134 results on '"Blokzijl H"'
Search Results
2. Protocol for a randomized controlled multicenter trial assessing the efficacy of leuprorelin for severe polycystic liver disease: the AGAINST-PLD study
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Aapkes, S. E., Bernts, L. H. P., van den Berg, A. P., van den Berg, M., Blokzijl, H., Cantineau, A. E. P., van Gastel, M. D. A., de Haas, R. J., Kappert, P., Müller, R. U., Nevens, F., Torra, R., Visser, A., Drenth, J. P. H., and Gansevoort, R. T.
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- 2022
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3. WCN23-0748 HEALTH-RELATED QUALITY OF LIFE IS LINKED TO THE GUT MICROBIOME IN KIDNEY TRANSPLANT RECIPIENTS
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KNOBBE, T.J., primary, Swarte, J.C., additional, Björk, J.R., additional, Gacesa, R., additional, Zhang, S., additional, Vich Vila, A., additional, Investigators, T., additional, Kremer, D., additional, de Meijer, V.E., additional, Blokzijl, H., additional, Zhernakova, A., additional, Fu, J., additional, Harmsen, H.J.M., additional, Bakker, S.J.L., additional, and Weersma, R.K., additional
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- 2023
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4. Hepatitis C Elimination in the Netherlands (CELINE): How nationwide retrieval of lost to follow-up hepatitis C patients contributes to micro-elimination
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Isfordink, Cas J., primary, van Dijk, Marleen, additional, Brakenhoff, Sylvia M., additional, Kracht, Patricia A.M., additional, Arends, Joop E., additional, de Knegt, Robert J., additional, van der Valk, Marc, additional, Drenth, Joost P.H., additional, van den Berg, M., additional, Honkoop, P., additional, Abraham, S., additional, Bosman, S., additional, van Wijngaarden, P., additional, Steenhuisen, K., additional, Friederich, P., additional, Dofferhoff, A.S. M., additional, Berkhout, J., additional, ter Borg, F., additional, da Silva, J.M., additional, Verhagen, M.A.M.T., additional, Vos, X., additional, Vlaar, K., additional, Douma, R., additional, Erkelen, W.G., additional, den Reijer, M., additional, Hoebe, C.J.P.A., additional, Heil, J., additional, Baven, M., additional, van Soest, H., additional, Korkmaz, K. Sebib, additional, Bezemer, G., additional, Lammers, A.J.J., additional, Debast, S.B., additional, de Jong, H.J.M., additional, Bus, P., additional, Sturm, P., additional, den Hollander, J., additional, Kampschreur, L.M., additional, Venneman, N., additional, Bosma, F., additional, Koc, O.M., additional, Ackens, R., additional, van Oorschot, E., additional, Klemt-Kropp, M., additional, Baak, L.C., additional, Brouwer, J.T., additional, Spanier, B.W.M., additional, Swanink, C., additional, Blokzijl, H., additional, Knoester, M., additional, Liedorp, P., additional, van Bergeijk, J., additional, and van Nunen, A., additional
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- 2022
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5. Ribavirin steady‐state plasma level is a predictor of sustained virological response in hepatitis C–infected patients treated with direct‐acting antivirals
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van Tilborg, M., Lieveld, F. I., Smolders, E. J., van Erpecum, K. J., de Kanter, C. T. M. M., Maan, R., van der Valk, M., Arends, J. E., Dofferhoff, A. S. M., Blokzijl, H., Bijmolen, M., Drenth, J. P. H., de Knegt, R. J., and Burger, D. M.
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- 2017
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6. Diagnostic value of liver stiffness as marker of hepatic marker of hepatic amyloid deposition in systemic AL amyloidosis
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Brunger, A. F., Bijzet, J., Blokzijl, H., Van Rheenen, R., Gans, R., Hazenberg, B., Nienhuis, H. L. A., Lifelong Learning, Education & Assessment Research Network (LEARN), Groningen Kidney Center (GKC), and Translational Immunology Groningen (TRIGR)
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- 2022
7. POS0124 DIAGNOSTIC VALUE OF LIVER STIFFNESS AS MARKER OF HEPATIC MARKER OF HEPATIC AMYLOID DEPOSITION IN SYSTEMIC AL AMYLOIDOSIS
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Brunger, A. F., primary, Bijzet, J., additional, Blokzijl, H., additional, Van Rheenen, R., additional, Gans, R., additional, Hazenberg, B., additional, and Nienhuis, H. L. A., additional
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- 2022
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8. Een patiënte met leverfalen en pseudocirrose
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Petra Hoogland, Evelien Duiker, Pennings, Jan P., Meijer, Vincent E., Blokzijl, H., Groningen Institute for Organ Transplantation, Center for Liver, Digestive and Metabolic Diseases, and Targeted Gynnaecologic Oncology
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Acute-On-Chronic Liver Failure/complications ,Breast Neoplasms/complications ,Liver Cirrhosis/complications ,Liver Neoplasms/diagnosis ,Humans ,Female ,Tomography, X-Ray Computed ,Aged - Abstract
Achtergrond Acuut-op-chronisch leverfalen wordt gekenmerkt door acute, ernstige verslechtering van de leverfunctie bij patiënten met pre-existente cirrose, gerelateerd aan een uitlokkende factor. Dat klinische beeld kan soms het gevolg zijn van een andere aandoening die niet primair de lever treft. Casus Een 65-jarige vrouw, bekend met cirrose, werd overgeplaatst naar ons transplantatiecentrum vanwege het beeld van acuut-op-chronisch leverfalen. Vanwege haar voorgeschiedenis van mammacarcinoom, onverwacht afwijkende laboratoriumuitslagen en een fenotype dat niet geheel bij de diagnose paste, verrichtten we een leverbiopsie. Het biopt toonde diffuse metastasering van mammacarcinoom. Eerder beeldvormend onderzoek had kenmerken van cirrose laten zien, zonder aanwijzingen voor maligniteit; dit misleidende beeld wordt pseudocirrose genoemd. Conclusie Een diffuus hepatogeen gemetastaseerde maligniteit kan lijken op gedecompenseerde cirrose en acuut-op-chronisch leverfalen, zowel in presentatie als bij beeldvormend onderzoek. Levertransplantatie is bij acuut-op-chronisch leverfalen soms de enige levensreddende behandeling, maar is gecontra-indiceerd bij maligniteit. Om een gegronde indicatie voor levertransplantatie te verkrijgen moet een leverbiopsie worden overwogen, ook in spoedsituaties.
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- 2022
9. Recent outcome of liver transplantation for Budd Chiari syndrome - analysis of the european liver transplant registry (ELTR) and affiliated centres
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Dongelmans, E., Polak, Wojciech, Adam, R., Karam, Vincent, Pirenne, Jacques, Acarlı, Koray, Hakeem, A., Dhakshinamoorthy, Vignesh, Fedaruk, Dzmitry, Rummo, Oleg, Kılıç, Merve, Nordin, Arno, Fischer, L., Parente, Annalisa, Mirza, Dimitra, Bennet, William, Tokat, Yaman, Faitot, F., Antonelli, Barbara, Muiesan, Paola, Nadalin, Sivio, Berlakovich, Gabrielle, Patch, D., Berrevoet, Frederik, Ribnikar, Mojca, Gerster, Thomas, Savier, E., Gruttadauria, S., Ericzon, B. G., Cuervas-Mons, Valentin, Saborido, B. Perez, Croner, R., Magini, G., Rossi, R., Popescu, I., Razvan, Lazea, Schneeberger, S., Blokzijl, H., Llado, L., Gomez Bravo, Miguel Angel, Duvoux, Christophe, Mezjlik, V., Oniscu, G., Pearson, K., Dayangaç, Murat, Lucidi, Valerio, Detry, Olivier, Rotellar, F., and Murad, S. Darwish
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European Liver Transplant Registry (ELTR) ,Budd Chiari Syndrome ,Liver Transplant - Published
- 2022
10. Erratum to: Direct-acting antiviral treatment for hepatitis C genotypes uncommon in high-income countries
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Isfordink, C.J., Laar, T.J.W. van de, Rebers, S.P.H., Wessels, E., Molenkamp, R., Knoester, M., Baak, B.C., Nieuwkoop, C. van, Hoek, B. van, Brakenhoff, S.M., Blokzijl, H., Arends, J.E., Valk, M. van der, Schinkel, J., and HepNed Study Grp
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Infectious Diseases ,Oncology - Abstract
[This corrects the article DOI: 10.1093/ofid/ofab006.].
