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  • 1
    Online Resource
    Online Resource
    Hepatobiliary phenotype of individuals with chronic intestinal disorders
    Springer Science and Business Media LLC ; 2021
    In:  Scientific Reports Vol. 11, No. 1 ( 2021-10-07)
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    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-10-07)
    Abstract: Despite the known functional relationship between the gut and the liver, the clinical consequences of this circuit remain unclear. We assessed the hepatobiliary phenotype of cohorts with celiac disease (CeD), Crohn´s disease (CD) and ulcerative colitis (UC). Baseline liver function tests and the frequency of hepatobiliary diseases were analyzed in 2377 CeD, 1738 CD, 3684 UC subjects and 488,941 controls from the population-based UK Biobank cohort. In this cohort study associations were adjusted for age, sex, BMI, diabetes, and alcohol consumption. Compared to controls, cohorts with CeD, but not CD/UC displayed higher AST/ALT values. Subjects with CD/UC but not CeD had increased GGT levels. Elevated ALP and cholelithiasis were significantly more common in all intestinal disorders. Non-alcoholic steatohepatitis and hepatocellular carcinoma (HCC) were enriched in CeD and CD (NASH: t aOR = 4.9 [2.2–11.0] in CeD, aOR = 4.2 [1.7–10.3] in CD, HCC: aOR = 4.8 [1.8–13.0] in CeD, aOR = 5.9 [2.2–16.1] in CD), while cholangitis was more common in the CD/UC cohorts (aOR = 11.7 [9.1–15.0] in UC, aOR = 3.5 [1.8–6.8] in CD). Chronic hepatitis, autoimmune hepatitis (AIH) and cirrhosis were more prevalent in all intestinal disorders. In UC/CD, a history of intestinal surgery was associated with elevated liver enzymes and increased occurrence of gallstones (UC: aOR = 2.9 [2.1–4.1], CD: 1.7 [1.2–2.3] ). Our data demonstrate that different intestinal disorders predispose to distinct hepatobiliary phenotypes. An increased occurrence of liver cirrhosis, NASH, AIH and HCC and the impact of surgery warrant further exploration.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-021-98843-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2615211-3
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  • 2
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    Shear Wave Elastography and Shear Wave Dispersion Imaging in the Assessment of Liver Disease in Alpha1-Antitrypsin Deficiency
    MDPI AG ; 2021
    In:  Diagnostics Vol. 11, No. 4 ( 2021-03-31), p. 629-
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    In: Diagnostics, MDPI AG, Vol. 11, No. 4 ( 2021-03-31), p. 629-
    Abstract: Liver affection of Alpha1-antitrypsin deficiency (AATD) can lead to cirrhosis and hepatocellular carcinoma (HCC). A noninvasive severity assessment of liver disease in AATD is urgently needed since laboratory parameters may not accurately reflect the extent of liver involvement. Preliminary data exist on two-dimensional shear wave elastography (2D-SWE) being a suitable method for liver fibrosis measurement in AATD. AATD patients without HCC were examined using 2D-SWE, shear wave dispersion imaging (SWD) and transient elastography (TE). Furthermore, liver steatosis was assessed using the controlled attenuation parameter (CAP) and compared to the new method of attenuation imaging (ATI). 29 AATD patients were enrolled, of which 18 had the PiZZ genotype, eight had PiMZ, two had PiSZ and one had a PiZP-Lowell genotype. 2D-SWE (median 1.42 m/S, range 1.14–1.83 m/S) and TE (median 4.8 kPa, range 2.8–24.6 kPa) values displayed a significant correlation (R = 0.475, p 〈 0.05). 2D-SWE, ATI (median 0.56 dB/cm/MHz, range 0.43–0.96 dB/cm/MHz) and CAP (median 249.5 dB/m, range 156–347 dB/m) values were higher in PiZZ when compared to other AATD genotypes. This study provides evidence that 2D-SWE is a suitable method for the assessment of liver disease in AATD. The newer methods of SWD and ATI require further evaluation in the context of AATD.
