Publications by authors named "Jef Verbeek"

37 Publications

Liver and/or Kidney Transplantation After SARS-CoV-2 Infection: Prevalence, Short-Term Outcome and Kinetics of Serum IgG Antibodies.

Transplantation 2021 Sep 16. Epub 2021 Sep 16.

Department of Gastroenterology & Hepatology, University Hospitals Leuven; Laboratory of Hepatology, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium Clinical Department of Laboratory Medicine and National Reference Center for Respiratory Pathogens, University Hospitals Leuven; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium Department of Abdominal Transplant Surgery, University Hospitals Leuven; Transplantation Research Group, Lab of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium Department of Respiratory Diseases, University Hospitals Leuven; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium. Department of Cardiology, University Hospitals Leuven; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium Department of Nephrology & Renal Transplantation, University Hospitals Leuven; Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Background: There is paucity of data on the prevalence, adequate timing and outcome of solid organ transplantation after SARS-CoV-2 infection and the kinetics of IgG antibodies in these patients.

Methods: SARS-CoV-2 anti-nucleocapsid (N) IgG and PCR via nasopharyngeal swab were analyzed in all patients within 24h before liver and/or kidney transplantation. Kinetics of IgG antibodies were analysed and compared with an immune-competent cohort.

Results: Between May 1st 2020 and March 18th 2021, 168 patients underwent liver and/or kidney transplantation in our centre, of which 11 (6.54%) patients with previous SARS-CoV-2 infection were identified. Median interval between SARS-CoV-2 infection and transplantation was 4.5 months (range 0.9-11). After a median post-transplant follow-up of 4.9 months, 10 out of 11 patients were alive without clinical signs of viral shedding or recurrent or active infection. One patient without symptom resolution at time of transplantation died after combined liver-kidney transplantation. In 9 out of 11 patients with previously PCR confirmed infection, SARS-CoV-2 anti-N and anti-spike (S) IgG were detectable at day of transplantation. Absolute levels of anti-N and anti-S IgG were positively correlated, declined over time in all patients and were significantly lower compared with immune-competent individuals. All patients remained anti-S IgG positive until last post-transplant follow-up, while three patients became anti-N negative.

Conclusions: We observed an uncomplicated course of liver and/or kidney transplantation after SARS-CoV-2 infection in selected patients. Although having lower absolute IgG antibody levels than immune-competent individuals, all seroconverted patients remained anti-S IgG positive. These encouraging data need validation in larger studies.
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http://dx.doi.org/10.1097/TP.0000000000003955DOI Listing
September 2021

Insulin resistance is positively associated with plasma cathepsin D activity in NAFLD patients.

Biomol Concepts 2021 Aug 9;12(1):110-115. Epub 2021 Aug 9.

Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Universiteitssingel 50, 6229ER Maastricht, the Netherlands.

Previous studies associated plasma cathepsin D (CTSD) activity with hepatic insulin resistance in overweight and obese humans. Insulin resistance is a major feature of non-alcoholic fatty liver disease (NAFLD) and is one of the multiple hits determining the progression towards non-alcoholic steatohepatitis (NASH). In line, we have previously demonstrated that plasma CTSD levels are increased in NASH patients. However, it is not known whether insulin resistance associates with plasma CTSD activity in NAFLD. To increase our understanding regarding the mechanisms by which insulin resistance mediates NAFLD, fifty-five liver biopsy or MRI-proven NAFLD patients (BMI>25kg/m) were included to investigate the link between plasma CTSD activity to insulin resistance in NAFLD. We concluded that HOMA-IR and plasma insulin levels are independently associated with plasma CTSD activity in NAFLD patients (standardized coefficient β: 0.412, 95% Cl: 0.142~0.679, p=0.004 and standardized coefficient β: 0.495, 95% Cl: 0.236~0.758, p=0.000, respectively). Together with previous studies, these data suggest that insulin resistance may link to NAFLD via elevation of CTSD activity in plasma. As such, these data pave the way for testing CTSD inhibitors as a pharmacological treatment of NAFLD.
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http://dx.doi.org/10.1515/bmc-2021-0011DOI Listing
August 2021

Treatment of severe alcoholic hepatitis: A systematic review.

Curr Opin Pharmacol 2021 Aug 5;60:91-101. Epub 2021 Aug 5.

Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, Belgium; Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Severe alcoholic hepatitis is the most severe form of alcohol-related liver disease. Corticosteroids remain the first choice of treatment. However, they are only effective in a subset of patients and are associated with an increased infection risk. Furthermore, nonresponders to corticosteroids have a poor prognosis with a mortality of 70% over 6 months. As such, there is a high need for a more personalized use of corticosteroids and the development and identification of alternative therapeutic strategies. In this review, we summarize the recent and ongoing randomized controlled trials concerning the treatment of severe alcoholic hepatitis.
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http://dx.doi.org/10.1016/j.coph.2021.06.011DOI Listing
August 2021

Liver-Related and Cardiovascular Outcome of Patients Transplanted for Nonalcoholic Fatty Liver Disease: A European Single-Center Study.

Transplant Proc 2021 Jun 18;53(5):1674-1681. Epub 2021 May 18.

Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Leuven, Belgium. Electronic address:

Background: The increasing rate of liver transplantation (LT) for nonalcoholic fatty liver disease (NAFLD) raises concerns on cardiovascular morbidity and mortality after LT in these patients.

Methods: We collected variables regarding the presence of metabolic risk factors, NAFLD recurrence, cardiovascular morbidity, and overall survival at time of listing and after LT of 112 patients with NAFLD and a control group of 120 patients with hepatitis C (HCV).

Results: Metabolic syndrome and cardiovascular morbidity component rates (24.1% vs 12.5%) at the time of LT listing were higher in patients with NAFLD compared with patients with HCV (for all, P < .0390). Median follow-up after LT was 5.6 years in patients with NAFLD vs 13.5 years in patients with HCV (P = .0009). There was no difference in 6-weeks postoperative mortality (1.7% vs 2.5%) (P =1.0000). Metabolic syndrome components after LT were more frequent in patients with NAFLD than in patients with HCV (for all, P < .0008). The incidence of NAFLD 5 years after LT was higher in patients transplanted for NAFLD compared with HCV (43.5% vs 4.2%) (P < .0001). Patients with recurrent NAFLD more often had myocardial infarction compared with those without recurrence (8.3% vs 0%) (P = .0313). Five years after LT, cardiovascular morbidity was more frequent in the NAFLD group than in the HCV group (12.8% vs 9.3%) (P = .0256), whereas no difference in overall survival was observed.

Conclusion: LT for NAFLD is associated with satisfactory 5-year outcomes; however, our data underscore the need for close monitoring and aggressive management of cardiovascular risk factors in these patients.
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http://dx.doi.org/10.1016/j.transproceed.2021.02.025DOI Listing
June 2021

Myosteatosis in NAFLD patients correlates with plasma Cathepsin D.

Biomol Concepts 2021 May 15;12(1):27-35. Epub 2021 May 15.

Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Universiteitssingel 50, 6229ER Maastricht, the Netherlands.

Previously, we have shown that hepatic lipid accumulation induces the secretion of cathepsin D (CTSD), and that plasma CTSD levels are associated with increased inflammation and disease severity in nonalcoholic fatty liver disease (NAFLD). Although it is clear that the liver is a major source of plasma CTSD, it is unknown whether other metabolically active organs such as the muscle, also associate with plasma CTSD levels in NAFLD patients. Therefore, the aim of this study was to explore the relation between lipid accumulation in the muscle (myosteatosis) and plasma CTSD levels in forty-five NAFLD patients. We observed that hepatic steatosis positively associated with plasma CTSD levels, confirming the previously established link between plasma CTSD and the liver. Furthermore, a positive association between myosteatosis and plasma CTSD levels was observed, which was independent of sex, age, BMI, waist circumference and hepatic steatosis. By establishing a positive association between myosteatosis and plasma CTSD levels, our findings suggest that, in addition to the liver, the muscle is also linked to plasma CTSD levels in NAFLD patients. The observed link between myosteatosis and plasma CTSD levels supports the concept of a significant role of the skeletal muscle in metabolic disturbances in metabolic syndrome-related disorders.
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http://dx.doi.org/10.1515/bmc-2021-0004DOI Listing
May 2021

Is there a role for neuregulin 4 in human nonalcoholic fatty liver disease?

PLoS One 2021 14;16(5):e0251822. Epub 2021 May 14.

Laboratory of Hepatology, Department Chronic Diseases, Metabolism & Ageing (CHROMETA), KU Leuven, Leuven, Belgium.

Background: Neuregulin 4 (Nrg4), a novel adipokine enriched in brown adipose tissue has been observed to negatively regulate de novo hepatic lipogenesis and limit nonalcoholic fatty liver disease (NAFLD) progression to nonalcoholic steatohepatitis (NASH) in rodents. However, the role of Nrg4 in human NAFLD remains unclear to date. We analysed Nrg4 plasma levels and its association with liver disease severity together with the transcriptional profile of the Nrg4 pathway in liver and visceral adipose tissue (VAT) of NAFLD patients.

