BackgroundGuidelines recommend standard pre-operative cardiac screening in all liver transplantation (LT) recipients, despite the relatively low prevalence of obstructive coronary artery disease.... Show moreBackgroundGuidelines recommend standard pre-operative cardiac screening in all liver transplantation (LT) recipients, despite the relatively low prevalence of obstructive coronary artery disease. Most LT recipients often have non-gated computed tomography (CT) performed of the chest and abdomen. This study evaluated the ability of coronary artery calcification (CAC) assessment on consecutively available scans, to identify a selection of low-risk patients, in whom further cardiac imaging can be safely withheld.MethodsLT recipients with prior non-gated CT chest-abdomen were included. CAC was visually scored on a semi-quantitative ordinal scale. Stress myocardial perfusion, coronary CT angiography (CCTA) and invasive coronary angiography (ICA) were used as golden standard. The sensitivity and specificity of CAC to exclude and predict obstructive CAD were assessed. In addition, peri- and postoperative mortality and cardiac events were analyzed.Results149 LT recipients (ranged 31–71 years) were included. In 75% of patients, no CAC and mild CAC could rule out obstructive CAD on CCTA and ICA with 100% certainty. The threshold of mild CAC had a sensitivity of 100% for both CCTA and ICA and a specificity of 91% and 68%, respectively. None of the patients with no or mild calcifications experienced peri- and post-operative cardiac events or died of cardiac causes.ConclusionVisual evaluation of CAC on prior non-gated CT can accurately and safely exclude obstructive CAD in LT recipients. Incorporation of these already available data can optimize cardiac screening, by safely withholding or correctly allocating dedicated cardiac imaging in LT recipients. Thereby, reducing patients' test burden and save health care expenses. Show less
Bot, D.; Lucassen, C.; Werkman, M.; Dijk, S. van; Feshtali, S.S.; Tushuizen, M.E.; Hoek, B. van 2023
Background: Physical fitness is an important modifiable factor related to quality of life. Sarcopenia and myosteatosis are associated with morbidity and mortality in patients with end-stage liver... Show moreBackground: Physical fitness is an important modifiable factor related to quality of life. Sarcopenia and myosteatosis are associated with morbidity and mortality in patients with end-stage liver disease (ESLD). However, their relationship with physical fitness has not been established yet. Therefore, the main purpose of this study was to investigate the association between both low skeletal muscle index (SMI) and myosteatosis with physical fitness in patients with ESLD.Methods: In this retrospective cross-sectional cohort study, a cohort of patients with ESLD who were evaluated for liver transplantation (LT) was included. Physical fitness was reflected by cardiorespiratory fitness (CRF) and skeletal muscle strength, as measured by the 6-min walking distance (6MWD) and handgrip strength (HGS), respectively. Both were included in routine LT evaluation. Skeletal Muscle Index (SMI) and Muscle Radiation Attenuation (MRA) were evaluated based on the routine abdominal computed tomography. Linear and logistic regression analyses were performed.Results: Out of the 130 patients 94 (72%) were male, mean age was 56 +/- 11 years. Myosteatosis was significantly associated with low 6MWD as percentage of predicted (b =-12.815 (CI-24.608 to-1.022, p-value 0.034)) as well as with low absolute 6MWD (<250 m) (OR 3.405 (CI 1.134-10.220, p-value 0.029)). No association was found between SMI and/or myosteatosis with HGS, or between SMI and 6MWD.Conclusion: In contrast to SMI, myosteatosis is associated with low CRF. Neither low SMI nor myo-steatosis was associated with skeletal muscle strength. Therefore physical exercise training might be especially beneficial for LT candidates with myosteatosis.(c) 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY license (http://creativecommons.org/licenses/ by/4.0/). Show less
Bot, D.; Lucassen, C.; Werkman, M.; Dijk, S. van; Feshtali, S.S.; Tushuizen, M.E.; Hoek, B. van 2023
BackgroundPhysical fitness is an important modifiable factor related to quality of life. Sarcopenia and myosteatosis are associated with morbidity and mortality in patients with end-stage liver... Show moreBackgroundPhysical fitness is an important modifiable factor related to quality of life. Sarcopenia and myosteatosis are associated with morbidity and mortality in patients with end-stage liver disease (ESLD). However, their relationship with physical fitness has not been established yet. Therefore, the main purpose of this study was to investigate the association between both low skeletal muscle index (SMI) and myosteatosis with physical fitness in patients with ESLD.MethodsIn this retrospective cross-sectional cohort study, a cohort of patients with ESLD who were evaluated for liver transplantation (LT) was included. Physical fitness was reflected by cardiorespiratory fitness (CRF) and