Publications by authors named "Joost P H Drenth"

361 Publications

Reduction of Gastrointestinal Bleeding in Patients With Heyde Syndrome Undergoing Transcatheter Aortic Valve Implantation.

Circ Cardiovasc Interv 2022 Jul 5;15(7):e011848. Epub 2022 Jul 5.

Department of Cardiology (M.J.P.R., M.H.v.W., K.v.d.W., N.v.R.), Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Heyde syndrome is the co-occurrence of aortic stenosis and gastrointestinal bleeding secondary to angiodysplasias. Surgical aortic valve replacement effectively reduces bleeding, but the effects of transcatheter aortic valve implantation (TAVI) are largely unknown. This study aimed to describe the reduction of gastrointestinal bleeding in patients with Heyde syndrome after TAVI and to identify the factors associated with rebleeding.

Methods: We enrolled patients with Heyde syndrome from a prospective TAVI registry. Gastrointestinal bleeding episodes were assessed by the Bleeding Academic Research Consortium classification, and cumulative incidence functions were used to calculate cessation rates. Factors potentially associated with rebleeding were analyzed using logistic regression. Differences between Heyde and non-Heyde patients were assessed through a case-cohort study.

Results: Between December 2008 and June 2020, 1111 patients underwent TAVI. There were 70 patients with Heyde syndrome (6.3%). In the first year following TAVI, gastrointestinal bleeding ceased in 46 of 70 patients (62% [95% CI, 50%-74%]). Bleeding episodes decreased from 3.2 (95% CI, 2.5-4.2) to 1.6 ([95% CI, 1.2-2.2] =0.001) and hemoglobin levels increased from 10.3 (95% CI, 10.0-10.8) to 11.3 (95% CI, 10.8-11.6) g/dL (=0.007). Between 1 and 5 years after TAVI (35 [interquartile range, 21-51] months), 53 of 62 patients (83% [95% CI, 72%-92%]) no longer experienced gastrointestinal bleeding. Paravalvular leakage (≥mild) was associated with rebleeding risk (odds ratio, 3.65 [95% CI, 1.36-9.80]; =0.010). Periprocedural bleeding was more common in Heyde than in control patients (adjusted odds ratio, 2.55 [95% CI, 1.37-4.73]; =0.003).

Conclusions: Patients with Heyde syndrome are at increased risk for periprocedural bleeding. Post-TAVI, gastrointestinal bleeding disappears in the majority of patients. Paravalvular leakage may curtail these clinical benefits.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.122.011848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287099PMC
July 2022

How to Train the Next Generation to Provide High-Quality Peer-Reviews.

Clin Gastroenterol Hepatol 2022 Jun 29. Epub 2022 Jun 29.

Department of Gastroenterology, Royal Cornwall Hospitals NHS Trust, Truro, United Kingdom; Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.cgh.2022.05.018DOI Listing
June 2022

UEG journal: The voice of European Gastroenterology.

United European Gastroenterol J 2022 Jul 3;10(6):523-524. Epub 2022 Jun 3.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, Netherlands.

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http://dx.doi.org/10.1002/ueg2.12264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278586PMC
July 2022

Premenstrual syndrome predicts alcohol craving in women with substance use disorders.

Women Health 2022 May-Jun;62(5):430-438. Epub 2022 May 31.

Behavioral Science Institute, Radboud University Nijmegen, The Netherlands.

Premenstrual Syndrome (PMS) comprises psychological, somatic, and behavioral symptoms during the luteal phase of almost every menstrual cycle. PMS and premenstrual dysphoric disorder (PMDD) may be associated with substance use. Between 2018 and 2020 we studied the relationship between PMS and substance use within a prospective case-control design comparing a consecutive series of women having a substance use disorder and being treated in an addiction treatment center (ATC group, n = 151)) and one with community dwelling women attending their general practitioner (GP group, n = 101). The psychoactive substance use disorder women in the ATC were most frequently treated for was alcohol (39.7 percent), cannabis (20.5) and cocaine 7.9 percent) respectively. The relationship between PMS, problematic alcohol use, and craving for alcohol was explored with the Alcohol Use Disorders Identification Test (AUDIT), Premenstrual Screening Symptoms Tool (PSST), and Penn Alcohol Craving Scale (PACS). Descriptive analyses were used to report demographic variables, and the prevalence and nature of SUD according to DSM-5 and PMS in the two study populations and a two-step multiple hierarchical linear regression to assess the contribution of the variance of the AUDIT and PSST to craving, as measured with PACS. The frequency of PMS and PMDD is significantly higher in the ATC group than in the GP group (48.3 versus 26.7 percent and 16.6 versus 5.9 percent). Craving in the ATC group is better predicted (50 percent) by alcohol-related problems as measured by the AUDIT than in the GP group (25 percent). PMS complaints do contribute to craving in ATC group and not in GP group. There is a high prevalence of PMS/PMDD in the population with a substance use disorder. If these patients with PMS symptoms experience higher levels of craving, it may increase the risk of substance use relapse.
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http://dx.doi.org/10.1080/03630242.2022.2084212DOI Listing
June 2022

Dose-Escalating (50-500 mg) Gluten Administration Leads to Detectable Gluten-Immunogenic-Peptides in Urine of Patients with Coeliac Disease Which Is Unrelated to Symptoms, a Placebo Controlled Trial.

Nutrients 2022 Apr 23;14(9). Epub 2022 Apr 23.

Department of Gastroenterology and Hepatology, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands.

Background: To determine the applicability and sensitivity of a urine self-test to detect gluten-immunogenic-peptides (GIP) in daily-life for patients with coeliac disease and correlate the test results with reported symptoms.

Methods: We performed a prospective double-blinded placebo-controlled study, including adults with coeliac disease adhering to a strictly gluten-free diet. Patients were administered gluten in test-cycles of ascending doses of 50, 100, 200, and 500 mg alternated with placebo. Urine portions from 2, 5-17 h after the ingestion were collected and analyzed for GIP using the iVYCHECK-GIP-Urine rapid lateral flow test. Patients completed a diary mapping symptoms (nausea, bloating, diarrhea, abdominal pain, and lower level of energy).