Methods: Plasma Nrg4 levels were measured in 65 NAFLD patients and 43 healthy controls (HC). Hepatic steatosis and fibrosis were diagnosed and quantified with chemical shift MRI and transient elastography respectively. Furthermore, blood lipid levels, HOMA-IR and systemic pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ) were analysed. Microarray analyses to assess differences in the Nrg4 and its receptor family ErbB pathway in liver and VAT from an independent patient group with biopsy proven NAFL (simple steatosis) (n = 4), NASH (n = 5) and normal liver (n = 6) were performed.

Results: Plasma Nrg4 levels were not significantly different between NAFLD patients and HC (p = 0.622). Furthermore, plasma Nrg4 levels did not correlate with the hepatic fat fraction (r = -0.028, p = 0.829) and were not significantly different between NAFLD patients with or without hepatic fibrosis (p = 0.087). Finally, the expression profile of 82 genes related to the Nrg4-ErbB pathway in liver and VAT was not significantly different between NAFL, NASH or obese controls.

Conclusion: Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251822PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121306PMC
May 2021

Absorption of nonheme iron during gastric acid suppression in patients with hereditary hemochromatosis and healthy controls.

Am J Physiol Gastrointest Liver Physiol 2021 06 5;320(6):G1105-G1110. Epub 2021 May 5.

Department of Internal Medicine, Gastroenterology and Clinical Geriatrics, Zuyderland Medical Center, Sittard-Geleen, The Netherlands.

Phlebotomies are performed in hereditary hemochromatosis (HH) to maintain normal iron concentrations. Proton-pump inhibitors (PPIs) can reduce the number of phlebotomies in patients with HH. However, in patients without HH, the iron concentrations do not appear to be compromised when using PPIs. Therefore, we aim to explain the differences in iron absorption between patients with and without HH. In 10 p.cysteine282tyrosine (p.C282Y) homozygous HH patients with normalized iron stores and 10 healthy control subjects (HCs), the iron parameters and hepcidin concentrations were determined before ingestion of a pharmacological dose of 50 mg iron [ferric iron (Fe)] polymaltose and hourly for 4 h afterward. This was repeated after 7 days of treatment with pantoprazole 40 mg once daily. Serum iron concentrations and transferrin saturation percentages dropped significantly during PPI use in the patients with HH, whereas no changes were observed in the HCs. Hepcidin concentrations were lower in the patients with HH compared with the HCs both before and during PPI use. In both groups, hepcidin levels did not significantly decrease during the treatment. Seven-day PPI use significantly reduces iron absorption in patients with HH but not in HCs. Changes in hepcidin concentrations could not explain these different PPI effects on iron absorption probably due to a small sample size. This study confirms that lowering gastric acidity by proton pump inhibitors results in a reduction in iron absorption in patients with hemochromatosis and not in healthy control subjects. The presupposition that a decrease in hepcidin concentration in healthy control subjects in response to lowering gastric acidity can explain the difference in iron absorption between these groups could not be confirmed probably because of a small sample size.
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http://dx.doi.org/10.1152/ajpgi.00371.2020DOI Listing
June 2021

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

Gut 2021 Feb 25. Epub 2021 Feb 25.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.

Objective: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.

Design: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.

Results: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.

Conclusion: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.
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http://dx.doi.org/10.1136/gutjnl-2020-323729DOI Listing
February 2021

Percutaneous transhepatic portal vein stenting as rescue treatment for recurrent oesophageal variceal bleeding in a 31-year-old woman with haepatocellular carcinoma in a non-cirrhotic liver.

BMJ Case Rep 2020 Dec 21;13(12). Epub 2020 Dec 21.

Department of Radiology, Maastricht University Medical Centre+, Maastricht, Limburg, The Netherlands

A 31-year-old woman with hepatocellular carcinoma suffered from recurrent oesophageal variceal bleeding due to portal hypertension, which was caused by severe compression of the portal vein by metastatic lymph nodes. Endoscopic band ligation and pharmacological treatment did not suffice to prevent recurrence of variceal bleeding. Eventually, after the fifth variceal bleeding within 6 months, the patient was admitted to the intensive care unit in a haemodynamic shock. A Sengstaken-Blakemore tube was inserted and all treatment options were discussed, but only percutaneous transhepatic recanalisation of the portal vein with stent placement to reduce portal vein pressure was thought to be feasible with any chance to relieve portal vein pressure. After successful portal vein stenting, our patient did not have any recurrent bleeding in the remaining year of her life. We suggest that percutaneous transhepatic portal vein stenting may be a feasible and adequate last line treatment for complications of portal hypertension.
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http://dx.doi.org/10.1136/bcr-2020-235161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754658PMC
December 2020

Unusual White-Yellowish Dots in the Colon Reveal a Rare Metabolic Disease.