skeletal muscle strength, as measured by the 6-min walking distance (6MWD) and handgrip strength (HGS), respectively. Both were included in routine LT evaluation. Skeletal Muscle Index (SMI) and Muscle Radiation Attenuation (MRA) were evaluated based on the routine abdominal computed tomography. Linear and logistic regression analyses were performed.ResultsOut of the 130 patients 94 (72%) were male, mean age was 56 ± 11 years. Myosteatosis was significantly associated with low 6MWD as percentage of predicted (β = −12.815 (CI -24.608 to −1.022, p-value 0.034)) as well as with low absolute 6MWD (<250 m) (OR 3.405 (CI 1.134–10.220, p-value 0.029)). No association was found between SMI and/or myosteatosis with HGS, or between SMI and 6MWD.ConclusionIn contrast to SMI, myosteatosis is associated with low CRF. Neither low SMI nor myosteatosis was associated with skeletal muscle strength. Therefore physical exercise training might be especially beneficial for LT candidates with myosteatosis. Show less
Ruijter, B.N.; Inderson, A.; Berg, A.P. van den; Metselaar, H.J.; Dubbeld, J.; Tushuizen, M.E.; ... ; Hoek, B. van 2023
Background and Aims: Previous trials comparing cyclo-sporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclo-sporine (C0), leading... Show moreBackground and Aims: Previous trials comparing cyclo-sporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclo-sporine (C0), leading to less accurate dosing than with 2-h monitoring (C2). Only one larger trial compared C2 with tac-rolimus based on trough level (T0) after LT, with similar treat-ed biopsy-proven acute rejection (tBPAR) and graft loss, while a smaller trial had less tBPAR with C2 compared to T0. There-fore, it is still unclear which calcineurin inhibitor is preferred after LT. We aimed to demonstrate superior efficacy (tBPAR), tolerability, and safety of C2 or T0 after first LT. Methods: Patients after first LT were randomized to C2 or T0. tBPAR, patient-and graft survival, safety and tolerability were the main endpoints, with analysis by Fisher test, Kaplan-Meier survival analysis and log-rank test. Results: In intention-to- treat analysis 84 patients on C2 and 85 on T0 were included. Cumulative incidence of tBPAR C2 vs. T0 was 17.7% vs. 8.4% at 3 months (p=0.104), and 21.9% vs. 9.7% at 6 and 12 months (p=0.049). One-year cumulative mortality C2 vs. T0 was 15.5% vs. 5.9% (p=0.049) and graft loss 23.8% vs. 9.4% (p=0.015). Serum triglyceride and LDL-cholesterol was lower with T0 than with C2. Incidence of diarrhea in T0 vs, C2 was 64% vs. 31% (p <= 0.001), with no other differences in safety and tolerability. Conclusions: In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2. Show less
Shi, S.J.; Roest, H.P.; Bosch, T.P.P. van den; Bijvelds, M.J.C.; Boehnert, M.U.; Jonge, J. de; ... ; Laan, L.J.W. van der 2023
Background Ischemia of the bile duct is a common feature in liver disease and transplantation, which represents a major cause of morbidity and mortality, especially after liver transplantation.... Show moreBackground Ischemia of the bile duct is a common feature in liver disease and transplantation, which represents a major cause of morbidity and mortality, especially after liver transplantation. Detailed knowledge of its pathogenesis remains incomplete due to the lack of appropriate in vitro models.Methods To recapitulate biliary damage induced by ischemia and reperfusion in vitro, human intrahepatic cholangiocyte organoids (ICOs) were grown at low oxygen levels of 1% up to 72 h, followed by re-oxygenation at normal levels.Findings ICOs stressed by ischemia and subsequent re-oxygenation represented the dynamic change in biliary cell proliferation, upregulation of epithelial-mesenchymal transition (EMT)-associated markers, and the evocation of phase-dependent cell death programs similar to what is described in patients. Clinical-grade alpha-1 antitrypsin was identified as a potent inhibitor of both ischemia-induced apoptosis and necroptosis.Interpretation These findings demonstrate that ICOs recapitulate ischemic cholangiopathy in vitro and enable drug assessment studies for the discovery of new therapeutics for ischemic cholangiopathies. Show less
Background & Aims: Liver transplantation (LT) for primary sclerosing cholangitis (PSC) is complicated by recurrence of PSC (rPSC) in up to 25% of recipients. Recurrence has been shown to be... Show moreBackground & Aims: Liver transplantation (LT) for primary sclerosing cholangitis (PSC) is complicated by recurrence of PSC (rPSC) in up to 25% of recipients. Recurrence has been shown to be detrimental for both graft and patient survival. For both PSC and rPSC, a medical cure is not available. To predict and ideally to prevent rPSC, it is imperative to find risk factors for rPSC that can be potentially modified. Therefore, we aimed to identify such factors for rPSC in a large international multicentre study including 6 centres in PSC-prevalent countries. Methods: In this international multicentre, retrospective cohort study, 531 patients who underwent transplantation for PSC were