Results: We enrolled 15 patients and 7 received all 4 cycles with increasing gluten dosing. GIP was detected from urine in 47% of the patients receiving 50 mg gluten and in 86% with 500 mg gluten. We detected GIP in 20-50% of urine samples after placebo. There was no correlation between symptoms, gluten administration and/or GIP in urine.

Conclusions: Gluten intake, even with a dose as low as 50 mg, leads to detectable urinary GIP concentrations. There is no correlation of coeliac disease ascribed symptoms with detection of urinary GIP.
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http://dx.doi.org/10.3390/nu14091771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105321PMC
April 2022

Genetics, pathobiology and therapeutic opportunities of polycystic liver disease.

Nat Rev Gastroenterol Hepatol 2022 May 13. Epub 2022 May 13.

Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.

Polycystic liver diseases (PLDs) are inherited genetic disorders characterized by progressive development of intrahepatic, fluid-filled biliary cysts (more than ten), which constitute the main cause of morbidity and markedly affect the quality of life. Liver cysts arise in patients with autosomal dominant PLD (ADPLD) or in co-occurrence with renal cysts in patients with autosomal dominant or autosomal recessive polycystic kidney disease (ADPKD and ARPKD, respectively). Hepatic cystogenesis is a heterogeneous process, with several risk factors increasing the odds of developing larger cysts. Depending on the causative gene, PLDs can arise exclusively in the liver or in parallel with renal cysts. Current therapeutic strategies, mainly based on surgical procedures and/or chronic administration of somatostatin analogues, show modest benefits, with liver transplantation as the only potentially curative option. Increasing research has shed light on the genetic landscape of PLDs and consequent cholangiocyte abnormalities, which can pave the way for discovering new targets for therapy and the design of novel potential treatments for patients. Herein, we provide a critical and comprehensive overview of the latest advances in the field of PLDs, mainly focusing on genetics, pathobiology, risk factors and next-generation therapeutic strategies, highlighting future directions in basic, translational and clinical research.
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http://dx.doi.org/10.1038/s41575-022-00617-7DOI Listing
May 2022

Hepatitis C Elimination in the Netherlands (CELINE): How nationwide retrieval of lost to follow-up hepatitis C patients contributes to micro-elimination.

Eur J Intern Med 2022 Jul 5;101:93-97. Epub 2022 May 5.

Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address:

Background & Aims: The number of chronic hepatitis C virus (HCV)-infected patients who have been lost to follow-up (LTFU) is high and threatens HCV elimination. Micro-elimination focusing on the LTFU population is a promising strategy for low-endemic countries like the Netherlands (HCV prevalence 0.16%). We therefore initiated a nationwide retrieval project in the Netherlands targeting LTFU HCV patients.

Methods: LTFU HCV-infected patients were identified using laboratory and patient records. Subsequently, the Municipal Personal Records database was queried to identify individuals eligible for retrieval, defined as being alive and with a known address in the Netherlands. These individuals were invited for re-evaluation. The primary endpoint was the number of patients successfully re-linked to care.

Results: Retrieval was implemented in 45 sites in the Netherlands. Of 20,183 ever-diagnosed patients, 13,198 (65%) were known to be cured or still in care and 1,537 (8%) were LTFU and eligible for retrieval. Contact was established with 888/1,537 (58%) invited individuals; 369 (24%) had received prior successful treatment elsewhere, 131 (9%) refused re-evaluation and 251 (16%) were referred for re-evaluation. Finally, 219 (14%) were re-evaluated, of whom 172 (79%) approved additional data collection. HCV-RNA was positive in 143/172 (83%), of whom 38/143 (27%) had advanced fibrosis or cirrhosis and 123/143 (86%) commenced antiviral treatment.

Conclusion: Our nationwide micro-elimination strategy accurately mapped the ever-diagnosed HCV population in the Netherlands and indicates that 27% of LTFU HCV-infected patients re-linked to care have advanced fibrosis or cirrhosis. This emphasizes the potential value of systematic retrieval for HCV elimination.
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http://dx.doi.org/10.1016/j.ejim.2022.04.024DOI Listing
July 2022

Optimal timing of rectal diclofenac in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis.

Endosc Int Open 2022 Mar 14;10(3):E246-E253. Epub 2022 Mar 14.

Department of Gastroenterology and Hepatology, Radboud Institute for Molecular Life Science, Radboudumc, Nijmegen, the Netherlands.

Rectal nonsteroidal anti-inflammatory drug (NSAID) prophylaxis reduces incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Direct comparisons to the optimal timing of administration, before or after ERCP, are lacking. Therefore, we aimed to assess whether timing of rectal NSAID prophylaxis affects the incidence of post-ERCP pancreatitis. We conducted an analysis of prospectively collected data from a randomized clinical trial. We included patients with a moderate to high risk of developing post-ERCP pancreatitis, all of whom received rectal diclofenac monotherapy 100-mg prophylaxis. Administration was within 30 minutes before or after the ERCP at the discretion of the endoscopist. The primary endpoint was post-ERCP pancreatitis. Secondary endpoints included severity of pancreatitis, length of hospitalization, and Intensive Care Unit (ICU) admittance. We included 346 patients who received the rectal NSAID before ERCP and 63 patients who received it after ERCP. No differences in baseline characteristics were observed. Post-ERCP pancreatitis incidence was lower in the group that received pre-procedure rectal NSAIDs (8 %), compared to post-procedure (18 %) (relative risk: 2.32; 95% confidence interval: 1.21 to 4.46,  = 0.02). Hospital stays were significantly longer with post-procedure prophylaxis (1 day; interquartile range [IQR] 1-2 days vs. 1 day; IQR 1-4 days;  = 0.02). Patients from the post-procedure group were more likely to be admitted to the ICU (1 patient [0.3 %] vs. 4 patients [6 %];  = 0.002). Pre-procedure administration of rectal diclofenac is associated with a significant reduction in post-ERCP pancreatitis incidence compared to post-procedure use.
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http://dx.doi.org/10.1055/a-1675-2108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8920594PMC
March 2022

A non-invasive score for nonalcoholic fatty liver disease (NAFLD) cirrhosis.

Eur J Intern Med 2022 04 3;98:43-44. Epub 2022 Mar 3.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands.