Gastroenterology 2021 Aug 18;161(2):e39-e40. Epub 2020 Dec 18.

Division of Gastroenterology-Hepatology, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1053/j.gastro.2020.12.025DOI Listing
August 2021

The Role of Brown Adipose Tissue in the Development and Treatment of Nonalcoholic Steatohepatitis: An Exploratory Gene Expression Study in Mice.

Horm Metab Res 2020 Dec 1;52(12):869-876. Epub 2020 Dec 1.

Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8-9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p<0.05) and energy expenditure (Ucp1 and Ucp3; p<0.05) were significantly increased after 4 weeks HF-HSD compared with NCD, whereas in the occurrence of NASH after 20 weeks HF-HSD no difference was observed. We observed no differences in gene expression regarding lipid metabolism or energy expenditure at 8 weeks after dietary intervention (no NASH) compared with HF-HSD mice (NASH), nor in mice that underwent RYGB compared with SHAM. However, dietary intervention and RYGB both decreased the BAT gene expression of inflammatory cytokines (Il1b, Tnf-α and MCP-1; p<0.05). Gene expression of the neuregulin 4 was significantly decreased after 20 weeks HF-HSD (p<0.05) compared with NCD, but was restored by dietary intervention and RYGB (p<0.05). In conclusion, BAT is hallmarked by dynamic alterations in the gene expression profile during the development of NASH and can be modulated by dietary intervention and bariatric surgery.
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http://dx.doi.org/10.1055/a-1301-2378DOI Listing
December 2020

Diagnostic Accuracy of Biomarkers of Alcohol Use in Patients With Liver Disease: A Systematic Review.

Alcohol Clin Exp Res 2021 01 25;45(1):25-37. Epub 2020 Dec 25.

Department of Gastroenterology and Hepatology, (FN, JV), University Hospitals KU Leuven, Leuven, Belgium.

Background And Aims: Alcohol-related liver disease is the most frequent cause of cirrhosis and a major indication for liver transplantation. Several alcohol use biomarkers have been developed in recent years and are already in use in several centers. However, in patients with liver disease their diagnostic performance might be influenced by altered biomarker formation by hepatic damage, altered excretion by kidney dysfunction and diuretics use, and altered deposition in hair and nails. We systematically reviewed studies on the diagnostic accuracy of biomarkers of alcohol use in patients with liver disease and performed a detailed study quality assessment.

Methods: A structured search in PubMed/Medline/Embase databases was performed for relevant studies, published until April 28, 2019. The risk of bias and applicability concerns was assessed according to the adapted quality assessment of diagnostic accuracy studies-2 (QUADAS-2) checklist.

Results: Twelve out of 6,449 studies met inclusion criteria. Urinary ethyl glucuronide and urinary ethyl sulfate showed high sensitivity (70 to 89 and 73 to 82%, respectively) and specificity (93 to 99 and 86 to 89%, respectively) for assessing any amount of alcohol use in the past days. Serum carbohydrate-deficient transferrin showed low sensitivity but higher specificity (40 to 79 and 57 to 99%, respectively) to detect excessive alcohol use in the past weeks. Whole blood phosphatidylethanol showed high sensitivity and specificity (73 to 100 and 90 to 96%, respectively) to detect any amount of alcohol use in the previous weeks. Scalp hair ethyl glucuronide showed high sensitivity (85 to 100%) and specificity (97 to 100%) for detecting chronic excessive alcohol use in the past 3 to 6 months. Main limitations of the current evidence are the lack of an absolute gold standard to assess alcohol use, heterogeneous study populations, and the paucity of studies.

Conclusions: Urinary and scalp hair ethyl glucuronide are currently the most validated alcohol use biomarkers in patients with liver disease with good diagnostic accuracies. Phosphatidylethanol is a highly promising alcohol use biomarker, but so far less validated in liver patients. Alcohol use biomarkers can complement each other regarding diagnostic time window. More validation studies on alcohol use biomarkers in patients with liver disease are needed.
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http://dx.doi.org/10.1111/acer.14512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898850PMC
January 2021

Improved Markers of Cholestatic Liver Injury in Patients With Primary Biliary Cholangitis Treated With Obeticholic Acid and Bezafibrate.

Hepatology 2021 Jun 25;73(6):2598-2600. Epub 2021 May 25.

Laboratory of Hepatology, CHROMETA Department, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1002/hep.31613DOI Listing
June 2021

Intestinal permeability in human nonalcoholic fatty liver disease: A systematic review and meta-analysis.