included. In 25% of cases (n = 131), rPSC was diagnosed after a median follow-up of 6.72 (3.29-10.11) years post-LT. Results: In the multivariable competing risk model with time-dependent covariates, we found that factors representing an increased inflammatory state increase the risk for rPSC. Recurrent cholangitis before LT as indication for LT (hazard ratio [HR] 3.6, 95% CI 2.5-5.2), increased activity of inflammatory bowel disease after LT (HR 1.7, 95% CI 1.08-2.75), and multiple acute cellular rejections (HR: non-linear) were significantly and independently associated with an increased risk of rPSC. In contrast to the findings of previous studies, pretransplant colectomy was not found to be independently protective against the development of rPSC. Conclusions: An increased inflammatory state before and after LT may play a causal and modifiable role in the development of rPSC. Pretransplant colectomy did not reduce the risk of rPSC per se. Recurrent cholangitis as indication for LT was asso-ciated with an increased risk of rPSC. Impact and implications: Recurrence of PSC (rPSC) negatively affects survival after liver transplant (LT). Modifiable risk factors could guide clinical management and prevention of rPSC. We demonstrate that an increased inflammatory state both before and after LT increases the incidence of rPSC. As these are modifiable factors, they could serve as targets for future studies and therapies. We also added further evidence to the ongoing debate regarding preventive colectomy for rPSC by reporting that in our multicenter study, we could not find an independent association between colectomy and risk of rPSC. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Background & AimsLiver transplantation (LT) for primary sclerosing cholangitis (PSC) is complicated by recurrence of PSC (rPSC) in up to 25% of recipients. Recurrence has been shown to be... Show moreBackground & AimsLiver transplantation (LT) for primary sclerosing cholangitis (PSC) is complicated by recurrence of PSC (rPSC) in up to 25% of recipients. Recurrence has been shown to be detrimental for both graft and patient survival. For both PSC and rPSC, a medical cure is not available. To predict and ideally to prevent rPSC, it is imperative to find risk factors for rPSC that can be potentially modified. Therefore, we aimed to identify such factors for rPSC in a large international multicentre study including 6 centres in PSC-prevalent countries.MethodsIn this international multicentre, retrospective cohort study, 531 patients who underwent transplantation for PSC were included. In 25% of cases (n = 131), rPSC was diagnosed after a median follow-up of 6.72 (3.29–10.11) years post-LT.ResultsIn the multivariable competing risk model with time-dependent covariates, we found that factors representing an increased inflammatory state increase the risk for rPSC. Recurrent cholangitis before LT as indication for LT (hazard ratio [HR] 3.6, 95% CI 2.5–5.2), increased activity of inflammatory bowel disease after LT (HR 1.7, 95% CI 1.08–2.75), and multiple acute cellular rejections (HR: non-linear) were significantly and independently associated with an increased risk of rPSC. In contrast to the findings of previous studies, pretransplant colectomy was not found to be independently protective against the development of rPSC.ConclusionsAn increased inflammatory state before and after LT may play a causal and modifiable role in the development of rPSC. Pretransplant colectomy did not reduce the risk of rPSC per se. Recurrent cholangitis as indication for LT was associated with an increased risk of rPSC. Show less
In general the prognosis of treated autoimmune hepatitis is comparable to the general population. The knowledge on risk factors predicting long term survival is still limited. Better knowledge on... Show moreIn general the prognosis of treated autoimmune hepatitis is comparable to the general population. The knowledge on risk factors predicting long term survival is still limited. Better knowledge on risk factors can lead to tailored treatment of patients in the future, preventing side effects in patients currently overtreated and preventing disease progression in patients currently undertreated.At diagnosis age, ethnicity, cirrhosis and ALT level were the main predictors for long-term survival. During treatment ALT level but not IgG level was associated with long-term survival. In patients presenting with acute or acute severe AIH improvement of liver function within 2 weeks after start of treatment was the main predictor for survival. In patients with AIH-PBC variant syndrome more patients than the guidelines indicate are treated with a combination of immunosupression and ursodeoxycholic acid.New treatment options are urgently needed in AIH which requires a better understanding of changes in the immune system. To our suprise complement did not play a role in autoimmune hepatitis. Using B-cell related cytokines, patients could be divided into immunological subgroups with each a different presentation, treatment response and outcome. Show less