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http://dx.doi.org/10.1016/j.ejim.2022.02.025DOI Listing
April 2022

The present and future of gastroenterology and hepatology: an international SWOT analysis (the GASTROSWOT project).

Lancet Gastroenterol Hepatol 2022 05 2;7(5):485-494. Epub 2022 Mar 2.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, Netherlands. Electronic address:

GASTROSWOT is a strategic analysis of the current and projected states of the different subspecialties in gastroenterology that aims to provide guidance for research, clinical, and financial planning in gastroenterology. We executed a consensus-based international strengths, weaknesses, opportunities, and threats (SWOT) analysis. Four general coordinators, six field coordinators, and 12 experts participated in the study. SWOTs were provided for the following fields: neurogastroenterology, functional gastrointestinal disorders, and upper gastrointestinal diseases; inflammatory bowel disease; pancreatology and biliary diseases; endoscopy; gastrointestinal oncology; and hepatology. The GASTROSWOT analysis highlights the following in the current state of the field of gastroenterology: the incidence and complexity of several gastrointestinal diseases, including malignancies, are increasing; the COVID-19 pandemic has affected patient care on several levels; and with the advent of technical innovations in gastroenterology, a well trained workforce and strategic planning are required to optimise health-care utilisation. The analysis calls attention to the following in the future of gastroenterology: artificial intelligence and the use of big data will speed up discovery and smarter health-care provision in the field; the growth and diversification of gastroenterological specialties will improve specialised care for patients, but could promote fragmentation of care and health system inefficiencies; and furthermore, thoughtful planning is needed to reach an effective balance between the need for subspecialists and the value of general gastroenterology services.
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http://dx.doi.org/10.1016/S2468-1253(21)00442-8DOI Listing
May 2022

Against All Odds? Addiction History Associated with Better Viral Hepatitis Care: A Dutch Nationwide Claims Data Study.

J Clin Med 2022 Feb 21;11(4). Epub 2022 Feb 21.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

The elimination of viral hepatitis in target populations is crucial in reaching WHO viral hepatitis elimination goals. Several barriers for the treatment of viral hepatitis in people with addictive disorders have been identified, yet nationwide data on hepatitis healthcare utilization (HCU) in these patients are limited. We investigated whether a history of addictive disorder is associated with suboptimal hepatitis HCU, indicating failure to receive diagnostic care or treatment. We identified all newly referred viral hepatitis patients in the Netherlands between 2014 and 2019 by query of the Dutch national hospital claims database. Each patient's first year of HBV or HCV care activities was collected and clustered in two categories, 'optimal' or 'suboptimal' hepatitis HCU. Optimal HCU includes antiviral therapy. We tested the association between addiction history and HCU, adjusted for sex, age, migrant status, and comorbidity. In secondary analyses, we explored additional factors affecting hepatitis HCU. We included 10,513 incident HBV and HCV patients, with 13% having an addiction history. Only 47% of all patients achieved optimal hepatitis HCU. Addiction history was associated with less suboptimal HCU (adjusted OR = 0.73, 95% CI = 0.64-0.82). Migration background was associated with suboptimal HCU (OR = 1.62, 95% CI = 1.50-1.76). This study shows that addiction history is associated with higher viral hepatitis HCU; thus, this population performs better compared to non-addicted patients. However, less than 50% of all patients received optimal hepatitis care. This study highlights the need to improve hepatitis HCU in all patients, with a focus on migrant populations. Linkage to care in the addicted patients is not studied here and may be a remaining obstacle to be studied and improved to reach WHO viral hepatitis elimination goals.
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http://dx.doi.org/10.3390/jcm11041146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8878485PMC
February 2022

Polycystic liver: automatic segmentation using deep learning on CT is faster and as accurate compared to manual segmentation.

Eur Radiol 2022 Jul 10;32(7):4780-4790. Epub 2022 Feb 10.

Service d'imagerie médicale et interventionnelle, Hôpital Edouard Herriot, 5 Place d'Arsonval, 69003, Lyon, France.

Objective: This study aimed to develop and investigate the performance of a deep learning model based on a convolutional neural network (CNN) for the automatic segmentation of polycystic livers at CT imaging.

Method: This retrospective study used CT images of polycystic livers. To develop the CNN, supervised training and validation phases were performed using 190 CT series. To assess performance, the test phase was performed using 41 CT series. Manual segmentation by an expert radiologist (Rad1a) served as reference for all comparisons. Intra-observer variability was determined by the same reader after 12 weeks (Rad1b), and inter-observer variability by a second reader (Rad2). The Dice similarity coefficient (DSC) evaluated overlap between segmentations. CNN performance was assessed using the concordance correlation coefficient (CCC) and the two-by-two difference between the CCCs; their confidence interval was estimated with bootstrap and Bland-Altman analyses. Liver segmentation time was automatically recorded for each method.

Results: A total of 231 series from 129 CT examinations on 88 consecutive patients were collected. For the CNN, the DSC was 0.95 ± 0.03 and volume analyses yielded a CCC of 0.995 compared with reference. No statistical difference was observed in the CCC between CNN automatic segmentation and manual segmentations performed to evaluate inter-observer and intra-observer variability. While manual segmentation required 22.4 ± 10.4 min, central and graphics processing units took an average of 5.0 ± 2.1 s and 2.0 ± 1.4 s, respectively.

Conclusion: Compared with manual segmentation, automated segmentation of polycystic livers using a deep learning method achieved much faster segmentation with similar performance.

Key Points: • Automatic volumetry of polycystic livers using artificial intelligence method allows much faster segmentation than expert manual segmentation with similar performance. • No statistical difference was observed between automatic segmentation, inter-observer variability, or intra-observer variability.
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http://dx.doi.org/10.1007/s00330-022-08549-1DOI Listing
July 2022

Abdominal wall hernia is a frequent complication of polycystic liver disease and associated with hepatomegaly.

Liver Int 2022 04 17;42(4):871-878. Epub 2022 Feb 17.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands.

Background And Aim: Polycystic liver disease (PLD) is related to hepatomegaly which causes an increased mechanical pressure on the abdominal wall. This may lead to abdominal wall herniation (AWH). We set out to establish the prevalence of AWH in PLD and explore risk factors.

