Pub Date : 2024-07-01DOI: 10.1136/egastro-2024-100067
Amy Cross, James M. Harris, Edward Arbe-Barnes, Colin Nixon, R. Dhairyawan, Andrew Hall, Alberto Quaglia, Fadi Issa, Patrick T F Kennedy, Jane A. McKeating, U. Gill, Dimitra Peppa
The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of hepatitis delta virus (HDV) and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalised treatments. Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus (HBV) and HDV or HIV co-infection.The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded (FFPE) biopsies from three treatment-naïve patients with chronic HBV and HDV or HIV co-infection. The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest (ROIs). Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas. A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions.Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses. Shared features including ‘cytotoxicity’ and ‘B cell receptor signalling’ were consistent across patients, suggesting common elements alongside individual traits. HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment, whereas HIV/HBV co-infection featured genes related to interferon response regulation. Varied cellular characteristics and immune cell populations, with an abundance of γδT cells in the HDV/HBV sample, were observed within analysed regions. Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression.This proof-of-principle study shows the value of this platform in investigating the complex immune landscape, highlighting relevant host pathways to disease pathogenesis.
{"title":"Characterisation of HBV and co-infection with HDV and HIV through spatial transcriptomics","authors":"Amy Cross, James M. Harris, Edward Arbe-Barnes, Colin Nixon, R. Dhairyawan, Andrew Hall, Alberto Quaglia, Fadi Issa, Patrick T F Kennedy, Jane A. McKeating, U. Gill, Dimitra Peppa","doi":"10.1136/egastro-2024-100067","DOIUrl":"https://doi.org/10.1136/egastro-2024-100067","url":null,"abstract":"The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of hepatitis delta virus (HDV) and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalised treatments. Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus (HBV) and HDV or HIV co-infection.The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded (FFPE) biopsies from three treatment-naïve patients with chronic HBV and HDV or HIV co-infection. The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest (ROIs). Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas. A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions.Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses. Shared features including ‘cytotoxicity’ and ‘B cell receptor signalling’ were consistent across patients, suggesting common elements alongside individual traits. HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment, whereas HIV/HBV co-infection featured genes related to interferon response regulation. Varied cellular characteristics and immune cell populations, with an abundance of γδT cells in the HDV/HBV sample, were observed within analysed regions. Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression.This proof-of-principle study shows the value of this platform in investigating the complex immune landscape, highlighting relevant host pathways to disease pathogenesis.","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141699020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1136/egastro-2023-100055
Amin Ariaee, Sabrina Koentgen, Hannah R. Wardill, Georgina L Hold, C. Prestidge, H. Armstrong, P. Joyce
Inflammatory bowel disease (IBD) is characterised by chronic inflammation in the gastrointestinal tract, with unclear aetiology but with known factors contributing to the disease, including genetics, immune responses, environmental factors and dysbiosis of the gut microbiota. Existing pharmacotherapies mainly target the inflammatory symptoms of disease, but recent research has highlighted the capacity for microbial-accessible carbohydrates that confer health benefits (ie, prebiotics) to selectively stimulate the growth of beneficial gut bacteria for improved IBD management. However, since prebiotics vary in source, chemical composition and microbiota effects, there is a clear need to understand the impact of prebiotic selection on IBD treatment outcomes. This review subsequently explores and contrasts the efficacy of prebiotics from various sources (β-fructans, galacto-oligosaccharides, xylo-oligosaccharides, resistant starch, pectin, β-glucans, glucomannans and arabinoxylans) in mitigating IBD symptomatology, when used as either standalone or adjuvant therapies. In preclinical animal colitis models, prebiotics have revealed type-dependent effects in positively modulating gut microbiota composition and subsequent attenuation of disease indicators and proinflammatory responses. While prebiotics have demonstrated therapeutic potential in animal models, clinical evidence for their precise efficacy remains limited, stressing the need for further investigation in human patients with IBD to facilitate their widespread clinical translation as microbiota-targeting IBD therapies.