Liver Int 2020 12 21;40(12):2906-2916. Epub 2020 Oct 21.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre+, Maastricht, the Netherlands.

Background: The gut-liver axis is considered to play a critical role in the development and progression of nonalcoholic fatty liver disease (NAFLD). The integrity of the epithelial barrier is crucial to protect the liver against the invasion of microbial products from the gut, although its exact role in NAFLD onset and progression is not clear.

Methods: We performed a systematic review and meta-analysis of studies that addressed the intestinal permeability (IP) in association with NAFLD presence or severity as defined by the presence of nonalcoholic steatohepatitis (NASH) and the degree of steatosis, hepatic inflammation or fibrosis. A total of 14 studies were eligible for inclusion.

Results: Studies investigating IP in adult (n = 6) and paediatric (n = 8) NAFLD showed similar results. Thirteen of the included studies focussed on small IP, two studies on whole gut permeability and none on colonic permeability. In the pooled analysis, NAFLD patients showed an increased small intestinal permeability compared to healthy controls based on dual sugar tests (standardized mean difference 0.79, 95% CI 0.49-1.08) and serum zonulin levels (standardized mean difference 1.04 ng/mL, 95% CI 0.40-1.68). No clear difference in IP was observed between simple steatosis and NASH patients. Furthermore, whole gut and small intestinal permeability increased with the degree of hepatic steatosis in 4/4 studies, while no association with hepatic inflammation or fibrosis was observed.

Conclusion: Based on the limited number of studies available, IP appears to be increased in NAFLD patients compared to healthy controls and is associated with the degree of hepatic steatosis.
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http://dx.doi.org/10.1111/liv.14696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756870PMC
December 2020

Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial.

Gastroenterology 2021 02 5;160(3):734-743.e6. Epub 2020 Oct 5.

Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands. Electronic address:

Background And Aims: Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary cholangitis (PBC). Pharmacologic strategies show limited efficacy and can provoke serious side effects. We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury. The aim of this investigator-initiated FITCH trial (Fibrates for cholestatic ITCH) was to assess effects of bezafibrate on pruritus in patients with PSC, PBC, and SSC.

Methods: Patients with moderate to severe pruritus (≥5 of 10 on visual analog scale [VAS]) due to PSC, PBC, or SSC were recruited for this double-blind, randomized, placebo-controlled trial between 2016 and 2019. Patients received once-daily bezafibrate (400 mg) or placebo for 21 days. The primary end point was ≥50% reduction of pruritus (VAS; intention-to-treat).

Results: Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to ≥50% reduction of severe or moderate pruritus (P = .003). For secondary end points, bezafibrate reduced morning (P = .01 vs placebo) and evening (P = .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P = .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, P = .03 vs placebo) correlating with improved pruritus (VAS, P = .01) suggesting reduced biliary damage. Serum bile acids and autotaxin activity remained unchanged. Serum creatinine levels tended to mildly increase (3% bezafibrate, 5% placebo, P = .14).

Conclusions: Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC.

Trial Registration: Netherlands Trial Register, ID: NTR5436 (August 3, 2015), ClinicalTrials.gov ID: NCT02701166 (March 2, 2016).
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http://dx.doi.org/10.1053/j.gastro.2020.10.001DOI Listing
February 2021

The effect of universal infant vaccination on the prevalence of hepatitis B immunity in adult solid organ transplant candidates.

J Viral Hepat 2021 01 14;28(1):105-111. Epub 2020 Oct 14.

Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.

Background: Hepatitis B virus (HBV) immunity is recommended to optimize outcomes after solid organ transplantation (SOT). This study assessed the prevalence and predictors of HBV immunity at the time patients were placed on transplant waiting list over a period from 1997 to 2019 in a low HBV endemic region.

Methods: Data were obtained from the University Hospitals Leuven transplant database. Minors and patients with past/current HBV infection were excluded. From 1986, Belgian patients are covered by the universal infant vaccination; therefore, birth cohort was stratified in those born ≥1986 vs <1986.

Results: The study population consisted of 3297 SOT candidates. HBV immunity rate was superior in renal transplant candidates (55.3%), and this number was 21.5%, 15.4% and 16.8% for liver, cardiac and pulmonary transplant candidates, respectively, P < .001. Among liver transplant candidates, HBV immunity rate was 14.8% in decompensated cirrhotic patients and 27.9% in those without advanced cirrhosis (P < .001). The overall immunity rate increased from 19.3% in period 1997-2008 to 32.8% in 2009-2019, P < .001. In multivariable analyses, younger age (odds ratio (OR) 95% confidence interval (CI): 0.97-0.98, P < .001) and birth cohort ≥ 1986 (OR 95% CI: 1.18-2.66, P = .006) were associated with increased HBV immunity.