Methods: In this cross-sectional cohort study, we assessed the presence of AWHs from PLD patients with at least 1 abdominal computed tomography or magnetic resonance imaging scan. AWH presence on imaging was independently evaluated by two researchers. Data on potential risk factors were extracted from clinical files.

Results: We included 484 patients of which 40.1% (n = 194) had an AWH. We found a clear predominance of umbilical hernias (25.8%, n = 125) while multiple hernias were present in 6.2% (n = 30). Using multivariate analysis, male sex (odds ratio [OR] 2.727 p < .001), abdominal surgery (OR 2.575, p < .001) and disease severity according to the Gigot classification (Type 3 OR 2.853, p < .001) were identified as risk factors. Height-adjusted total liver volume was an independent PLD-specific risk factor in the subgroup of patients with known total liver volume (OR 1.363, p = .001). Patients with multiple hernias were older (62.1 vs. 55.1, p = .001) and more frequently male (22.0% vs. 50.0%, p = .001).

Conclusion: AWHs occur frequently in PLD with a predominance of umbilical hernias. Hepatomegaly is a clear disease-specific risk factor.
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http://dx.doi.org/10.1111/liv.15177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307001PMC
April 2022

Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group.

J Hepatol 2022 Apr 20;76(4):841-849. Epub 2022 Jan 20.

Institute of Liver Studies, King's College Hospital, London, United Kingdom; European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Electronic address:

Background & Aims: Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment.

Methods: A systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis.

Results: The consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term 'complete biochemical response' defined as 'normalization of serum transaminases and IgG below the upper limit of normal' be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as '<50% decrease of serum transaminases within 4 weeks after initiation of treatment'. Remission is defined as liver histology with a Hepatitis Activity Index <4/18. Intolerance to treatment was agreed to stand for 'any adverse event possibly related to treatment leading to potential drug discontinuation'.

Conclusions: These definitions provide a simple and reproducible framework to define treatment response and non-response, irrespective of the therapeutic intervention. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable inter-study comparisons. Future prospective database studies are needed to validate these endpoints.

Lay Summary: Consensus among international experts on response criteria and endpoints in autoimmune hepatitis is lacking. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable the comparison of results between clinical trials. Therefore, the International Autoimmune Hepatitis Group (IAIHG) herein presents a statement on 5 agreed response criteria and endpoints: complete biochemical response, insufficient response, non-response, remission, and intolerance to treatment, which can be used to guide future reporting.
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http://dx.doi.org/10.1016/j.jhep.2021.12.041DOI Listing
April 2022

Performance of diagnostic tools for acute cholangitis in patients with suspected biliary obstruction.

J Hepatobiliary Pancreat Sci 2022 Apr 21;29(4):479-486. Epub 2021 Dec 21.

Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands.

Background: Acute cholangitis is an infection requiring endoscopic retrograde cholangiopancreatography (ERCP) and antibiotics. Several diagnostic tools help to diagnose cholangitis. Because diagnostic performance of these tools has not been studied and might therefore impose unnecessary ERCPs, we aimed to evaluate this.

Methods: We established a nationwide prospective cohort of patients with suspected biliary obstruction who underwent an ERCP. We assessed the diagnostic performance of Tokyo Guidelines (TG18), Dutch Pancreatitis Study Group (DPSG) criteria, and Charcot triad relative to real-world cholangitis as the reference standard.

Results: 127 (16%) of 794 patients were diagnosed with real-world cholangitis. Using the TG18, DPSG, and Charcot triad, 345 (44%), 55 (7%), and 66 (8%) patients were defined as having cholangitis, respectively. Sensitivity for TG18 was 82% (95% CI 74-88) and specificity 60% (95% CI 56-63). The sensitivity for DPSG and Charcot was 42% (95% CI 33-51) and 46% (95% CI 38-56), specificity was 99.7% (95% CI 99-100) and 99% (95% CI 98-100), respectively.

Conclusions: TG18 criteria incorrectly diagnoses four out of ten patients with real-world cholangitis, while DPSG and Charcot criteria failed to diagnose more than half of patients. As the cholangitis diagnosis has many consequences for treatment, there is a need for more accurate diagnostic tools or work-up towards ERCP.
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http://dx.doi.org/10.1002/jhbp.1096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306734PMC
April 2022

Effects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis.

Liver Int 2022 03 13;42(3):607-614. Epub 2021 Dec 13.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH).

Patients And Methods: Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression.

Results: We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients.

Conclusion: Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH.
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http://dx.doi.org/10.1111/liv.15121DOI Listing
March 2022

Healthcare utilisation of patients with cholecystolithiasis in primary care: a multipractice comparative analysis.

BMJ Open 2021 11 3;11(11):e053188. Epub 2021 Nov 3.

Surgery, Radboudumc, Nijmegen, The Netherlands

Objectives: To examine general practitioners' (GP) management of cholecystolithiasis and to evaluate persisting abdominal complaints in the years after the diagnosis.

Design: Retrospective analysis of registry data and a subset of individual medical records.

Setting: Seventeen primary care practices affiliated with the Radboudumc Practice Based Research Network in the Netherlands.

Participants: 633 patients with cholecystolithiasis diagnosed between 2012 and 2016.

Primary And Secondary Outcome Measures: The primary outcome of this study was the healthcare utilisation of patients with cholecystolithiasis diagnosed by the GP in terms of referrals to secondary care, laboratory diagnostics, prescribed medication and the prevalence of concomitant abdominal-related diagnoses in a time interval of 3 years before and 3 years after diagnosis of cholecystolithiasis. For secondary outcomes, electronic medical records were studied from seven practices to assess emergency department visits, operation rates and repeat visits for persistent abdominal symptoms. We compared the non-referred group with the referred group.

Results: In 57% of patients, concomitant abdominal-related diagnoses were recorded besides the diagnosis cholecystolithiasis. In-depth analyses of 294 patients showed a referral rate of 79.3% (n=233); 62.9% (n=185) underwent cholecystectomy. After referral, 55.4% (129/233) returned to the GP for persistent abdominal symptoms. Patients returning after referral were more often treated for another abdominal-related diagnosis before cholecystolithiasis was recorded (51.9% vs 28.8%, p<0.001).