Bariatric surgery is the most effective treatment for obesity and improves several manifestations of the metabolic syndrome, including nonalcoholic fatty liver disease. Strict nutritional... Show moreBariatric surgery is the most effective treatment for obesity and improves several manifestations of the metabolic syndrome, including nonalcoholic fatty liver disease. Strict nutritional counseling after bariatric surgery is a key in realizing these outcomes. When postoperative nutrient intake or nutrient uptake is compromised, bariatric surgery can also lead to severe hepatic complications. Here, we describe 3 cases of acute liver injury and acute liver failure caused by bariatric surgery, all with different management strategies and outcomes. Show less
Objectives: The utilization of liver allografts could be optimized if nonacceptance is predicted. This study aimed to evaluate the prognostic ability of an updated Discard Risk Index in... Show moreObjectives: The utilization of liver allografts could be optimized if nonacceptance is predicted. This study aimed to evaluate the prognostic ability of an updated Discard Risk Index in Eurotransplant.Materials and Methods: Potential deceased donors from January 2010 to December 2015 who had been reported to Eurotransplant were included in our analyses. Liver utilization was defined by transplant status as the primary outcome to evaluate the performance of the Eurotransplant-developed Discard Risk Index.Results: Of 11 670 potential livers, 9565 (81%) were actually transplanted. Donor sex, age, history of diabetes, drug abuse, use of vasopressors, body mass index category, serum sodium, cause of death, donor type, and levels of C-reactive protein, bilirubin, aspartate and alanine aminotransferases, international normalized ratio, and gamma-glutamyl transpeptidase were associated with discard and combined in the Eurotransplant-developed Discard Risk Index. Correlation between the two Discard Risk Indexes was high (r = 0.86), and both achieved high C statistics of 0.72 and 0.75 (P <.001), respectively. Despite strong calibration, discard rates of 0.8% for overall donors and 6% of donors after circulatory death could be predicted with 80% accuracy.Conclusions: The Eurotransplant-developed Discard Risk Index showed a high prognostic ability to predict liver utilization in a European setting. The model could therefore be valuable for identifying livers at high risk of not being transplanted in an early stage. These organs might profit the most from modified allocation strategies or advanced preservation techniques. Show less
In dit proefschrift is gekeken naar de kwaliteit van uitname en naar de uitkomsten na transplantatie om zo goed mogelijk om te gaan met het tekort aan donororganen. Met de ET-DSRI kan de kans op... Show moreIn dit proefschrift is gekeken naar de kwaliteit van uitname en naar de uitkomsten na transplantatie om zo goed mogelijk om te gaan met het tekort aan donororganen. Met de ET-DSRI kan de kans op acceptatie voor een donorlever ingeschat worden. Daardoor kunnen er in een vroeg stadium maatregelen genomen worden om de kans op transplantatie te vergroten voor suboptimale levers. Alhoewel het aantal levers geschikt voor transplantatie geoptimaliseerd kan worden zal het tekort de komende jaren blijven bestaan. Daarmee zal ook de toewijzing van levers aan patiënten op de wachtlijsten complex blijven. De uitkomst na transplantatie is daarin een belangrijk punt. De resultaten beschreven in dit proefschrift laten zien dat statistische modellen een goede benadering kunnen geven van deze uitkomsten. Het toepassen van deze modellen zal leiden tot een meer evidence-based manier van het selecteren, toewijzen en daadwerkelijk transplanteren van levers in patiënten op de wachtlijst. Show less
Bot, D.; Droop, A.; Lucassen, C.J.; Veen, M.E. van; Vugt, J.L. van; Feshtali, S.S.; ... ; Hoek, B. van 2021
Background and aims: Malnutrition is highly prevalent in patients with end-stage liver disease (ESLD) and associated with impaired clinical outcome. Previous studies focused on one component of... Show moreBackground and aims: Malnutrition is highly prevalent in patients with end-stage liver disease (ESLD) and associated with impaired clinical outcome. Previous studies focused on one component of body composition and not in combination with nutritional intake, while both are components of the nutritional status. We aimed to evaluate the most important risk factors regarding body composition (muscle mass, muscle quality and fat mass) and nutritional intake (energy and protein intake) for waiting list mortality in patients with ESLD awaiting liver transplantation (LTx).Methods: Consecutive patients with ESLD listed for LTx between 2007 and 2014 were investigated. Muscle mass quantity (Skeletal Muscle Mass Index, SMI), and muscle quality (Muscle Attenuation, MA), and various body fat compartments were measured on computed tomography using SliceOmatic. Nutritional intake (e.g. energy and protein intake) was assessed. Multivariable stepwise forward Cox regression analysis was used for statistical analysis.Results: 261 Patients (mean age 54 years, 74.7% male) were included. Low SMI and MA were found to be statistically significant predictors of an increased risk for waiting list mortality in patients with ESLD, with a HR of 2.580 (95%CI 1.055-6.308) and HR of 9.124 (95%CI 2.871-28.970), respectively. No association between percentage adipose tissue, and protein and energy intake with waiting list mortality was found in this study.Conclusion: Both low muscle quantity and quality, and not nutritional intake, were independent risk factors for mortality in patients with ESLD. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. Show less