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- 2021
11. Direct-Acting Antiviral Treatment for Hepatitis C Genotypes Uncommon in High-Income Countries: A Dutch Nationwide Cohort Study (vol 8, ofab006, 2021)
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Isfordink, C.J., Laar, T.J.W. van de, Rebers, S.P.H., Wessels, E., Molenkamp, R., Knoester, M., Baak, B.C., Nieuwkoop, C. van, Hoek, B. van, Brakenhoff, S.M., Blokzijl, H., Arends, J.E., Valk, M. van der, Schinkel, J., and HepNed Study Grp
- Published
- 2021
12. Decreased haemoglobin levels are associated with lower muscle mass and strength in kidney transplant recipients.
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Vinke, Joanna Sophia J., Wouters, Hanneke J.C.M., Stam, Suzanne P., Douwes, Rianne M., Post, Adrian, Gomes‐Neto, Antonio W., van der Klauw, Melanie M., Berger, Stefan P., Bakker, Stephan J.L., Annema, C, Bakker, S J L, Berger, S P, Blokzijl, H, Bodewes, F A J A, de Boer, M T, Damman, K, De Borst, M H, Diepstra, A, Dijkstra, G, and Douwes, R M
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- 2022
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13. Employment Status and Work Functioning among Kidney Transplant Recipients
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Knobbe, Tim J., Kremer, Daan, Abma, Femke I., Annema, Coby, Berger, Stefan P., Navis, Gerjan J., van der Mei, Sijrike F., B?ltmann, Ute, Visser, Annemieke, Bakker, Stephan J.L., Annema-de Jong, C., Bakker, S.J.L., Berger, S.P., Blokzijl, H., Bodewes, F.A.J.A., de Boer, M.T., Damman, K., de Borst, M.H., Diepstra, A., Dijkstra, G., Douwes, R.M., Eisenga, M.F., Erasmus, M.E., Gan, C.T., Gomes Neto, A.W., Hak, E., Hepkema, B.G., Klont, F., Knobbe, T.J., Kremer, D., Leuvenink, H.G.D., Lexmond, W.S., de Meijer, V.E., Niesters, H.G.M., van Pelt, L.J., Pol, R.A., Porte, R.J., Ranchor, A.V., Sanders, J.S.F., Siebelink, M.J., Slart, R.J.H.J.A., Swarte, J.C., Touw, D.J., van den Heuvel, M.C., van Leer-Buter, C., van Londen, M., Verschuuren, E.A.M., Vos, M.J., and Weersma, R.K.
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- 2022
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14. Increased anticoagulant response to drugs targeting thrombin, but not to drugs targeting FXa, in plasma from patients with cirrhosis: PB 1.46–5
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Potze, W, Arshad, F, Adelmeijer, J, Blokzijl, H, Van Den Berg, A P, Porte, R J, and Lisman, T
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- 2013
15. Retrieval of chronic hepatitis C patients. A manifesto for action to eliminate hepatitis C in the Netherlands: the CELINE project
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Dijk, M. van, Kracht, P.A.M., Arends, J.E., Blokzijl, H., Burger, D.M., Erpecum, K.J. van, Hoek, B. van, Knegt, R.J. de, Posthouwer, D., Ramsoekh, D., Rijnders, B.J.A., Schinkel, J., Willemse, S.B., Valk, M. van der, Drenth, J.P.H., HepNed Study Grp, Center for Reproductive Medicine, Gastroenterology and Hepatology, Infectious diseases, Amsterdam Gastroenterology Endocrinology Metabolism, APH - Digital Health, APH - Personalized Medicine, and APH - Global Health
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Antiviral Agents/therapeutic use ,Hepatitis C, Chronic/drug therapy ,elimination ,Mass Screening/methods ,HCV ,Prevalence ,virus diseases ,Humans ,chronic hepatitis C ,Disease Eradication/methods ,Netherlands/epidemiology ,Epidemics ,retrieval - Abstract
Chronic hepatitis C virus (HCV) infection is a global public health issue, which is associated with high rates of morbidity and mortality. The development of direct acting antivirals (DAAs) has transformed treatment: they offer us highly-effective therapy with superior tolerability compared to interferon-containing regimens. In 2016, the World Health Organization (WHO) therefore adopted several ambitious viral hepatitis elimination targets, aiming for a 90% reduction in new infections and a 65% reduction in mortality by 2030. The ultimate goal is to eliminate HCV completely. It is reasonable that these goals may be achieved in the Netherlands due to the low prevalence of chronic HCV, the availability of DAAs, and excellent healthcare infrastructure. This paper describes a national effort to curtail the HCV epidemic in the Netherlands through an HCV retrieval and linkage to care project (CELINE: Hepatitis C Elimination in the Netherlands).
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- 2019
16. Free triiodothyronine as determinant of non-alcoholic fatty liver disease in euthyroid subjects: The lifelines cohort study
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Van Den Berg, Eline, van Tienhoven-Wind, Lynnda, Amini, Marzyeh, Schreuder, Tim C.M.A., Faber, Klaas Nico, Blokzijl, H., Dullaart, Robin P.F., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Lifestyle Medicine (LM)
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endogenous compound ,alcohol consumption ,liver cirrhosis ,prevalence ,abdominal obesity ,thyrotropin ,health behavior ,male ,lipid ,middle aged ,nonalcoholic fatty liver ,biochemistry ,cross-sectional study ,controlled study ,hepatitis ,human ,glucose ,Netherlands ,thyroid function ,adult ,clinical trial ,cohort analysis ,waist circumference ,major clinical study ,female ,gamma glutamyltransferase ,liver function ,young adult ,metabolic syndrome X ,liothyronine ,neoplasm - Abstract
Background: Non-alcoholic fatty live disease (NAFLD) is becoming the leading cause of chronic liver disease in de Western world. The liver plays a crucial role in the metabolism of cholesterol and triglycerides and thyroid hormones interact on hepatic lipid homeostasis. Given the importance of variations in thyroid function within the euthyroid range for a considerable number of health issues, including (subclinical) atherosclerosis and biochemical markers of increased cardiovascular risk, it is relevant to examine the relationship of NAFLD with thyroid function parameters in an euthyroid population. Methods: The study was conducted in the LifeLines Cohort Study (N=167,729), a population-based cohort study examining the health and health-related behaviors of participants living in the North of The Netherlands. Only euthyroid subjects (TSH 0.5-4.0 mU/L, FT4 11-19.5 pmol/L and FT3 4.4-6.7 pmol/L) older than 18 years were included. Exclusion criteria were participants with missing data, excessive alcohol use, known hepatitis or cirrhosis, liver functions ≥ three times the upper limit, current cancer, non-white ancestry, previous or current use of thyroid medication and current use of lipid and glucose lowering medication. A priori defined liver biochemistry, thyroid function parameters and metabolic syndrome (MetS) were studied. NAFLD was defined by using the validated Fatty Liver Index (FLI); FLI ≥60 was categorized as NAFLD. A p
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- 2016
17. Etiology-specific hemostatic profiles in cirrhosis
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Bos, S., primary, Adelmeijer, J., additional, Blokzijl, H., additional, Kamphuisen, P.W., additional, Tim, S., additional, and Lisman, T., additional
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- 2018
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18. Prevalence of Non-Alcoholic Fatty Liver Disease and Fibrosis in a Large Population Cohort in the North of the Netherlands: A Lifelines Cohort Study
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van den Berg, E.H., primary, Amini, M., additional, Schreuder, T.C.M.A., additional, Dullaart, R.P.F., additional, Faber, K.N., additional, Alizadeh, B.Z., additional, and Blokzijl, H., additional
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- 2016
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19. FRI-242 - Etiology-specific hemostatic profiles in cirrhosis
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Bos, S., Adelmeijer, J., Blokzijl, H., Kamphuisen, P.W., Tim, S., and Lisman, T.