Conclusions: The majority of patients in general practice with gallstones are referred and undergo cholecystectomy. Patients with concomitant abdominal-related diagnoses are likely to return to their physician. GPs should inform patients about these outcomes to improve the shared decision-making process before gallbladder surgery.
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http://dx.doi.org/10.1136/bmjopen-2021-053188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572399PMC
November 2021

The Netherlands Is on Track to Meet the World Health Organization Hepatitis C Elimination Targets by 2030.

J Clin Med 2021 Sep 30;10(19). Epub 2021 Sep 30.

Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands.

Background: The Netherlands strives for hepatitis C virus (HCV) elimination, in accordance with the World Health Organization targets. An accurate estimate when HCV elimination will be reached is elusive. We have embarked on a nationwide HCV elimination project (CELINE) that allowed us to harvest detailed data on the Dutch HCV epidemic. This study aims to provide a well-supported timeline towards HCV elimination in The Netherlands.

Methods: A previously published Markov model was used, adopting published data and unpublished CELINE project data. Two main scenarios were devised. In the Status Quo scenario, 2020 diagnosis and treatment levels remained constant in subsequent years. In the Gradual Decline scenario, an annual decrease of 10% in both diagnoses and treatments was implemented, starting in 2020. WHO incidence target was disregarded, due to low HCV incidence in The Netherlands (≤5 per 100,000).

Results: Following the Status Quo and Gradual Decline scenarios, The Netherlands would meet WHO's elimination targets by 2027 and 2032, respectively. From 2015 to 2030, liver-related mortality would be reduced by 97% in the Status Quo and 93% in the Gradual Decline scenario. Compared to the Status Quo scenario, the Gradual Decline scenario would result in 12 excess cases of decompensated cirrhosis, 18 excess cases of hepatocellular carcinoma, and 20 excess cases of liver-related death from 2020-2030.

Conclusions: The Netherlands is on track to reach HCV elimination by 2030. However, it is vital that HCV elimination remains high on the agenda to ensure adequate numbers of patients are being diagnosed and treated.
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http://dx.doi.org/10.3390/jcm10194562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509638PMC
September 2021

Defective Lipid Droplet-Lysosome Interaction Causes Fatty Liver Disease as Evidenced by Human Mutations in TMEM199 and CCDC115.

Cell Mol Gastroenterol Hepatol 2022 7;13(2):583-597. Epub 2021 Oct 7.

Department of Vascular Medicine, Amsterdam UMC, location AMC, Amsterdam, The Netherlands. Electronic address:

Background & Aims: Recently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model.

Methods And Results: Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity.

Conclusions: Our data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease.
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http://dx.doi.org/10.1016/j.jcmgh.2021.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688563PMC
April 2022

Effectiveness and predictors of response to somatostatin analogues in patients with gastrointestinal angiodysplasias: a systematic review and individual patient data meta-analysis.

Lancet Gastroenterol Hepatol 2021 11 9;6(11):922-932. Epub 2021 Sep 9.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, Netherlands.

Background: Gastrointestinal angiodysplasias are vascular malformations that often cause red blood cell transfusion-dependent anaemia. Several studies suggest that somatostatin analogues might decrease rebleeding rates, but the true effect size is unknown. We therefore aimed to investigate the efficacy of somatostatin analogues on red blood cell transfusion requirements of patients with gastrointestinal angiodysplasias and to identify subgroups that might benefit the most from somatostatin analogue therapy.

Methods: We did a systematic review and individual patient data meta-analysis. We searched MEDLINE, Embase, and Cochrane on Jan 15, 2016, with an updated search on April 25, 2021. All published randomised controlled trials and cohort studies that reported on somatostatin analogue therapy in patients with gastrointestinal angiodysplasias were eligible for screening. We excluded studies without original patient data, single case reports, small case series (ie, <10 participants), studies in which patients had a specific aetiology of gastrointestinal angiodysplasias, and studies in which somatostatin analogue therapy was initiated simultaneously with other treatment modalities. Authors of eligible studies were invited to share individual patient data. Aggregated data was used if individual patient data were not provided. The primary outcome was the mean reduction in the number of red blood cell transfusions during somatostatin analogue therapy, compared with baseline, expressed as the incidence rate ratio (IRR) and absolute mean decrease. We defined patients as either good responders (≥50% reduction in the number of red blood cell transfusions) or poor responders (<50% reduction). A mixed-effects negative binomial regression was used to account for clustering of patients and skewness in data. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42020213985.

Findings: We identified 11 eligible studies (one randomised controlled trial and ten cohort studies) of moderate-to-high quality and obtained individual patient data from the authors of nine (82%) studies. The remaining two (18%) studies provided sufficient information in the published manuscript to extract individual patient data. In total, we analysed data from 212 patients. Somatostatin analogues reduced the number of red blood cell transfusions with an IRR of 0·18 (95% CI 0·14-0·24; p<0·0001) during a median treatment duration of 12 months (IQR 6·0-12·0) and follow-up period of 12 months (12·0-12·0), correlating with a mean absolute decrease in the number of red blood cell transfusions from 12·8 (95% CI 10·4-15·8) during baseline to 2·3 (1·9-2·9) during follow-up-ie, a reduction of 10·5 red blood cell transfusions (p<0·0001). 177 (83%) of 212 patients had a good response to somatostatin analogue therapy (defined as at least a 50% reduction in the number of red blood cell transfusions). Heterogeneity across studies was moderate (I=53%; p=0·02). Location of gastrointestinal angiodysplasias in the stomach compared with angiodysplasias in the small bowel and colon (IRR interaction 1·92 [95% CI 1·13-3·26]; p=0·02) was associated with worse treatment response. Octreotide was associated with a better treatment response than lanreotide therapy (IRR interaction 2·13 [95% CI 1·12-4·04]; p=0·02). The certainty of evidence was high for the randomised controlled trial and low for the ten cohort studies. Adverse events occurred in 38 (18%) of 212 patients receiving somatostatin analogue therapy, with ten (5%) discontinuing this therapy because of adverse events. The most common adverse events were loose stools (seven [3%] of 212), cholelithiasis (five [2%]), flatulence (four [2%]), and administration site reactions (erythema, five [2%]).