Conclusion: An increase in HBV immunity was observed over a 20-year period related to the introduction of universal infant HBV vaccination. Nevertheless, this study highlights the low overall HBV immunity at the time of listing for organ transplantation and points out the need of an increased awareness and vaccination strategy at an early disease stage.
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http://dx.doi.org/10.1111/jvh.13414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756211PMC
January 2021

Myosteatosis in nonalcoholic fatty liver disease: An exploratory study.

Clin Res Hepatol Gastroenterol 2021 May 20;45(3):101500. Epub 2020 Aug 20.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands; School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands; Department of Visceral and Transplantation Surgery, Klinikum, RWTH, Pauwelsstraße 30, 52074 Aachen, Germany.

Background And Aim: Insulin resistance (IR) plays a central role in the complex pathophysiology of nonalcoholic fatty liver disease (NAFLD). IR is linked to fat infiltration in skeletal muscle (myosteatosis) and loss of skeletal muscle mass and function (sarcopenia). The clinical significance of myosteatosis in NAFLD is not well investigated. In this exploratory study we aimed to investigate the association between myosteatosis and NAFLD related hepatic and systemic variables in a well characterized NAFLD cohort.

Methods: We cross-sectionally studied forty-five NAFLD patients. The muscle fat fraction (MFF) was measured with chemical shift gradient echo MRI. In addition, the hepatic fat fraction (MRI), liver stiffness (FibroScan) and appendicular skeletal muscle mass (Dual-energy X-ray absorptiometry) were analyzed.

Results: The median hepatic fat fraction was 15.64% (IQR 12.05-25.13) and significant (F2-F3) liver fibrosis (liver stiffness ≥7kPa) was diagnosed in 18 NAFLD patients (40%). MFF was not correlated with hepatic fat fraction (r=-0.035, P=0.823) and did not differ between subjects with or without significant fibrosis (P=0.980). No patient was diagnosed with sarcopenia based on the skeletal muscle mass index. In a linear regression model, anthropometric parameters, including body mass index (BMI) (P=0.018) and total body fat percentage (P=0.005), were positively associated with MFF while no association with insulin resistance (HOMA-IR) was observed.

Conclusion: Myosteatosis did not correlate with the degree of hepatic steatosis or fibrosis in this well characterized NAFLD cohort, but was positively correlated with total body fat percentage and BMI.
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http://dx.doi.org/10.1016/j.clinre.2020.06.021DOI Listing
May 2021

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.

Gastroenterology 2020 08 4;159(2):534-548.e11. Epub 2020 May 4.

Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zürich, Switzerland.

Background & Aims: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease.

Methods: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank.

Results: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals.

Conclusions: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.
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http://dx.doi.org/10.1053/j.gastro.2020.04.058DOI Listing
August 2020

Effect of Plasmapheresis on Cholestatic Pruritus and Autotaxin Activity During Pregnancy.

Hepatology 2019 06 14;69(6):2707-2710. Epub 2019 Feb 14.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.

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http://dx.doi.org/10.1002/hep.30496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593664PMC
June 2019

Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders.

Mol Psychiatry 2019 01 11;24(1):10-17. Epub 2018 Jun 11.

Governor Kremers Centre, Maastricht University Medical Centre+, Maastricht, The Netherlands.

Alcohol exposure during pregnancy affects the development of the fetus in various ways and may lead to Fetal Alcohol Spectrum Disorders (FASD). FASD is one of the leading preventable forms of neurodevelopmental disorders. In the light of prevention and early intervention, knowledge on how ethanol exposure induces fetal damage is urgently needed. Besides direct ethanol and acetaldehyde toxicity, alcohol increases oxidative stress, and subsequent general effects (e.g., epigenetic imprinting, gene expression, and metabolite levels). The current review provides an overview of the existing knowledge about specific downstream pathways for FASD that affects e.g., the SHH pathway, cholesterol homeostasis, neurotransmitter signaling, and effects on the cytoskeleton. Available human data vary greatly, while animal studies with controlled ethanol exposition are only to a certain limit transferable to humans. The main deficits in knowledge about FASD are the lack of pathophysiological understanding and dose-response relationships, together with the lack of reliable biomarkers for either FASD detection or estimation of susceptibility. In addition to single outcome experiments, omics data should be generated to overcome this problem. Therefore, for future studies we recommend holistic data driven analysis, which allows integrative analyses over multiple levels of genetic variation, transcriptomics and metabolomics data to investigate the whole image of FASD development and to provide insight in potential drug targets for intervention.
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http://dx.doi.org/10.1038/s41380-018-0095-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325721PMC
January 2019

Carbohydrate Deficient Transferrin in Patients with Cirrhosis: A Tale of Bridges.