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- 2018
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20. Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C-infected patients treated with direct-acting antivirals.
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Tilborg, M., Lieveld, F. I., Smolders, E. J., Erpecum, K. J., Kanter, C. T. M. M., Maan, R., Valk, M., Arends, J. E., Dofferhoff, A. S. M., Blokzijl, H., Bijmolen, M., Drenth, J. P. H., Knegt, R. J., and Burger, D. M.
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RIBAVIRIN ,CHRONIC hepatitis C ,ANTIVIRAL agents ,HEPATITIS C virus ,SOFOSBUVIR ,PATIENTS ,THERAPEUTICS - Abstract
Background In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. Aim To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). Methods Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. Results A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). Conclusion In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR. [ABSTRACT FROM AUTHOR]
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- 2017
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21. P0488 : Dissecting the complexity of interferon response that cross talks with 4E-BP1 in hepatitis E virus infection
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Zhou, X., primary, Xu, L., additional, Wang, W., additional, Blokzijl, H., additional, Wang, Y., additional, Sprengers, D., additional, Janssen, H.L.A., additional, de Ruiter, P.E., additional, van der Laan, L.J., additional, Neyts, J., additional, Metselaar, H.J., additional, Kamar, N., additional, Peppelenbosch, M.P., additional, and Pan, Q., additional
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- 2015
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22. Hepatitis E Virus Genotype 3 in Solid Organ Transplant Recipients: Occurrence and the Option of Ribavirin Treatment
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Riezebos-Brilman, Annelies, primary, Blokzijl, H., additional, Sanders, Jan-Stephan, additional, Verschuuren, Erik, additional, and Niesters, Bert, additional
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- 2015
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23. Hepatitis E virus genotype 3; an under diagnosed pathogen causing chronic hepatitis in solid organ transplant recipients
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Riezebos-Brilman, A., primary, Blokzijl, H., additional, Sanders, J.S.F., additional, E.A.M., Verschuuren, additional, and Niesters, H.G.M., additional
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- 2014
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24. Predictive factors of response to cyclosporine and quality of life in steroid-refractory ulcerative colitis: A long-term follow-up
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Blokzijl, H., Makelburg, A. B. U., Jansman, F. G. A., Poen, A. C., Westerveld, B. D., and Vecht, J.
- Published
- 2008
25. Long-term effect of treatment of acute Budd-Chiari syndrome with a transjugular intrahepatic portosytemic shunt
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Blokzijl, H and de Knegt, RJ
- Published
- 2002
26. FRI-296 - Prevalence of Non-Alcoholic Fatty Liver Disease and Fibrosis in a Large Population Cohort in the North of the Netherlands: A Lifelines Cohort Study
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van den Berg, E.H., Amini, M., Schreuder, T.C.M.A., Dullaart, R.P.F., Faber, K.N., Alizadeh, B.Z., and Blokzijl, H.
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- 2016
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27. Cytoprotective role of Multidrug Resistance associated Protein (MRP1) in severe intestinal inflammation: involvement of the leukotriene pathway
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van Steenpaal, A, primary, Blokzijl, H, additional, Vander Borght, S, additional, Bok, LIH, additional, Geuken, M, additional, Dijkstra1, G, additional, Roskams, TAD, additional, Jansen, PLM, additional, and Faber, K.N, additional
- Published
- 2006
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28. Post-transplant muscle mass measured by urinary creatinine excretion rate predicts long-term outcomes after liver transplantation
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Stam, S. P., Oste, M. C. J., Eisenga, M. F., Blokzijl, H., Den Berg, A. P., Bakker, S. J., Vincent E. de Meijer, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
29. Predictive factors of response to cyclosporine and quality-of-life in steroid-refractory ulcerative colitis: A long term Foilow-up
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Blokzijl, H., Makelburg, A., Jansman, F., Poen, A., Westerveld, B., and Vecht, J.
30. Use of Proton-Pump Inhibitors is Associated with Lower Magnesium and Iron Status and Excess Mortality in Renal Transplant Recipients
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Gomes-Neto, A., Douwes, R., Eisenga, M., Berger, S., Gans, R., Berg, E., Navis, G., Blokzijl, H., Bakker, S., Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Value, Affordability and Sustainability (VALUE), and Lifelong Learning, Education & Assessment Research Network (LEARN)
31. Liver Transplantation in Groningen, The Netherlands
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Yvonne de Vries, Iris de Jong, Berendsen, Tim A., Ton Lisman, Henkjan J Verkade, René Scheenstra, Koen Reyntjens, Boer, Marieke T., Blokzijl, H., Peeters, Paul M. G., Den Berg, Aad P., and Porte, Robert J.
32. Diagnostic performance of liver stiffness as marker of liver involvement in systemic immunoglobulin light chain (AL) amyloidosis.
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Brunger AF, Tingen HSA, Bijzet J, van Rheenen R, Blokzijl H, Roeloffzen WWH, Houwerzijl EJ, Muntinghe FLH, Slart RHJA, Gans ROB, Kimmich C, Hazenberg BPC, and Nienhuis HLA
- Abstract
Objective: To investigate the diagnostic performance of liver stiffness for detecting liver involvement in immunoglobulin light chain (AL) amyloidosis., Methods: Liver stiffness was measured using transient elastography in 71 patients with systemic AL amyloidosis and 18 patients with wild type transthyretin (ATTRwt) amyloidosis with cardiomyopathy. Both non-invasive consensus criteria and serum amyloid P component (SAP) scintigraphy were used as substitute standards instead of liver biopsy for establishing liver involvement., Results: Liver stiffness was higher in AL amyloidosis patients with liver involvement than in those without: this was observed using both consensus criteria (median 14.4 kPa vs. 8.1 kPa; p = 0.001) and SAP scintigraphy (median 20.9 kPa vs. 6.2 kPa; p < 0.001). Liver stiffness was also higher in AL amyloidosis patients with liver involvement compared to AL and ATTRwt amyloidosis patients with cardiac involvement. Based on receiver operating characteristic (ROC) curves a cut-off value of 14.4 kPa for stiffness was optimal to indicate liver involvement, providing sensitivity and specificity of 50% and 74%, respectively, using the consensus criteria and 63% and 90%, respectively, using SAP scintigraphy as standard., Conclusion: Liver stiffness is a promising tool to establish liver involvement in AL amyloidosis having potential to become part of updated criteria for liver involvement., (© 2024. The Author(s).)
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- 2024
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33. Genome-wide Studies Reveal Genetic Risk Factors for Hepatic Fat Content.