Interpretation: Somatostatin analogue therapy is safe and effective in most patients with red blood cell transfusion-dependent bleeding due to gastrointestinal angiodysplasias. Somatostatin analogue therapy is more effective in patients with angiodysplasias located in the small bowel and colon, and octreotide therapy seems to be more effective than lanreotide therapy.

Funding: The Netherlands Organisation for Health Research and Development and the Radboud University Medical Center.
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http://dx.doi.org/10.1016/S2468-1253(21)00262-4DOI Listing
November 2021

Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.

Hepatology 2022 01 5;75(1):13-27. Epub 2021 Dec 5.

European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany.

Background And Aims: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray.

Approach And Results: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD.

Conclusions: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.
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http://dx.doi.org/10.1002/hep.32134DOI Listing
January 2022

Tamoxifen for the treatment of polycystic liver disease: A case report.

Medicine (Baltimore) 2021 Aug;100(32):e26797

Department Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Rationale: Polycystic liver disease is a rare disease characterized by the growth of numerous cysts in the liver. The liver function remains well preserved, but liver volumes can grow very large, and some patients ultimately need a liver transplantation. Other treatment options are limited and there is an unmet need for new therapeutic options.

Patient Concerns: We describe a 59-year-old patient with pain in the abdomen, especially when bending forward. Five years ago, she was diagnosed with breast cancer and as an incidental finding a couple of large liver cysts were diagnosed, explaining her abdominal pain.

Diagnosis: Polycystic liver disease with several large liver cysts.

Interventions: The patient was treated with tamoxifen, an estrogen receptor modulator, as treatment for her hormone receptor positive breast cancer. One of the liver cysts was aspirated.

Outcomes: In the 4.6 years after the start of tamoxifen treatment, 20 mg once daily, the volume of her liver cysts decreased remarkably. There was a reduction of combined cyst volume from 311 mL to 22 mL without percutaneous drainage.

Lessons: Epidemiological as well as experimental evidence supports a pivotal role for estrogens as a driver for growth of polycystic livers. Estrogen antagonism has often been proposed as a therapeutic target, but supporting evidence is lacking in the literature. We hypothesize that the decrease in cyst size in this patient was caused by tamoxifen therapy, suggesting an in vivo antagonistic effect on cystic cholangiocytes. This is an important finding because tamoxifen could be a promising new treatment option for polycystic liver disease.
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http://dx.doi.org/10.1097/MD.0000000000026797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360467PMC
August 2021

Aggressive hydration and post-ERCP pancreatitis-Authors' reply.

Lancet Gastroenterol Hepatol 2021 09;6(9):686-687

Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen 6525 GA, Netherlands.

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http://dx.doi.org/10.1016/S2468-1253(21)00235-1DOI Listing
September 2021

Histological activity despite normal ALT and IgG serum levels in patients with autoimmune hepatitis and cirrhosis.

JHEP Rep 2021 Aug 12;3(4):100321. Epub 2021 Jun 12.

Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Background & Aims: In autoimmune hepatitis (AIH), normal levels of transaminases and IgG define biochemical remission and are considered the best surrogate markers for histological remission. This study assessed whether this also applies to patients with AIH cirrhosis.

Methods: In this European multicentric study, we included 125 biopsies from 113 patients with AIH and histologically proven cirrhosis; 105 biopsies from 104 patients with AIH without cirrhosis served as controls. Biochemical parameters were available within 4 weeks of biopsy. AIH activity was graded according to the modified Hepatitis Activity Index (mHAI), with mHAI ≥4/18 considered to indicate risk of disease progression.

Results: In total, 47 out of 125 liver biopsies were obtained from patients with AIH cirrhosis and normal ALT levels at time of biopsy. Only 26% (12/47) of those livers showed histological remission (mHAI <4/18), whereas 36% (17/47) showed moderate to high histological activity (mHAI ≥6/18). In patients with noncirrhotic AIH, 88% (46/52 biopsies) of cases with normal ALT levels had histological remission and only 4% (2/52) had an mHAI ≥6/18 ( <0.001). The addition of IgG to define complete biochemical remission only slightly improved the association with histological remission in the limited number of patients with AIH cirrhosis available for analysis [29% (5/17) of biopsies with mHAI <4/18]. ALT correlated closely with mHAI in AIH without cirrhosis but poorly in AIH with cirrhosis.

Conclusions: In contrast to patients with noncirrhotic AIH, in patients with AIH cirrhosis, who are at risk of disease progression, normal ALT levels and potentially also complete biochemical remission are poor surrogate markers of histological remission. Thus, new biomarkers are needed to monitor disease activity and progression in patients with AIH cirrhosis.

Lay Summary: Autoimmune hepatitis (AIH) is an inflammatory disease of the liver that usually responds to immunosuppressive therapy. Serum transaminases and IgG levels within the normal ranges define complete biochemical remission and are considered as surrogate markers for histological disease activity. Here, we show that those biochemical markers are not sufficient to indicate low disease activity in patients with AIH and already established cirrhosis. Consequently, until better biomarkers for disease activity are found, only liver biopsy can reliably indicate disease activity in the presence of cirrhosis. Additional investigations, such as measurements of liver stiffness, should be undertaken to monitor non-invasively for disease progression in patients with AIH and established cirrhosis.
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http://dx.doi.org/10.1016/j.jhepr.2021.100321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333110PMC
August 2021

A Clinical Decision Tool for Selection of Patients With Symptomatic Cholelithiasis for Cholecystectomy Based on Reduction of Pain and a Pain-Free State Following Surgery.

JAMA Surg 2021 10 13;156(10):e213706. Epub 2021 Oct 13.

Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.

Importance: There is currently no consensus on the indication for cholecystectomy in patients with uncomplicated gallstone disease.

Objective: To report on the development and validation of a multivariable prediction model to better select patients for surgery.

Design, Setting, And Participants: This study evaluates data from 2 multicenter prospective trials (the previously published Scrutinizing (In)efficient Use of Cholecystectomy: A Randomized Trial Concerning Variation in Practice [SECURE] and the Standardized Work-up for Symptomatic Cholecystolithiasis [Success] trial) collected from the outpatient clinics of 25 Dutch hospitals between April 2014 and June 2019 and including 1561 patients with symptomatic uncomplicated cholelithiasis, defined as gallstone disease without signs of complicated cholelithiasis (ie, biliary pancreatitis, cholangitis, common bile duct stones or cholecystitis). Data were analyzed from January 2020 to June 2020.