    Type of Medium: Online Resource
    ISSN: 2075-4418
    URL: Article
    DOI: 10.3390/diagnostics11040629
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662336-5
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  • 3
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    A Model‐Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs
    Wiley ; 2021
    In:  Clinical Pharmacology & Therapeutics Vol. 110, No. 5 ( 2021-11), p. 1293-1301
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    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 110, No. 5 ( 2021-11), p. 1293-1301
    Abstract: We present a generic workflow combining physiology‐based computational modeling and in vitro data to assess the clinical cholestatic risk of different drugs systematically. Changes in expression levels of genes involved in the enterohepatic circulation of bile acids were obtained from an in vitro assay mimicking 14 days of repeated drug administration for 10 marketed drugs. These changes in gene expression over time were contextualized in a physiology‐based bile acid model of glycochenodeoxycholic acid. The simulated drug‐induced response in bile acid concentrations was then scaled with the applied drug doses to calculate the cholestatic potential for each compound. A ranking of the cholestatic potential correlated very well with the clinical cholestasis risk obtained from medical literature. The proposed workflow allows benchmarking the cholestatic risk of novel drug candidates. We expect the application of our workflow to significantly contribute to the stratification of the cholestatic potential of new drugs and to support animal‐free testing in future drug development.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.v110.5
    DOI: 10.1002/cpt.2406
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2040184-X
    SSG: 15,3
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  • 4
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    Comparing in vitro human liver models to in vivo human liver using RNA-Seq
    Springer Science and Business Media LLC ; 2021
    In:  Archives of Toxicology Vol. 95, No. 2 ( 2021-02), p. 573-589
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    In: Archives of Toxicology, Springer Science and Business Media LLC, Vol. 95, No. 2 ( 2021-02), p. 573-589
    Abstract: The liver plays an important role in xenobiotic metabolism and represents a primary target for toxic substances. Many different in vitro cell models have been developed in the past decades. In this study, we used RNA-sequencing (RNA-Seq) to analyze the following human in vitro liver cell models in comparison to human liver tissue: cancer-derived cell lines (HepG2, HepaRG 3D), induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-HLCs), cancerous human liver-derived assays (hPCLiS, human precision cut liver slices), non-cancerous human liver-derived assays (PHH, primary human hepatocytes) and 3D liver microtissues. First, using CellNet, we analyzed whether these liver in vitro cell models were indeed classified as liver, based on their baseline expression profile and gene regulatory networks (GRN). More comprehensive analyses using non-differentially expressed genes (non-DEGs) and differential transcript usage (DTU) were applied to assess the coverage for important liver pathways. Through different analyses, we noticed that 3D liver microtissues exhibited a high similarity with in vivo liver, in terms of CellNet (C/T score: 0.98), non-DEGs (10,363) and pathway coverage (highest for 19 out of 20 liver specific pathways shown) at the beginning of the incubation period (0 h) followed by a decrease during long-term incubation for 168 and 336 h. PHH also showed a high degree of similarity with human liver tissue and allowed stable conditions for a short-term cultivation period of 24 h. Using the same metrics, HepG2 cells illustrated the lowest similarity (C/T: 0.51, non-DEGs: 5623, and pathways coverage: least for 7 out of 20) with human liver tissue. The HepG2 are widely used in hepatotoxicity studies, however, due to their lower similarity, they should be used with caution. HepaRG models, iPSC-HLCs, and hPCLiS ranged clearly behind microtissues and PHH but showed higher similarity to human liver tissue than HepG2 cells. In conclusion, this study offers a resource of RNA-Seq data of several biological replicates of human liver cell models in vitro compared to human liver tissue.