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Li Y, van den Berg EH, Kurilshikov A, Zhernakova DV, Gacesa R, Hu S, Lopera-Maya EA, Zhernakova A, de Meijer VE, Sanna S, Dullaart RPF, Blokzijl H, Festen EAM, Fu J, and Weersma RK
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- Humans, Female, Male, Risk Factors, Middle Aged, Polymorphism, Single Nucleotide genetics, Magnetic Resonance Imaging, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease diagnostic imaging, Adult, Aged, Fatty Liver genetics, Fatty Liver diagnostic imaging, Genome-Wide Association Study, Genetic Predisposition to Disease genetics, Liver diagnostic imaging, Liver metabolism, Liver pathology
- Abstract
Genetic susceptibility to metabolic associated fatty liver disease (MAFLD) is complex and poorly characterized. Accurate characterization of the genetic background of hepatic fat content would provide insights into disease etiology and causality of risk factors. We performed genome-wide association study (GWAS) on two noninvasive definitions of hepatic fat content: magnetic resonance imaging proton density fat fraction (MRI-PDFF) in 16,050 participants and fatty liver index (FLI) in 388,701 participants from the United Kingdom (UK) Biobank (UKBB). Heritability, genetic overlap, and similarity between hepatic fat content phenotypes were analyzed, and replicated in 10,398 participants from the University Medical Center Groningen (UMCG) Genetics Lifelines Initiative (UGLI). Meta-analysis of GWASs of MRI-PDFF in UKBB revealed five statistically significant loci, including two novel genomic loci harboring CREB3L1 (rs72910057-T, P = 5.40E-09) and GCM1 (rs1491489378-T, P = 3.16E-09), respectively, as well as three previously reported loci: PNPLA3, TM6SF2, and APOE. GWAS of FLI in UKBB identified 196 genome-wide significant loci, of which 49 were replicated in UGLI, with top signals in ZPR1 (P = 3.35E-13) and FTO (P = 2.11E-09). Statistically significant genetic correlation (rg) between MRI-PDFF (UKBB) and FLI (UGLI) GWAS results was found (rg = 0.5276, P = 1.45E-03). Novel MRI-PDFF genetic signals (CREB3L1 and GCM1) were replicated in the FLI GWAS. We identified two novel genes for MRI-PDFF and 49 replicable loci for FLI. Despite a difference in hepatic fat content assessment between MRI-PDFF and FLI, a substantial similar genetic architecture was found. FLI is identified as an easy and reliable approach to study hepatic fat content at the population level., (© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)
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- 2024
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34. Multiple indicators of gut dysbiosis predict all-cause and cause-specific mortality in solid organ transplant recipients.
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Swarte JC, Zhang S, Nieuwenhuis LM, Gacesa R, Knobbe TJ, De Meijer VE, Damman K, Verschuuren EAM, Gan TC, Fu J, Zhernakova A, Harmsen HJM, Blokzijl H, Bakker SJL, Björk JR, and Weersma RK
- Abstract
Objective: Gut microbiome composition is associated with multiple diseases, but relatively little is known about its relationship with long-term outcome measures. While gut dysbiosis has been linked to mortality risk in the general population, the relationship with overall survival in specific diseases has not been extensively studied. In the current study, we present results from an in-depth analysis of the relationship between gut dysbiosis and all-cause and cause-specific mortality in the setting of solid organ transplant recipients (SOTR)., Design: We analysed 1337 metagenomes derived from faecal samples of 766 kidney, 334 liver, 170 lung and 67 heart transplant recipients part of the TransplantLines Biobank and Cohort-a prospective cohort study including extensive phenotype data with 6.5 years of follow-up. To analyze gut dysbiosis, we included an additional 8208 metagenomes from the general population of the same geographical area (northern Netherlands). Multivariable Cox regression and a machine learning algorithm were used to analyse the association between multiple indicators of gut dysbiosis, including individual species abundances, and all-cause and cause-specific mortality., Results: We identified two patterns representing overall microbiome community variation that were associated with both all-cause and cause-specific mortality. The gut microbiome distance between each transplantation recipient to the average of the general population was associated with all-cause mortality and death from infection, malignancy and cardiovascular disease. A multivariable Cox regression on individual species abundances identified 23 bacterial species that were associated with all-cause mortality, and by applying a machine learning algorithm, we identified a balance (a type of log-ratio) consisting of 19 out of the 23 species that were associated with all-cause mortality., Conclusion: Gut dysbiosis is consistently associated with mortality in SOTR. Our results support the observations that gut dysbiosis is associated with long-term survival. Since our data do not allow us to infer causality, more preclinical research is needed to understand mechanisms before we can determine whether gut microbiome-directed therapies may be designed to improve long-term outcomes., Competing Interests: Competing interests: The TransplantLines Biobank and Cohort study received funding from Astellas BV (TransplantLines Biobank and Cohort study) and Chiesi Pharmaceuticals BV (PA-SP/PRJ-2020-9136) and was cofinanced by the Dutch Ministry of Economic Affairs and Climate Policy by means of the PPP allowance made available by the Top Sector Life Sciences and Health to stimulate public–private partnerships. Sequencing of the kidney part of the TransplantLines cohort was funded by a grant from the Dutch NWO/TTW/DSM partnership programme Animal Nutrition and Health (project number 14939) to SJLB, RKW is supported by the Seerave Foundation, the Netherlands Organization for Scientific Research (NWO) and the EU Horizon Europe Programme grant miGut-Health: personalised blueprint of intestinal health (101095470). JF is supported by the Dutch Heart Foundation IN-CONTROL (CVON2018-27), the ERC Consolidator grant (grant agreement No. 101001678), NWO-VICI grant VI.C.202.022, the AMMODO Science Award 2023 for Biomedical Sciences from Stichting Ammodo and the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of The Netherlands., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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35. Recent outcomes of liver transplantation for Budd-Chiari syndrome: A study of the European Liver Transplant Registry (ELTR) and affiliated centers.
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Dongelmans E, Erler N, Adam R, Nadalin S, Karam V, Yilmaz S, Kelly C, Pirenne J, Acarli K, Allison M, Hakeem A, Dhakshinamoorthy V, Fedaruk D, Rummo O, Kilic M, Nordin A, Fischer L, Parente A, Mirza D, Bennet W, Tokat Y, Faitot F, Antonelli BB, Berlakovich G, Patch D, Berrevoet F, Ribnikar M, Gerster T, Savier E, Gruttadauria S, Ericzon BG, Valdivieso A, Cuervas-Mons V, Perez Saborido B, Croner RS, De Carlis L, Magini G, Rossi R, Popescu I, Razvan L, Schneeberger S, Blokzijl H, Llado L, Gomez Bravo MA, Duvoux C, Mezjlík V, Oniscu GC, Pearson K, Dayangac M, Lucidi V, Detry O, Rotellar F, den Hoed C, Polak WG, and Darwish Murad S
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- Humans, Male, Female, Europe epidemiology, Adult, Middle Aged, Treatment Outcome, Young Adult, Adolescent, Retrospective Studies, Budd-Chiari Syndrome surgery, Liver Transplantation statistics & numerical data, Registries statistics & numerical data, Graft Survival
- Abstract
Background and Aims: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplant (post-LT) outcomes in Europe., Approach and Results: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years, with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%)., Conclusions: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes., (Copyright © 2024 American Association for the Study of Liver Diseases.)
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- 2024
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36. The Risk of Microbial Transmission in Recipients of Donor Livers That Underwent Hypothermic or Normothermic Machine Perfusion.