Exposures: Patient characteristics, comorbidity, surgical outcomes, pain, and symptoms measured at baseline and at 6 months' follow-up.

Main Outcomes And Measures: A multivariable regression model to predict a pain-free state or a clinically relevant reduction in pain after surgery. Model performance was evaluated using calibration and discrimination.

Results: A total of 1561 patients were included (494 patients in 7 hospitals in the development cohort and 1067 patients in 24 hospitals in the validation cohort; 6 hospitals included patients in both cohorts). In the development cohort, 395 patients (80.0%) underwent cholecystectomy. After surgery, 225 patients (57.0%) reported that they were pain free and 295 (74.7%) reported a clinically relevant reduction in pain. A multivariable prediction model showed that increased age, no history of abdominal surgery, increased visual analog scale pain score at baseline, pain radiation to the back, pain reduction with simple analgesics, nausea, and no heartburn were independent predictors of clinically relevant pain reduction after cholecystectomy. After internal validation, good discrimination was found (C statistic, 0.80; 95% CI, 0.74-0.84) between patients with and without clinically relevant pain reduction. The model had very good overall calibration and minimal underestimation of the probability. External validation indicated a good discrimination between patients with and without clinically relevant pain reduction (C statistic, 0.74; 95% CI, 0.70-0.78) and fair calibration with some overestimation of probability by the model.

Conclusions And Relevance: The model validated in this study may help predict the probability of pain reduction after cholecystectomy and thus aid surgeons in deciding whether patients with uncomplicated cholelithiasis will benefit from cholecystectomy.
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http://dx.doi.org/10.1001/jamasurg.2021.3706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358816PMC
October 2021

Complications of percutaneous transhepatic cholangiography and biliary drainage, a multicenter observational study.

Abdom Radiol (NY) 2021 Aug 6. Epub 2021 Aug 6.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Objectives: Over 2500 percutaneous transhepatic cholangiography and biliary drainage (PTCD) procedures are yearly performed in the Netherlands. Most interventions are performed for treatment of biliary obstruction following unsuccessful endoscopic biliary cannulation. Our aim was to evaluate complication rates and risk factors for complications in PTCD patients after failed ERCP.

Methods: We performed an observational study collecting data from a cohort that was subjected to PTCD during a 5-year period in one academic and four teaching hospitals. Primary objective was the development of infectious (sepsis, cholangitis, abscess, or cholecystitis) and non-infectious complications (bile leakage, severe hemorrhage, etc.) and mortality within 30 days of the procedure. Subsequently, risk factors for complications and mortality were analyzed with a multilevel logistic regression analysis.

Results: A total of 331 patients underwent PTCD of whom 205 (61.9%) developed PTCD-related complications. Of the 224 patients without a pre-existent infection, 91 (40.6%) developed infectious complications, i.e., cholangitis in 26.3%, sepsis in 24.6%, abscess formation in 2.7%, and cholecystitis in 1.3%. Non-infectious complications developed in 114 of 331 patients (34.4%). 30-day mortality was 17.2% (N = 57). Risk factors for infectious complications included internal drainage and drain obstruction, while multiple re-interventions were a risk factor for non-infectious complications.

Conclusion: Both infectious and non-infectious complications are frequent after PTCD, most often due to biliary drain obstruction.
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http://dx.doi.org/10.1007/s00261-021-03207-4DOI Listing
August 2021

Inhibition of NAE-dependent protein hyper-NEDDylation in cystic cholangiocytes halts cystogenesis in experimental models of polycystic liver disease.

United European Gastroenterol J 2021 09 26;9(7):848-859. Epub 2021 Jul 26.

Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), Donostia-San Sebastian, Spain.

Background: Polycystic liver diseases (PLDs) are genetic inherited disorders characterized by the progressive growth of numerous intrahepatic biliary cysts, which are the main cause of morbidity. Previous studies revealed that cystic cholangiocytes are characterized by endoplasmic reticulum stress and aberrant posttranslational modification (PTM) of proteins, in particular hyper-SUMOylation, that promote PLD pathobiology. Protein NEDDylation is a newly characterized PTM that modulates a plethora of biological processes and its dysregulation is associated with the development and progression of several human diseases. However, the role of NEDDylation in PLD remains elusive.

Objective: To explore the role of protein NEDDylation in PLD and its potential therapeutic regulatory value.

Methods: Levels and functional effects of NEDDylation, including response to Pevonedistat (first-in-class selective inhibitor of the NEDDylation E1 enzyme NAE), were assessed in vitro, in vivo, and/or in patients with PLD. NEDDylated protein levels in normal and cystic human cholangiocytes were assessed by immunoprecipitation, and the proteomic profile was further analyzed by mass spectrometry.

Results And Conclusion: The genes involved in the NEDDylation pathway were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture, compared to controls. Elevated levels of NEDDylated proteins were further confirmed in cystic cholangiocytes in vitro, which diminished under Pevonedistat incubation. Pevonedistat promoted apoptotic cell death and reduced proliferation in cystic cholangiocytes in vitro. Comparative proteomic profiling of NEDD8-immunoprecipitated proteins between normal and cystic cholangiocytes in culture reported candidate proteins involved in cystogenesis, mostly associated with protein biogenesis and quality control. All these data indicate that cystic cholangiocytes display increased protein NEDDylation, contributing to cell survival and proliferation, ultimately supporting hepatic cystogenesis. Targeting of protein hyper-NEDDylation in cystic cholangiocytes inhibits cystogenesis in experimental models, representing a novel therapeutic opportunity in PLD.
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http://dx.doi.org/10.1002/ueg2.12126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435261PMC
September 2021

Budget Impact of Restrictive Strategy Versus Usual Care for Cholecystectomy (SECURE-Trial).

J Surg Res 2021 12 17;268:59-70. Epub 2021 Jul 17.