Alcohol Alcohol 2018 05;53(3):350-351

Department of Gastroenterology & Hepatology, University Hospitals KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

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http://dx.doi.org/10.1093/alcalc/agy008DOI Listing
May 2018

Lower Limbic Metabotropic Glutamate Receptor 5 Availability in Alcohol Dependence.

J Nucl Med 2018 04 18;59(4):682-690. Epub 2018 Jan 18.

Division of Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Animal studies suggest an important role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the pathophysiology of alcohol dependence, but direct human evidence is lacking. The goal of this study was to investigate cerebral mGlu5 availability in alcohol-dependent subjects versus controls using F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (F-FPEB) PET. Dynamic 90-min F-FPEB scans combined with arterial blood sampling were acquired for 16 recently abstinent alcohol-dependent subjects and 32 age-matched controls. Regional mGlu5 availability was quantified by the F-FPEB total distribution volume using both a voxel-by-voxel and a volume-of-interest analysis with partial-volume effect correction. Alcohol consumption within the last 3 mo was assessed by questionnaires and by hair ethyl glucuronide analysis. Craving was assessed using the Desire for Alcohol Questionnaire. mGlu5 availability was lower in mainly limbic regions of alcohol-dependent subjects than in controls ( < 0.05, familywise error-corrected), ranging from 14% in the posterior cingulate cortex to 36% in the caudate nucleus. Lower mGlu5 availability was associated with higher hair ethyl glucuronide levels for most regions and was related to a lower level of craving specifically in the middle frontal gyrus, cingulate cortex, and inferolateral temporal lobe. These findings provide human in vivo evidence that limbic mGlu5 has a role in the pathophysiology of alcohol dependence, possibly involved in a compensatory mechanism helping to reduce craving during abstinence.
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http://dx.doi.org/10.2967/jnumed.117.199422DOI Listing
April 2018

Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice.

Lipids Health Dis 2017 Feb 23;16(1):46. Epub 2017 Feb 23.

Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

Background: Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. However, histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. The efficacy of the angiotensin receptor type 1 blocker losartan is controversial because of varying results in a few animal and human studies. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model.

Methods: Male C57BL/6 J mice with high fat-high sucrose diet (HF-HSD) induced NASH, obesity, insulin resistance and hypercholesterolemia were subjected to dietary intervention (switch from HF-HSD to normal chow diet (NCD)) (n = 9), continuation HF-HSD together with losartan (30 mg/kg/day) (n = 9) or continuation HF-HSD only (n = 9) for 8 weeks. 9 mice received NCD during the entire experiment (20 weeks). We assessed the systemic metabolic effects and performed a detailed hepatic histological and molecular profiling. A P-value of < 0.05, using the group with continuation of HF-HSD only as control, was considered as statistically significant.

Results: Dietary intervention normalized obesity, insulin resistance, and hypercholesterolemia (for all P < 0.001), and remarkably, completely reversed all histological features of pre-existent NASH (for all P < 0.001), including fibrosis measured by quantification of collagen proportional area (P < 0.01). At the hepatic molecular level, dietary intervention targeted fibrogenesis with a normalization of collagen type I alpha 1, transforming growth factor β1, tissue inhibitor of metalloproteinase 1 mRNA levels (for all P < 0.01), lipid metabolism with a normalization of fatty acid translocase/CD36, fatty acid transport protein 5, fatty acid synthase mRNA levels (P < 0.05) and markers related to mitochondrial function with a normalization of hepatic ATP content (P < 0.05) together with sirtuin1 and uncoupling protein 2 mRNA levels (for both P < 0.001). Dietary intervention abolished p62 accumulation (P < 0.01), suggesting a restoration of autophagic flux. Losartan did not significantly affect obesity, insulin resistance, hypercholesterolemia or any histological NASH feature.

Conclusions: Dietary intervention, and not losartan, completely restores the metabolic phenotype in a representative mouse model with pre-existent NASH, obesity, insulin resistance and hypercholesterolemia.
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http://dx.doi.org/10.1186/s12944-017-0432-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324232PMC
February 2017

The increasing burden of NAFLD fibrosis in the general population: Time to bridge the gap between hepatologists and primary care.

Hepatology 2017 03 3;65(3):1078. Epub 2017 Jan 3.

Division of Gastroenterology and Hepatology Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands.

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http://dx.doi.org/10.1002/hep.28940DOI Listing
March 2017

Development of a Representative Mouse Model with Nonalcoholic Steatohepatitis.