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Endo C, Lascaris B, Brüggenwirth IMA, Roggeveld J, Blokzijl H, de Meijer VE, Doting MHE, and Porte RJ
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Background: Ex situ machine perfusion is increasingly used to preserve and assess donor livers before transplantation. Compared with traditional static cold storage (SCS), machine perfusion exposes livers to an additional risk of microbial contamination. However, information on the risk of microbial transmission during machine perfusion is lacking., Methods: All livers that underwent either hypothermic oxygenated machine perfusion (HOPE) or normothermic machine perfusion (NMP) in our center between September 2021 and September 2023, and during which samples were taken from SCS fluid and/or machine perfusion solution for microbiological examination, were included in this retrospective, observational clinical study. Microbial transmission was examined from SCS fluid to machine perfusion solution fluid and, subsequently, to recipients of these livers., Results: A total of 90 cases of liver machine perfusion were included: 59 HOPE and 31 NMP. SCS preservation fluid cultures before HOPE or NMP were positive for at least 1 microorganism in 52% of the cases. After HOPE, there were no cases of positive machine perfusion fluid or evidence of microbial transmission to the recipients. After NMP, in 1 (3%) patient Escherichia coli was grown from abdominal drain fluid, the same bacterial strain that was also grown from the SCS preservation fluid before NMP. This E coli was resistant to the antibiotics that are routinely added to the NMP perfusion fluid., Conclusions: The risk of microbial transmission after machine perfusion is very low but not absent. We recommend routine sampling of machine perfusion fluid at the end of the procedure for microbiological analysis., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)
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- 2024
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37. Circulating Trimethylamine-N-Oxide Is Elevated in Liver Transplant Recipients.
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Trillos-Almanza MC, Chvatal-Medina M, Connelly MA, Moshage H, TransplantLines Investigators, Bakker SJL, de Meijer VE, Blokzijl H, and Dullaart RPF
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- Adult, Aged, Female, Humans, Male, Middle Aged, Transplant Recipients, Biomarkers blood, Liver Transplantation adverse effects, Methylamines blood
- Abstract
Liver transplant recipients (LTRs) have lower long-term survival rates compared with the general population. This underscores the necessity for developing biomarkers to assess post-transplantation mortality. Here we compared plasma trimethylamine-N-oxide (TMAO) levels with those in the general population, investigated its determinants, and interrogated its association with all-cause mortality in stable LTRs. Plasma TMAO was measured in 367 stable LTRs from the TransplantLines cohort (NCT03272841) and in 4837 participants from the population-based PREVEND cohort. TMAO levels were 35% higher in LTRs compared with PREVEND participants (4.3 vs. 3.2 µmol/L, p < 0.001). Specifically, TMAO was elevated in LTRs with metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and polycystic liver disease as underlying etiology ( p < 0.001 for each). Among LTRs, TMAO levels were independently associated with eGFR (std. β = -0.43, p < 0.001) and iron supplementation (std. β = 0.13, p = 0.008), and were associated with mortality (29 deaths during 8.6 years follow-up; log-rank test p = 0.017; hazard ratio of highest vs. lowest tertile 4.14, p = 0.007). In conclusion, plasma TMAO is likely elevated in stable LTRs, with impaired eGFR and iron supplementation as potential contributory factors. Our preliminary findings raise the possibility that plasma TMAO could contribute to increased mortality risk in such patients, but this need to be validated through a series of rigorous and methodical studies., Competing Interests: M.A.C. is an employee of Labcorp. M.A.C. and assisted with the generation of the NMR measurements and with the interpretation of the data. Labcorp was not involved in the study design, the data analysis, or the decision to publish the results. The rest of the authors declared they have no competing interests.
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- 2024
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38. 'Effects of a home-based bimodal lifestyle intervention in frail patients with end-stage liver disease awaiting orthotopic liver transplantation': study protocol of a non-randomised clinical trial.
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Wijma AG, Bongers BC, Annema C, Dekker R, Blokzijl H, van der Palen JA, De Meijer VE, Cuperus FJ, and Klaase JM
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- Aged, Humans, Exercise Therapy methods, Frail Elderly, Life Style, Quality of Life, Clinical Trials as Topic, End Stage Liver Disease complications, End Stage Liver Disease surgery, Liver Transplantation
- Abstract
Introduction: Patients with end-stage liver disease awaiting orthotopic liver transplantation (OLT) are generally classified as frail due to disease-related malnutrition and a progressive decline in musculoskeletal and aerobic fitness, which is associated with poor pre-OLT, peri-OLT and post-OLT outcomes. However, frailty in these patients may be reversable with adequate exercise and nutritional interventions., Methods and Analysis: Non-randomised clinical trial evaluating the effect of a home-based bimodal lifestyle programme in unfit patients with a preoperative oxygen uptake (VO
2 ) at the ventilatory anaerobic threshold ≤13 mL/kg/min and/or VO2 at peak exercise ≤18 mL/kg/min listed for OLT at the University Medical Center Groningen (UMCG). The programme is patient tailored and comprises high-intensity interval and endurance training, and functional exercises three times per week, combined with nutritional support. Patients will go through two training periods, each lasting 6 weeks.The primary outcome of this study is the impact of the programme on patients' aerobic fitness after the first study period. Secondary outcomes include aerobic capacity after the second study period, changes in sarcopenia, anthropometry, functional mobility, perceived quality of life and fatigue, incidence of hepatic encephalopathy and microbiome composition. Moreover, number and reasons of intercurrent hospitalisations during the study and postoperative outcomes up to 12 months post OLT will be recorded. Finally, feasibility of the programme will be assessed by monitoring the participation rate and reasons for non-participation, number and severity of adverse events, and dropout rate and reasons for dropout., Ethics and Dissemination: This study was approved by the Medical Research Ethics Committee of the UMCG (registration number NL83612.042.23, August 2023) and is registered in the Clinicaltrials.gov register (NCT05853484). Good Clinical Practice guidelines and the principles of the Declaration of Helsinki will be applied. Results of this study will be submitted for presentation at (inter)national congresses and publication in peer-reviewed journals., Trial Registration Number: NCT05853484., Competing Interests: Competing interests: VEDM reports a VENI research grant by the Dutch Research Council (NWO; grant #09150161810030), a Research grant from the Dutch Ministry of Economic Affairs (Health~Holland Public Private Partnership grant #PPP-2019-024), and a Research grant from the Dutch Society for Gastroenterology (NVGE #01-2021), all outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2024
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39. Prolonged hypothermic machine perfusion enables daytime liver transplantation - an IDEAL stage 2 prospective clinical trial.
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Brüggenwirth IMA, Lantinga VA, Lascaris B, Thorne AM, Meerdink M, de Kleine RH, Blokzijl H, van den Berg AP, Reyntjens KMEM, Lisman T, Porte RJ, and de Meijer VE
- Abstract
Background: Liver transplantation is traditionally performed around the clock to minimize organ ischemic time. However, the prospect of prolonging preservation times holds the potential to streamline logistics and transform liver transplantation into a semi-elective procedure, reducing the need for nighttime surgeries. Dual hypothermic oxygenated machine perfusion (DHOPE) of donor livers for 1-2 h mitigates ischemia-reperfusion injury and improves transplant outcomes. Preclinical studies have shown that DHOPE can safely extend the preservation of donor livers for up to 24 h., Methods: We conducted an IDEAL stage 2 prospective clinical trial comparing prolonged (≥4 h) DHOPE to conventional (1-2 h) DHOPE for brain-dead donor livers, enabling transplantation the following morning. Liver allocation to each group was based on donor hepatectomy end times. The primary safety endpoint was a composite of all serious adverse events (SAE) within 30 days after transplantation. The primary feasibility endpoint was defined as the number of patients assigned and successfully receiving a prolonged DHOPE-perfused liver graft. Trial registration at: WHO International Clinical Trial Registry Platform, number NL8740., Findings: Between November 1, 2020 and July 16, 2022, 24 patients were enrolled. The median preservation time was 14.5 h (interquartile range [IQR], 13.9-15.5) for the prolonged group (n = 12) and 7.9 h (IQR, 7.6-8.6) for the control group (n = 12; p = 0.01). In each group, three patients (25%; 95% CI 3.9-46%, p = 1) experienced a SAE. Markers of ischemia-reperfusion injury and oxidative stress in both perfusate and recipients were consistently low and showed no notable discrepancies between the two groups. All patients assigned to either the prolonged group or control group successfully received a liver graft perfused with either prolonged DHOPE or control DHOPE, respectively., Interpretation: This first-in-human clinical trial demonstrates the safety and feasibility of DHOPE in prolonging the preservation time of donor livers to enable daytime transplantation. The ability to extend the preservation window to up to 20 h using hypothermic oxygenated machine preservation at a 10 °C temperature has the potential to reshape the landscape of liver transplantation., Funding: University Medical Center Groningen, the Netherlands., Competing Interests: Vincent E. de Meijer reports a VENI research grant by the Dutch Research Council (NWO; grant #09150161810030), a Research grant from the Dutch Ministry of Economic Affairs (Health ∼ Holland Public Private Partnership grant #PPP-2019-024), and a Research grant from the Dutch Society for Gastroenterology (NVGE #01-2021), all outside the submitted work. Other authors declare that they have no competing interests., (© 2023 The Author(s).)