Department of Surgery, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address:

Objectives: A cost-effectiveness analysis of a multicenter randomized-controlled trial comparing restrictive strategy versus usual care in patients with gallstones showed that savings by restrictive strategy could not compensate for the lower proportion of pain-free patients. However, four subgroups based on combined stratification factors resulted in less cholecystectomies and more pain-free patients in restrictive strategy (female-low volume-BMI > 30, female-low volume-BMI25-30, female-high volume-BMI25-30, and male-low volume-BMI < 25). The aim of this study was to explore the budget impact from a hospital healthcare perspective of implementation of restrictive strategy in these subgroups.

Methods: Data of the SECURE-trial were used to calculate the hospital budget impact with a time horizon of four years. Based on a study into practice variation, about 19% of hospitals treat patients according restrictive strategy. This represents the proportion of patients treated according restrictive strategy at the start of budget period. Three subanalyses were performed: a scenario analysis in which 30% of patients fall under a restrictive strategy in clinical practice, a sensitivity analysis in which we calculated the budget impact with the low and high 95% confidence limits of the expected future number of patients, a subgroup analysis in which restrictive strategy was also implemented in two additional subgroups (male-high volume-BMI < 25 and female-high volume-BMI >30).

Results: Budget impact analysis showed savings of €6.7-€15.6 million (2.2%-5.6%) for the period 2021-2024/2025 by implementing the restrictive strategy in the four subgroups and provision of usual care in other patients. Sensitivity analysis with 30% of patients already in the restrictive strategy at the start of the budget period, resulted in savings between €5.4 million and €14.0 million (1.7%-5.0%).

Conclusion: Performing a restrictive strategy for selection of cholecystectomy in subgroups of patients and provision of usual care in other patients will result in a lower overall hospital budget needed to treat patients with abdominal pain and gallstones.

Trial Registration: The Netherlands National Trial Register NTR4022. Registered on June 5, 2013.
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http://dx.doi.org/10.1016/j.jss.2021.06.033DOI Listing
December 2021

Non-steroidal anti-inflammatory drugs, intravenous fluids, pancreatic stents, or their combinations for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a systematic review and network meta-analysis.

Lancet Gastroenterol Hepatol 2021 09 30;6(9):733-742. Epub 2021 Jun 30.

Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs), intravenous fluid, pancreatic stents, or combinations of these have been evaluated in randomised controlled trials (RCTs) for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, but the comparative efficacy of these treatments remains unclear. Our aim was to do an exploratory network meta-analysis of previous RCTs to systematically compare the direct and indirect evidence and rank NSAIDs, intravenous fluids, pancreatic stents, or combinations of these to determine the most efficacious method of prophylaxis for post-ERCP pancreatitis.

Methods: We searched PubMed, Embase, and the Cochrane Central Register from inception to Nov 15, 2020, for full-text RCTs that evaluated the efficacy of NSAIDs, pancreatic stents, intravenous fluids, or combinations of these for post-ERCP pancreatitis prevention in adult (aged ≥18 years) patients undergoing ERCP. Summary data from intention-to-treat analyses were extracted from published reports. We analysed incidence of post-ERCP pancreatitis across studies using network meta-analysis under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% CIs. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system for the confidence rating. This study is registered with PROSPERO, CRD42020172606.

Findings: We identified 1503 studies, of which 55 RCTs evaluating 20 interventions in 17 062 patients were included in the network meta-analysis. The mean incidence of post-ERCP pancreatitis in the placebo or active control group was 12·2% (95% CI 11·4-13·0). Normal saline plus rectal indometacin (OR 0·02, 95% CI 0·00-0·40), intramuscular diclofenac 75 mg (0·24, 0·09-0·69), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (0·30, 0·16-0·55), intravenous high-volume Ringer's lactate (0·31, 0·12-0·78), 5-7 Fr pancreatic stents (0·35, 0·26-0·48), rectal diclofenac 100 mg (0·36, 0·25-0·52), 3 Fr pancreatic stents (0·47, 0·26-0·87), and rectal indometacin 100 mg (0·60, 0·50-0·73) were all more efficacious than placebo for preventing post-ERCP pancreatitis in pairwise comparisons. 5-7 Fr pancreatic stents (0·59, 0·41-0·84), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (0·49, 0·26-0·94), intravenous standard-volume normal saline plus rectal indometacin 100 mg (0·04, 0·00-0·66), and rectal diclofenac 100 mg (0·59, 0·40-0·89) were more efficacious than rectal indometacin 100 mg. The GRADE confidence rating was low to moderate for 98·3% of the pairwise comparisons.

Interpretation: This systematic review and network meta-analysis summarises the available literature on NSAIDs, pancreatic stents, intravenous fluids, or combinations of these for prophylaxis of post-ERCP pancreatitis. Rectal diclofenac 100 mg is the best performing rectal NSAID in this network meta-analysis. Combinations of prophylaxis might be more effective, but there is little evidence. These findings help to establish prophylaxis of post-ERCP pancreatitis for future research and practice, and could reduce costs and increase adoption of prophylaxis.

Funding: None.
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http://dx.doi.org/10.1016/S2468-1253(21)00170-9DOI Listing
September 2021

Estrogens in polycystic liver disease: A target for future therapies?

Liver Int 2021 09 10;41(9):2009-2019. Epub 2021 Jul 10.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands.

Background And Aims: Patients suffering from polycystic liver disease (PLD) can develop large liver volumes, leading to physical and psychological complaints, reducing quality of life. There is an unmet need for new therapies in these patients. Estrogen seems to be a promising target for new therapies. In this review, we summarize the available experimental and epidemiological evidence to unravel the role of estrogens and other female hormones in PLD, to answer clinical questions and identify new targets for therapy.

Methods: We identified all experimental and epidemiologial studies concerning estrogens or other female hormones and PLD, to answer pre-defined clinial questions.

Results: Female sex is the most important risk factor for the presence and severity of disease; estrogen supplementation enhances liver growth and after menopause, liver growth decreases. Experimental studies show the presence of the estrogen receptors alfa and beta on cystic cholangiocytes, and increased in vitro growth after administration of estrogen.

Conclusions: Based on the available evidence, female PLD patients should be discouraged from taking estrogen-containing contraceptives or hormone replacement therapy. Since liver growth rates decline after menopause, treatment decisions should be based on measured liver growth in postmenopausal women. Finally, blockage of estrogen receptors or estrogen production is a promising target for new therapies.
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http://dx.doi.org/10.1111/liv.14986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456902PMC
September 2021
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