In this thesis the impact of donor and recipient risk factors and the development of risk models in liver transplantation was investigated. These models can be used for multiple purposes, including... Show moreIn this thesis the impact of donor and recipient risk factors and the development of risk models in liver transplantation was investigated. These models can be used for multiple purposes, including risk indication, outcome prediction and benchmarking between transplant centers. As such, several steps have been made towards evidence-based liver allocation and proper selection of liver allografts in times of organ shortage and the current system of severitybased liver allocation (by MELD the score). Further refinement of these models is necessary in order to optimize donor to recipient matching and achieve an objective, transparent and well-informed system of liver allocation. Altogether, the efforts made here to improve waitlist and transplantation outcomes, are meant for the individual transplant candidate on the liver transplant waitlist and as a whole, for the transplant community. Show less
Het ontstaan van galwegstricturen na levertransplantatie is een veelvoorkomende complicatie. Het eerste deel van het proefschrift geeft een overzicht van de huidige inzichten over het ontstaan van... Show moreHet ontstaan van galwegstricturen na levertransplantatie is een veelvoorkomende complicatie. Het eerste deel van het proefschrift geeft een overzicht van de huidige inzichten over het ontstaan van galwegstricturen. Het blijkt dat de hoogte van het serum piek alanine-aminotransferase na transplantatie (mate van ischemie-reperfusieschade) een goede voorspeller is voor het ontstaan van galwegstricturen na transplantatie van een lever afkomstig van een hartdode donor. Ook werd de relatie van galwegstricturen met de vorming van donor-specifieke antilichamen onderzocht. Deze relatie werd niet gevonden, maar de aanwezigheid van antilichamen bleek wel geassocieerd met een verminderde graft survival. Het tweede deel van het proefschrift is gericht op niet-invasieve diagnostiek. Zo wordt een gevalideerd scoringssysteem beschreven waarbij het mogelijk is met een MRCP betrouwbaar galwegstricturen aan te tonen. Verder bleek dat patiënten met galwegstricturen en cholestase een verhoogde elasticiteitsmeting hebben ten opzichte van patiënten met galwegstricturen maar zonder cholestase, of patiënten zonder galwegstricturen. In het derde deel wordt beschreven hoe de behandeling van galwegstricturen verloopt. Galwegstricturen bleken in 60.5% van de gevallen succesvol behandeld te kunnen worden. Multiple en intrahepatische galwegstricturen zijn meer therapieresistent hebben frequent een retransplantatie nodig. Tenslotte werd een studie uitgevoerd die onderzoekt hoe de kwaliteit van leven is van patiënten met galwegstricturen. Show less
Meijer, B.; Simsek, M.; Blokzijl, H.; Man, R.A. de; Coenraad, M.J.; Dijkstra, G.; ... ; Boer, N.K.H. de 2017
In chronic liver diseases, disturbances in liver function, for example in absorption of vitamin D, as well as factors related to the underlying primary liver disease, such as toxicity of alcohol or... Show moreIn chronic liver diseases, disturbances in liver function, for example in absorption of vitamin D, as well as factors related to the underlying primary liver disease, such as toxicity of alcohol or bile salts, may influence bone turnover. Low bone mass and vertebral fractures are already highly prevalent in patients with end-stage liver disease awaiting liver transplantation. There is rapid bone loss early after transplantation and new vertebral fractures occur in a third of transplanted patients within the first year after transplantation despite significant recovery of bone mass. Neither clinical parameters nor bone turnover markers or bone mineral density could reliably predict the risk of fractures. Furthermore, it is yet unclear how these patients should be treated in order to prevent fractures. Results from our and previous studies suggest that bisphosphonate treatment may decrease bone loss when initiated immediately after transplantation. In conclusion, fractures represent a significant cause of morbidity and mortality so that it is of high clinical relevance to correct all reversible aspects of liver failure to try and avoid the increased bone fragility associated with altered bone quality. Show less