Curr Protoc Mouse Biol 2016 Jun 1;6(2):201-210. Epub 2016 Jun 1.

Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the Western world. It represents a disease spectrum ranging from isolated steatosis to non-alcoholic steatohepatitis (NASH). In particular, NASH can evolve to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The development of novel treatment strategies is hampered by the lack of representative NASH mouse models. Here, we describe a NASH mouse model, which is based on feeding non-genetically manipulated C57BL6/J mice a 'Western style' high-fat/high-sucrose diet (HF-HSD). HF-HSD leads to early obesity, insulin resistance, and hypercholesterolemia. After 12 weeks of HF-HSD, all mice exhibit the complete spectrum of features of NASH, including steatosis, hepatocyte ballooning, and lobular inflammation, together with fibrosis in the majority of mice. Hence, this model closely mimics the human disease. Implementation of this mouse model will lead to a standardized setup for the evaluation of (i) underlying mechanisms that contribute to the progression of NAFLD to NASH, and (ii) therapeutic interventions for NASH. © 2016 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpmo.1DOI Listing
June 2016

An Overview of Mouse Models of Nonalcoholic Steatohepatitis: From Past to Present.

Curr Protoc Mouse Biol 2016 Jun 1;6(2):185-200. Epub 2016 Jun 1.

Department of Laboratory Medicine, University Hospitals KU Leuven, Leuven, Belgium.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It is associated with obesity and type 2 diabetes and represents a spectrum of histological abnormalities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which can further progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver failure. To gain insight into the pathogenesis and evaluate treatment options, mouse models of NAFLD/NASH are of utmost importance. There is a high phenotypical variety in the available mouse models, however, models that truly display the full spectrum of histopathological and metabolic features associated with human NASH are rare. In this review, we summarize the most important NAFLD/NASH mouse models that have been developed over the years and briefly highlight the pros and cons. Also, we illustrate the preclinical research in which these models have been used. © 2016 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpmo.3DOI Listing
June 2016

De novo Malignancy and Recurrent Alcoholic Cirrhosis Account for 70% of Deaths in Patients Transplanted for End-Stage Alcoholic Liver Disease.

Am J Gastroenterol 2016 Mar;111(3):436-7

Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1038/ajg.2016.10DOI Listing
March 2016

Hair ethyl glucuronide and serum carbohydrate deficient transferrin for the assessment of relapse in alcohol-dependent patients.

Clin Biochem 2016 May 3;49(7-8):554-9. Epub 2016 Feb 3.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium; Toxicology and TDM Laboratory, ZNA Stuivenberg Hospital, Antwerp, Belgium.

Objectives: Ethyl glucuronide in hair (hEtG) and serum carbohydrate deficient transferrin (%CDT) are valuable markers for alcohol abuse, but their diagnostic accuracy to monitor abstinence and relapse is unclear. Here, we investigate to what extent repeated measurements of hEtG and %CDT can be used to monitor relapse in alcohol-dependent patients during abstinence treatment.

Design And Methods: HEtG and %CDT were measured in individuals starting treatment for alcohol dependence both at treatment entry and 3months later. Alcohol consumption and relapse episodes were recorded using the Time Line Follow Back and by alcohol breath and urine tests, and correlated with hEtG and %CDT measurements.

Results: Fifteen patients completed the study, of which nine had one or more relapses. Hair EtG and serum %CDT identified whether a relapse occurred in 78% and 57% of cases, respectively. Only hEtG correlated with the amount of alcohol consumed before treatment entry (Pearson r=0.92; p<0.001). The specificity of %CDT to assess abstinence during treatment was 100%. HEtG had a specificity of only 17%; however, in all patients who remained abstinent, hEtG decreased with >85% from initial values. Mean hEtG, but not %CDT, differed significantly between patients who relapsed and patients who remained abstinent (p=0.034).

Conclusions: HEtG was more sensitive than serum %CDT to assess relapse in alcohol-dependent patients and was positively correlated with the amounts of alcohol consumed. In contrast, serum %CDT was more specific for assessing abstinence. We highlight the benefit of repeated measurements of hEtG and serum %CDT for monitoring abstinence during treatment.
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http://dx.doi.org/10.1016/j.clinbiochem.2015.11.023DOI Listing
May 2016

Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin.

Microb Cell 2014 Oct 24;1(11):352-364. Epub 2014 Oct 24.

Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee, Belgium.

The human pathology Wilson disease (WD) is characterized by toxic copper (Cu) accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs) that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp). The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS) and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells.
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http://dx.doi.org/10.15698/mic2014.11.175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349125PMC
October 2014
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