    Type of Medium: Online Resource
    ISSN: 0340-5761 , 1432-0738
    URL: Article
    DOI: 10.1007/s00204-020-02937-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1458459-1
    SSG: 15,3
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  • 5
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    Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ)
    Elsevier BV ; 2023
    In:  Clinical Gastroenterology and Hepatology ( 2023-9)
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    In: Clinical Gastroenterology and Hepatology, Elsevier BV, ( 2023-9)
    Type of Medium: Online Resource
    ISSN: 1542-3565
    URL: Article
    DOI: 10.1016/j.cgh.2023.08.038
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 6
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    Phenome‐wide association study in adult coeliac disease: role of HLA subtype
    Wiley ; 2021
    In:  Alimentary Pharmacology & Therapeutics Vol. 53, No. 4 ( 2021-02), p. 510-518
    Details
    In: Alimentary Pharmacology & Therapeutics, Wiley, Vol. 53, No. 4 ( 2021-02), p. 510-518
    Abstract: Coeliac disease arises in genetically susceptible individuals, in particular in carriers of HLA‐DQ2/DQ8 risk alleles and is associated with various comorbidities. Coeliac disease may confer an increased mortality, but the data are conflicting. Aims We aimed to characterize mortality and morbidity in patients with coeliac disease with a special focus on the role of the number of HLA risk alleles. Methods We studied coeliac disease‐associated morbidity and mortality in ~500 000 participants of the UK Biobank including 2482 individuals with the diagnosis of coeliac disease. We used an unbiased, multivariable Phenome‐Wide Association Study (PheWAS) method to uncover the coeliac disease‐associated disorders. The tag SNP approach was used to divide the coeliac disease subjects into HLA‐DQ2/DQ8‐based risk categories. Results We found 225 ICD‐10 codes significantly associated with coeliac disease. During the median follow‐up of 10.7 years, coeliac disease individuals (n = 2482) had higher overall mortality (HR 1.6 [95% CI, 1.4‐1.8]) than controls and both an increased occurrence of and an increased mortality from cancer, respiratory and cardiovascular diseases (HR 1.4‐1.6). Coeliac disease individuals with 2 HLA‐DQ2/8 risk alleles had a similar overall mortality as coeliac disease participants with 0‐1 HLA‐DQ2/8 alleles, but were more likely to die from lymphoproliferative diseases (HR 7.6 [95% CI, 1.01‐57.25]). Conclusions Our data suggest that the increased mortality from lymphoproliferative diseases is restricted to those coeliac patients with 2 HLADQ2/8 alleles and that a combination of coeliac disease and HLADQ2/8 alleles is needed to increase the susceptibility. Once confirmed, closer monitoring may be warranted in this high‐risk subpopulation.
    Type of Medium: Online Resource
    ISSN: 0269-2813 , 1365-2036
    URL: Issue
    URL: Article
    DOI: 10.1111/apt.v53.4
    DOI: 10.1111/apt.16206
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2003094-0
    SSG: 15,3
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  • 7
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    Phenome of coeliac disease vs. inflammatory bowel disease
    Springer Science and Business Media LLC ; 2022
    In:  Scientific Reports Vol. 12, No. 1 ( 2022-08-26)
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    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2022-08-26)
    Abstract: Coeliac disease (CeD) is characterized by gliadin-induced intestinal inflammation appearing in genetically susceptible individuals, such as HLA-DQ2.5 carriers. CeD, as well as other chronic intestinal disorders, such as Crohn's disease (CD) and ulcerative colitis, has been associated with increased morbidity and mortality, but the causes are unknown. We systematically analysed CeD-associated diagnoses and compared them to conditions enriched in subjects with CD/UC as well as in HLA-DQ2.5 carriers without CeD. We compared the overall and cause-specific mortality and morbidity of 3,001 patients with CeD, 2,020 with CD, 4,399 with UC and 492,200 controls in the community-based UK Biobank. Disease-specific phenotypes were assessed with the multivariable Phenome Wide Association Study (PheWAS) method. Associations were adjusted for age, sex and body mass index. All disease groups displayed higher overall mortality than controls (CD: aHR = 1.91[1.70–2.17]; UC: aHR = 1.32 [1.20–1.46] ; CeD: aHR = 1.38 [1.22–1.55]). Cardiovascular and cancer-related deaths were responsible for the majority of fatalities. PheWAS analysis revealed 166 Phecodes overrepresented in all three disorders, whereas only ~ 20% of enriched Phecodes were disease specific. Seven of the 58 identified CeD-specific Phecodes were enriched in individuals homozygous for HLA-DQ2.5 without diagnosed CeD. Four out of these seven Phecodes and eight out of 19 HLA-DQ2.5 specific Phecodes were more common in homozygous HLA-DQ2.5 subjects with vs. without CeD, highlighting the interplay between genetics and diagnosis-related factors. Our study illustrates that the morbidity and mortality in CeD share similarities with CD/UC, while the CeD-restricted conditions might be driven by both inherited and acquired factors.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-022-18593-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2615211-3
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