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- 2024
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40. Health-related quality of life is linked to the gut microbiome in kidney transplant recipients.
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Swarte JC, Knobbe TJ, Björk JR, Gacesa R, Nieuwenhuis LM, Zhang S, Vila AV, Kremer D, Douwes RM, Post A, Quint EE, Pol RA, Jansen BH, de Borst MH, de Meijer VE, Blokzijl H, Berger SP, Festen EAM, Zhernakova A, Fu J, Harmsen HJM, Bakker SJL, and Weersma RK
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- Humans, Quality of Life, Feces microbiology, Dysbiosis microbiology, Gastrointestinal Microbiome genetics, Kidney Transplantation adverse effects
- Abstract
Kidney transplant recipients (KTR) have impaired health-related quality of life (HRQoL) and suffer from intestinal dysbiosis. Increasing evidence shows that gut health and HRQoL are tightly related in the general population. Here, we investigate the association between the gut microbiome and HRQoL in KTR, using metagenomic sequencing data from fecal samples collected from 507 KTR. Multiple bacterial species are associated with lower HRQoL, many of which have previously been associated with adverse health conditions. Gut microbiome distance to the general population is highest among KTR with an impaired physical HRQoL (R = -0.20, P = 2.3 × 10
-65 ) and mental HRQoL (R = -0.14, P = 1.3 × 10-3 ). Physical and mental HRQoL explain a significant part of variance in the gut microbiome (R2 = 0.58%, FDR = 5.43 × 10-4 and R2 = 0.37%, FDR = 1.38 × 10-3 , respectively). Additionally, multiple metabolic and neuroactive pathways (gut brain modules) are associated with lower HRQoL. While the observational design of our study does not allow us to analyze causality, we provide a comprehensive overview of the associations between the gut microbiome and HRQoL while controlling for confounders., (© 2023. The Author(s).)- Published
- 2023
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41. Patients with metabolic dysfunction-associated steatotic liver disease have preserved in vitro responses to antiplatelet drugs.
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van den Boom BP, van Beek AP, Adelmeijer J, Blokzijl H, and Lisman T
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Background: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at a risk of developing cardiovascular disease. Antiplatelet therapy not only prevents cardiovascular disease in these patients, but may also lower the risk of progression into advanced stages of fibrosis. However, patients with MASLD-associated cirrhosis often have complex changes in the hemostatic system and have been excluded from randomized trials., Objectives: The aim of this study was to assess the potency of antiplatelet drugs in these patients with MASLD-associated cirrhosis., Methods: We included patients with MASLD-associated cirrhosis ( n = 19), patients with type 2 diabetes (DM2) and steatosis ( n = 22), patients with steatosis only ( n = 15), and healthy controls ( n = 20). We measured basal platelet aggregation and activation using light transmission aggregometry and flow cytometry. We subsequently measured platelet aggregation and activation after in vitro addition of aspirin, cangrelor, and ticagrelor and compared the antiplatelet response in patients and healthy controls., Results: Rates of aspirin resistance as measured by light transmission aggregometry were similar between patients with MASLD-associated cirrhosis and healthy controls (21% vs 16%), but were significantly higher in patients with DM2 and steatosis (50% [ P = .02] vs controls) and patients with steatosis only (53% [ P = .05] vs controls). In patients with DM2 and steatosis, but not with MASLD-associated cirrhosis, the potency of cangrelor was significantly lower than that in healthy controls ( P = .028)., Conclusion: The in vitro potency of aspirin, cangrelor, and ticagrelor in samples of patients with MASLD-associated cirrhosis is similar to that of healthy controls. In contrast, the potency of commonly used antiplatelet drugs may be altered in patients with DM2 and steatosis and in patients with steatosis only., (© 2023 The Author(s).)
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- 2023
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42. Growth differentiation factor 7 autocrine signaling promotes hepatic progenitor cell expansion in liver fibrosis.
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Kong D, Mourtzinos A, Heegsma J, Blokzijl H, de Meijer VE, and Faber KN
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- Humans, Hepatic Stellate Cells metabolism, Liver metabolism, Liver Cirrhosis pathology, Stem Cells metabolism, Transforming Growth Factor beta1 metabolism, Autocrine Communication, Liver Diseases pathology
- Abstract
Background and Aim: Liver fibrosis is prevalent among chronic diseases of the liver and represents a major health burden worldwide. Growth differentiation factor 7 (GDF7), a member of the TGFβ protein superfamily, has been recently investigated for its role in repair of injured organs, but its role in chronic liver diseases remains unclear. Here, we examined hepatic GDF7 expression and its association with development and progression of human liver fibrosis. Moreover, we determined the source and target cells of GDF7 in the human liver., Methods: GDF7 expression was analyzed in fibrotic and healthy human liver tissues by immunohistochemistry and qPCR. Cell-specific accumulation of GDF7 was examined by immunofluorescence through co-staining of cell type-specific markers on formalin-fixed paraffin-embedded human liver tissues. Public single cell RNA sequence databases were analyzed for cell type-specific expression of GDF7. In vitro, human liver organoids and LX-2 hepatic stellate cells (LX-2) were treated with recombinant human GDF7. Human liver organoids were co-cultured with activated LX-2 cells to induce an autocrine signaling circuit of GDF7 in liver organoids., Results: GDF7 protein levels were elevated in fibrotic liver tissue, mainly detected in hepatocytes and cholangiocytes. In line, GDF7 mRNA was mainly detected in liver parenchymal cells. Expressions of BMPR1A and BMPR2, encoding GDF7 receptors, were readily detected in hepatocytes, cholangiocytes and stellate cells in vivo and in vitro. In vitro, recombinant GDF7 promoted liver organoid growth and enhanced expression of the progenitor cell markers (LGR5, AXIN2), but failed to activate LX-2 cells. Still, activated LX-2 cells induced GDF7 and LGR5 expression in co-cultured human liver organoids., Conclusions: Collectively, this study reveals a role of GDF7 in liver fibrosis and suggests a potential pro-regenerative function that can be utilized for amelioration of hepatic fibrosis caused by chronic liver disease., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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43. Hepatic stellate cells induce an inflammatory phenotype in Kupffer cells via the release of extracellular vesicles.
