliman T, de Jong KP, Pirenne J, Margreiter R, Pratschke J, Pinna AD, Hauss J, Schreiber S, Strasser S, Klempnauer J, Troisi RI, Bhoori S, Lerut J, Bilbao I, Klein CG, Königsrainer A, Mirza DF, Otto G, Mazzaferro V, Neuhaus P, Schlitt HJ. Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial. Transplantation. 2016 Jan;100(1):116-25. doi: 10.1097/TP.0000000000000965. PubMed PMID: 26555945; PubMed Central PMCID: PMC4683033.


den Dulk AC, Sebib Korkmaz K, de Rooij BJ, Sutton ME, Braat AE, Inderson A, Dubbeld J, Verspaget HW, Porte RJ, van Hoek B. High peak alanine aminotransferase determines extra risk for nonanastomotic biliary strictures after liver transplantation with donation after circulatory death. Transpl Int. 2015 Apr;28(4):492-501. doi: 10.1111/tri.12524. Epub 2015 Jan 30. PubMed PMID:

25601020.


de Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, Beuers U, van Buuren HR, Drenth JP, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MM, Vrolijk JM, Kraal G, Mulder CJ, van Nieuwkerk CM, Fischer J, Berg T, Stickel F, Sarrazin C, Schramm C, Lohse AW, Weiler-Normann C, Lerch MM, Nauck M, Volzke H, Homuth G, Bloemena E, Verspaget HW, Kumar V, Zhernakova A, Wijmenga C, Franke L, Bouma G. Dutch Autoimmune Hepatitis Study Group; LifeLines Cohort Study; Study of Health in Pomerania. Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1. Gastroenterology 2014;147 2: 443-452. 


Korkmaz KS, de Rooij BJF, van Hoek B, Janse M, Coenraad MJ, van der Reijden JJ, Weersma RK, Porte RJ, Voorneveld PW, Baranski AG, Verspaget HW. MMP-2 is a disease-modifying gene in primary sclerosing cholangitis. Liver International 2014; 34(2):274-280.


Krol CG, Dekkers OM, Kroon HM, Rabelink TJ, van Hoek B, Hamdy NA. Longitudinal Changes in BMD and fracture risk in orthotopic liver transplant recipients not using bone- modifying treatment. J Bone Miner Res 2014; 29(8): 1763-1769.


Langers P, Press RR, Inderson A, Cremers SCLM, den Hartigh J, Baranski AG, van Hoek B. Limited Sampling Model for Advanced Mycophenolic Acid Therapeutic Drug Monitoring After Liver Transplantation. Therapeutic Drug Monitoring 2014; 36(2):141-147.


Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BWM, Poen AC, van Nieuwkerk KM, Drenth JP, Witteman BJ, Tuynman HA, Naber AH, Kingma PJ, van Buuren HR, van Hoek B, Vleggaar FP, van Geloven N, Beuers U, Ponsioen CY. Population-Based Epidemiology, Malignancy Risk, and Outcome of Primary Sclerosing Cholangitis. Hepatology 2013; 58(6):2045-2055.


van Gerven NMF, de Boer YS, Zwiers A, van Hoek B, van Erpecum KJ, Beuers U, van Buuren HR, Drenth JPH, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MMJ, Vrolijk JM, Kraal G, Mulder CJJ, van Nieuwkerk CMJ, Bouma G. Cytotoxic T Lymphocyte Antigen-4+49A/G polymorphism does not affect susceptibility to autoimmune hepatitis. Liver International 2013; 33(7):1039-1043.


van Gerven NMF, Verwer BJ, Witte BI, van Hoek B, Coenraad MJ, van Erpecum KJ, Beuers U, van Buuren HR, de Man RA, Drenth JPH, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MMJ, Mulder CJJ, van Nieuwkerk KMJ, Bouma G. Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission. Journal of Hepatology 2013; 58(1):141-147.


Wesdorp DJW, Knoester M, Braat AE, Coenraad MJ, Vossen ACTM, Claas ECJ, Hoek B. Nucleoside plus nucleotide analogs and cessation of hepatitis B immunoglobulin after liver transplantation in chronic hepatitis B is safe and effective. Journal of Clinical Virology 2013; 58(1):67-73.


Mergental H, Adam R, Ericzon BG, Kalicinski P, Muhlbacher F, Hockerstedt K, Klempnauer JL, Friman S, Broelsch CE, Mantion G, Fernandez-Sellez C, van Hoek B, Fangmann J, Pirenne J, Muiesan P, Konigsrainer A, Mirza DF, Lerut J, Detry O, Le Treut YP, Mazzaferro V, Lohe F, Berenguer M, Clavien PA, Rogiers X, Belghiti J, Kobori L, Burra P, Wolf P, Schareck W, Pisarski P, Foss A, Filipponi F, Krawczyk M, Wolff M, Langrehr JM, Rolles K, Jamieson N, Hop WCJ, Porte RJ. Liver transplantation for unresectable hepatocellular carcinoma in normal livers. Journal of Hepatology 2012; 57(2):297-305.


Baven-Pronk AMC, Coenraad MJ, van Buuren HR, de Man RA, van Erpecum KJ, Lamers MMH, Drenth JPH, van den Berg AP, Beuers UH, den Ouden J, Koek GH, van Nieuwkerk CMJ, Bouma G, Brouwer JT, van Hoek B. The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes. Alimentary Pharmacology & Therapeutics 2011; 34(3):335-343.


de Rooij BJF, van der Beek MT, van Hoek B, Vossen ACTM, ten Hove WR, Roos A, Schaapherder AF, Porte RJ, van der Reijden JJ, Coenraad MJ, Hommes DW, Verspaget HW. Mannose-binding lectin and Ficolin-2 gene polymorphisms predispose to cytomegalovirus (re)infection after orthotopic liver transplantation. Journal of Hepatology 2011; 55(4):800-807.

Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, Ferenci P, Nevens F, Mullhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M. Telaprevir for Retreatment of HCV Infection. New England Journal of Medicine 2011; 364(25):2417-2428.


de Rooij BJF, van Hoek B, ten Hove WR, Roos A, Bouwman LH, Schaapherder AF, Porte RJ, Daha MR, van der Reijden JJ, Coenraad MJ, Ringers J, Baranski AG, Hepkema BG, Hommes DW, Verspaget HW. Lectin Complement Pathway Gene Profile of Donor and Recipient Determine the Risk of Bacterial Infections After Orthotopic Liver Transplantation. Hepatology 2010; 52(3):1100-1110.

Dubbeld J, Hoekstra H, Farid W, Ringers J, Porte RJ, Metselaar HJ, Baranski AG, Kazemiers G, van den Berg AP, van Hoek B. Similar liver transplantation survival with selected cardiac death donors and brain death donors (Br J Surg 2010; 97: 744-753) Reply. British Journal of Surgery 2010; 97(8):1310-1311.