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Geng Y, Wang J, Serna-Salas SA, Villanueva AH, Buist-Homan M, Arrese M, Olinga P, Blokzijl H, and Moshage H
- Abstract
Liver fibrosis is the response of the liver to chronic liver inflammation. The communication between the resident liver macrophages (Kupffer cells [KCs]) and hepatic stellate cells (HSCs) has been mainly viewed as one-directional: from KCs to HSCs with KCs promoting fibrogenesis. However, recent studies indicated that HSCs may function as a hub of intercellular communications. Therefore, the aim of the present study was to investigate the role of HSCs on the inflammatory phenotype of KCs. Primary rat HSCs and KCs were isolated from male Wistar rats. HSCs-derived conditioned medium (CM) was harvested from different time intervals (Day 0-2: CM-D2 and Day 5-7: CM-D7) during the activation of HSCs. Extracellular vesicles (EVs) were isolated from CM by ultracentrifugation and evaluated by nanoparticle tracking analysis and western blot analysis. M1 and M2 markers of inflammation were measured by quantitative PCR and macrophage function by assessing phagocytic capacity. CM-D2 significantly induced the inflammatory phenotype in KCs, but not CM-D7. Neither CM-D2 nor CM-D7 affected the phagocytosis of KCs. Importantly, the proinflammatory effect of HSCs-derived CM is mediated via EVs released from HSCs since EVs isolated from CM mimicked the effect of CM, whereas EV-depleted CM lost its ability to induce a proinflammatory phenotype in KCs. In addition, when the activation of HSCs was inhibited, HSCs produced less EVs. Furthermore, the proinflammatory effects of CM and EVs are related to activating Toll-like receptor 4 (TLR4) in KCs. In conclusion, HSCs at an early stage of activation induce a proinflammatory phenotype in KCs via the release of EVs. This effect is absent in CM derived from HSCs at a later stage of activation and is dependent on the activation of TLR4 signaling pathway., (© 2023 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)
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- 2023
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44. Immune Checkpoint Inhibitor-related Pancreatitis: A Case Series, Review of the Literature and an Expert Opinion.
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Kramer S, van Hee K, Blokzijl H, van der Heide F, and Visschedijk MC
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- Humans, Immune Checkpoint Inhibitors therapeutic use, Azathioprine therapeutic use, Tacrolimus therapeutic use, Expert Testimony, Steroids therapeutic use, Autoimmune Pancreatitis drug therapy, Pancreatitis diagnosis, Pancreatitis etiology, Exocrine Pancreatic Insufficiency drug therapy
- Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various malignancies, but are associated with serious adverse events like pancreatitis. Current guidelines are limited to the first step in treating acute ICI-related pancreatitis with steroids but lack treatment advices for steroid dependent pancreatitis. We describe a case series of 3 patients who developed ICI-related pancreatitis with chronic features such as exocrine insufficiency and pancreatic atrophy at imaging. Our first case developed after treatment with pembrolizumab. The pancreatitis responded well after discontinuation of immunotherapy but imaging showed pancreatic atrophy and exocrine pancreatic insufficiency persisted. Cases 2 and 3 developed after treatment with nivolumab. In both, pancreatitis responded well to steroids. However during steroid tapering, pancreatitis recurred and the latter developed exocrine pancreatic insufficiency and pancreatic atrophy at imaging. Our cases demonstrate resemblances with autoimmune pancreatitis based on clinical and imaging findings. In line, both diseases are T-cell mediated and for autoimmune pancreatitis azathioprine is considered as maintenance therapy. Guidelines of other T-cell mediated diseases like ICI-related hepatitis suggest tacrolimus. After adding tacrolimus in case 2 and azathioprine in case 3, steroids could be completely tapered and no new episodes of pancreatitis have occurred. These findings support the idea that the treatment modalities for other T-cell mediated diseases are worthwhile options for steroid dependent ICI-related pancreatitis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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45. Branched Chain Amino Acids Are Associated with Physical Performance in Patients with End-Stage Liver Disease.
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Trillos-Almanza MC, Wessel H, Martínez-Aguilar M, van den Berg EH, Douwes RM, Moshage H, Connelly MA, Bakker SJL, de Meijer VE, Dullaart RPF, and Blokzijl H
- Subjects
- Male, Humans, Female, Amino Acids, Branched-Chain, Hand Strength, Postural Balance, Time and Motion Studies, Physical Functional Performance, End Stage Liver Disease, Liver Diseases
- Abstract
Decreased circulating branched chain amino acids (BCAA) represent a prominent change in amino acid profiles in patients with end-stage liver disease (ESLD). These alterations are considered to contribute to sarcopenia and hepatic encephalopathy and may relate to poor prognosis. Here, we cross-sectionally analyzed the association between plasma BCAA levels and the severity of ESLD and muscle function in participants of the liver transplant subgroup of TransplantLines, enrolled between January 2017 and January 2020. Plasma BCAA levels were measured by nuclear magnetic resonance spectroscopy. Physical performance was analyzed with a hand grip strength test, 4 m walking test, sit-to-stand test, timed up and go test, standing balance test and clinical frailty scale. We included 92 patients (65% men). The Child Pugh Turcotte classification was significantly higher in the lowest sex-stratified BCAA tertile compared to the highest tertile ( p = 0.015). The times for the sit-to-stand (r = -0.352, p < 0.05) and timed up and go tests (r = -0.472, p < 0.01) were inversely correlated with total BCAA levels. In conclusion, lower circulating BCAA are associated with the severity of liver disease and impaired muscle function. This suggests that BCAA may represent a useful prognostic marker in the staging of liver disease severity.
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- 2023
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46. Expeditious quantification of plasma tacrolimus with liquid chromatography tandem mass spectrometry in solid organ transplantation.
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Zijp TR, Knobbe TJ, van Hateren K, Roggeveld J, Blokzijl H, Tji Gan C, Jl Bakker S, Jongedijk EM, Investigators T, and Touw DJ
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- Chromatography, Liquid methods, Immunosuppressive Agents, Tandem Mass Spectrometry methods, Prospective Studies, Chromatography, High Pressure Liquid methods, Reproducibility of Results, Tacrolimus, Organ Transplantation
- Abstract
Traditionally, tacrolimus is assessed in whole blood samples, but this is suboptimal from the perspective that erythrocyte-bound tacrolimus is not a good representative of the active fraction. In this work, a straightforward and rapid method was developed for determination of plasma tacrolimus in solid organ transplant recipients, using liquid chromatography tandem mass spectrometry (LC-MS/MS) with heated electrospray ionisation. Sample preparation was performed through protein precipitation of 200 µl plasma with 500 µl stable isotopically labelled tacrolimus I.S. in methanol, where 20 µl was injected on the LC-MS/MS system. Separation was done using a chromatographic gradient on a C18 column (50 × 2.1 mm, 2.6 µm). The method was linear in the concentration range 0.05-5.00 µg/L, with within-run and between-run precision in the range 2-6 % and a run time of 1.5 min. Furthermore, the method was validated for selectivity, sensitivity, carry-over, accuracy and precision, process efficiency, recovery, matrix effect, and stability following EMA and FDA guidelines. Clinical validation was performed in 2333 samples from 1325 solid organ transplant recipients using tacrolimus (liver n = 312, kidney n = 1714, and lung n = 307), which had median plasma tacrolimus trough concentrations of 0.10 µg/L, 0.15 µg/L and 0.23 µg/L, respectively. This method is suitable for measurement of tacrolimus in plasma and will facilitate ongoing observational and prospective studies on the relationship of plasma tacrolimus concentrations with clinical outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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47. Differential effects of oleate on vascular endothelial and liver sinusoidal endothelial cells reveal its toxic features in vitro.
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Geng Y, Arroyave-Ospina JC, Buist-Homan M, Plantinga J, Olinga P, Reijngoud DJ, Van Vilsteren FGI, Blokzijl H, Kamps JAAM, and Moshage H
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- Rats, Animals, Humans, Fatty Acids metabolism, Palmitic Acid toxicity, Palmitic Acid metabolism, Human Umbilical Vein Endothelial Cells metabolism, Liver metabolism, Palmitates toxicity, Palmitates metabolism, Oleic Acid pharmacology, Oleic Acid metabolism, Hepatocytes metabolism
- Abstract
Several fatty acids, in particular saturated fatty acids like palmitic acid, cause lipotoxicity in the context of non-alcoholic fatty liver disease . Unsaturated fatty acids (e.g. oleic acid) protect against lipotoxicity in hepatocytes. However, the effect of oleic acid on other liver cell types, in particular liver sinusoidal endothelial cells (LSECs), is unknown. Human umbilical vein endothelial cells (HUVECs) are often used as a substitute for LSECs, however, because of the unique phenotype of LSECs, HUVECs cannot represent the same biological features as LSECs. In this study, we investigate the effects of oleate and palmitate (the sodium salts of oleic acid and palmitic acid) on primary rat LSECs in comparison to their effects on HUVECs. Oleate induces necrotic cell death in LSECs, but not in HUVECs. Necrotic cell death of LSECs can be prevented by supplementation of 2-stearoylglycerol, which promotes cellular triglyceride (TG) synthesis. Repressing TG synthesis, by knocking down DGAT1 renders HUVECs sensitive to oleate-induced necrotic death. Mechanistically, oleate causes a sharp drop of intracellular ATP level and impairs mitochondrial respiration in LSECs. The combination of oleate and palmitate reverses the toxic effect of oleate in both LSECs and HUVECs. These results indicate that oleate is toxic and its toxicity can be attenuated by stimulating TG synthesis. The toxicity of oleate is characterized by mitochondrial dysfunction and necrotic cell death. Moreover, HUVECs are not suitable as a substitute model for LSECs., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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48. Tremor, Daily Functioning, and Health-Related Quality of Life in Solid Organ Transplant Recipients.
- Author
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Riemersma NL, Kremer D, Knobbe TJ, Gan CT, Nolte S, Gomes-Neto AW, Blokzijl H, de Meijer VE, Damman K, Eisenga MF, Drost G, Elting JWJ, Touw DJ, Berger SP, Bakker SJL, and van der Stouwe AMM
- Subjects
- Female, Humans, Male, Middle Aged, Activities of Daily Living, Cohort Studies, Cross-Sectional Studies, Quality of Life, Tacrolimus, Transplant Recipients, Tremor, Organ Transplantation
- Abstract
Solid organ transplant recipients (SOTR) frequently report tremor. Data concerning tremor-related impairment and its potential impact on health-related quality of life (HRQoL) are lacking. This cross-sectional study assesses impact of tremor on activities of daily living and HRQoL using validated questionnaires among SOTR enrolled in the TransplantLines Biobank and Cohort Study. We included 689 SOTR (38.5% female, mean [±SD] age 58 [±14] years) at median [interquartile range] 3 [1-9] years after transplantation, of which 287 (41.7%) reported mild or severe tremor. In multinomial logistic regression analyses, whole blood tacrolimus trough concentration was an independent determinant of mild tremor (OR per µg/L increase: 1.11, 95% CI: 1.02 to 1.21, p = 0.019). Furthermore, in linear regression analyses, severe tremor was strongly and independently associated with lower physical and mental HRQoL (β = -16.10, 95% CI: -22.23 to -9.98, p < 0.001 and β = -12.68, 95% CI: -18.23 to -7.14, p < 0.001 resp.). SOTR frequently report tremor-related impairment of activities of daily living. Tacrolimus trough concentrations appeared as a main determinant of tremor among SOTR. The strong and independent association of tremor-related impairment with lower HRQoL warrants further studies into the effects of tacrolimus on tremor. Clinical Trial Registration : ClinicalTrials.gov, Identifier NCT03272841., Competing Interests: The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Riemersma, Kremer, Knobbe, Gan, Nolte, Gomes-Neto, Blokzijl, de Meijer, Damman, Eisenga, Drost, Elting, Touw, Berger, Bakker, van der Stouwe and Transplantlines Investigators.)
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- 2023
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49. Variation in the management of benign liver tumors: A European survey and case vignette study.
- Author
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Haring MPD, de Haas RJ, van Vilsteren FGI, Klaase JM, Duiker EW, Blokzijl H, de Jong KP, de Meijer VE, and Cuperus FJC
- Subjects
- Humans, Europe, Liver pathology, Diagnosis, Differential, Magnetic Resonance Imaging methods, Contrast Media, Liver Neoplasms pathology, Adenoma, Liver Cell pathology, Focal Nodular Hyperplasia diagnosis, Focal Nodular Hyperplasia pathology
- Abstract
Background: Management of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), is multidisciplinary and subject to practice variation. We aimed to evaluate variation in clinical management of FNH and HCA in Europe., Methods: We distributed an online survey (November 2021-March 2022) among 294 European experts. The survey included questions on local practice and included eight clinical vignettes. The clinical vignettes focused on FNH or HCA management in the setting of sex, lifestyle modification, and pregnancy., Results: The response rate was 32% and respondents included surgeons (38%), gastroenterologists/hepatologists (25%), radiologists (32%), and pathologists (1.6%) from ten European countries. We observed practice variation with regard to lifestyle modification and imaging follow-up in patients with FNH, and with regard to the management of HCA >5 cm before and during pregnancy. Finally, the management of HCA >5 cm after lifestyle modification deviated from EASL guideline recommendations., Conclusion: Our survey illustrates variability in FNH and HCA management in Europe. Several areas were identified for future research and guideline recommendations, including FNH follow-up and the management of HCA >5 cm. We propose the organization of Delphi consensus meetings to prioritize areas of research and update current guidelines to optimize management for all patients with benign liver tumors., Competing Interests: Declaration of Competing Interest None to be reported., (Copyright © 2023. Published by Elsevier Masson SAS.)
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- 2023
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50. Multidisciplinary management of chronic refractory pain in autosomal dominant polycystic kidney disease.
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van Luijk F, Gansevoort RT, Blokzijl H, Groen GJ, de Haas RJ, Leliveld AM, Meijer E, Perdok JM, Stellema R, Wolff AP, and Casteleijn NF
- Subjects
- Female, Humans, Adult, Middle Aged, Male, Quality of Life, Nephrectomy, Polycystic Kidney, Autosomal Dominant, Chronic Pain therapy, Pain, Intractable surgery, Cysts
- Abstract
Background: Chronic pain is often difficult to manage in autosomal dominant polycystic kidney disease (ADPKD) patients and sometimes even leads to nephrectomy. We analyzed the long-term efficacy of our innovative multidisciplinary protocol to treat chronic refractory pain that aims to preserve kidney function by applying among other sequential nerve blocks., Methods: Patients were eligible if pain was present ≥3 months with a score of ≥50 on a visual analog scale (VAS) of 100, was negatively affecting quality of life and if there had been insufficient response to previous therapies, including opioid treatment. Treatment options were, in order, analgesics, cyst aspiration and fenestration, nerve blocks and nephrectomy., Results: A total of 101 patients were assessed in our clinic (mean age 50 ± 11 years, 65.3% females). Eight patients were treated with medication, 6 by cyst aspiration or fenestration, 63 by nerve blocks and 6 received surgery as the first treatment option. Overall, 76.9% experienced a positive effect on pain complaints shortly after treatment. The VAS score was reduced from 60/100 to 20/100 (P < 0.001) and patients decreased their number of nonopioid and opioid analgesics significantly (P < 0.001, P = 0.01, respectively). A substantial number of the patients (n = 51) needed additional treatment. At the end of follow-up in only 13 patients (12.9%) was surgical intervention necessary: 11 nephrectomies (of which 10 were in patients already on kidney function replacement treatment), 1 liver transplantation and 1 partial hepatectomy. After a median follow-up of 4.5 years (interquartile range 2.5-5.3), 69.0% of the patients still had fewer pain complaints., Conclusions: These data indicate that our multidisciplinary treatment protocol appears effective in reducing pain in the majority of patients with chronic refractory pain, while postponing or even avoiding in most patients surgical interventions such as nephrectomy in most patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)
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- 2023
- Full Text
- View/download PDF
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