{"title":"Prebiotic selection influencing inflammatory bowel disease treatment outcomes: a review of the preclinical and clinical evidence","authors":"Amin Ariaee, Sabrina Koentgen, Hannah R. Wardill, Georgina L Hold, C. Prestidge, H. Armstrong, P. Joyce","doi":"10.1136/egastro-2023-100055","DOIUrl":"https://doi.org/10.1136/egastro-2023-100055","url":null,"abstract":"Inflammatory bowel disease (IBD) is characterised by chronic inflammation in the gastrointestinal tract, with unclear aetiology but with known factors contributing to the disease, including genetics, immune responses, environmental factors and dysbiosis of the gut microbiota. Existing pharmacotherapies mainly target the inflammatory symptoms of disease, but recent research has highlighted the capacity for microbial-accessible carbohydrates that confer health benefits (ie, prebiotics) to selectively stimulate the growth of beneficial gut bacteria for improved IBD management. However, since prebiotics vary in source, chemical composition and microbiota effects, there is a clear need to understand the impact of prebiotic selection on IBD treatment outcomes. This review subsequently explores and contrasts the efficacy of prebiotics from various sources (β-fructans, galacto-oligosaccharides, xylo-oligosaccharides, resistant starch, pectin, β-glucans, glucomannans and arabinoxylans) in mitigating IBD symptomatology, when used as either standalone or adjuvant therapies. In preclinical animal colitis models, prebiotics have revealed type-dependent effects in positively modulating gut microbiota composition and subsequent attenuation of disease indicators and proinflammatory responses. While prebiotics have demonstrated therapeutic potential in animal models, clinical evidence for their precise efficacy remains limited, stressing the need for further investigation in human patients with IBD to facilitate their widespread clinical translation as microbiota-targeting IBD therapies.","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140768597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1136/egastro-2023-100001
Fenghua Xu, Lingyang Kong, Xiao Sun, WenXiang Hui, Lan Jiang, Wenxin Han, ZhiFeng Xiao, Ning Li, DongFeng Chen, Nan Zheng, Jing Han, Lei Liu
Colorectal cancer (CRC) is a common cancer worldwide. Although there are several treatments for cancer, the therapeutic effect on CRC remains unsatisfactory, and it is imperative to identify new therapeutic targets.Prefoldin (PFDN) is mainly used in the cytoskeleton assembly during the folding of actin and tubulin monomers. However, whether PFDN subunits are involved in regulating the development of CRC remains to be elucidated. In this study, molecular biology, cell culture, transcriptome sequencing and other experimental techniques, combined with bioinformatics, were used to verify the regulatory effects of PFDN6 on CRC.PFDN6 expression is elevated in patients with CRC and is closely associated with the development of CRC. Knockdown of PFDN6 reduced the tumour cell number, promoted apoptosis, and inhibited the migration and invasion of CRC cells in HCT-116 and RKO cell lines. Mechanistically, differentially expressed genes and related signalling pathways in RKO cells after PFDN6 knockdown were analysed by transcriptome sequencing.PFDN6 was found to regulate the generation and development of CRC by targeting ZNF575. These results open new avenues for therapeutic interventions for patients with CRC.
{"title":"PFDN6 contributes to colorectal cancer progression via transcriptional regulation","authors":"Fenghua Xu, Lingyang Kong, Xiao Sun, WenXiang Hui, Lan Jiang, Wenxin Han, ZhiFeng Xiao, Ning Li, DongFeng Chen, Nan Zheng, Jing Han, Lei Liu","doi":"10.1136/egastro-2023-100001","DOIUrl":"https://doi.org/10.1136/egastro-2023-100001","url":null,"abstract":"Colorectal cancer (CRC) is a common cancer worldwide. Although there are several treatments for cancer, the therapeutic effect on CRC remains unsatisfactory, and it is imperative to identify new therapeutic targets.Prefoldin (PFDN) is mainly used in the cytoskeleton assembly during the folding of actin and tubulin monomers. However, whether PFDN subunits are involved in regulating the development of CRC remains to be elucidated. In this study, molecular biology, cell culture, transcriptome sequencing and other experimental techniques, combined with bioinformatics, were used to verify the regulatory effects of PFDN6 on CRC.PFDN6 expression is elevated in patients with CRC and is closely associated with the development of CRC. Knockdown of PFDN6 reduced the tumour cell number, promoted apoptosis, and inhibited the migration and invasion of CRC cells in HCT-116 and RKO cell lines. Mechanistically, differentially expressed genes and related signalling pathways in RKO cells after PFDN6 knockdown were analysed by transcriptome sequencing.PFDN6 was found to regulate the generation and development of CRC by targeting ZNF575. These results open new avenues for therapeutic interventions for patients with CRC.","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140791923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-05-31DOI: 10.1136/egastro-2024-100074
Tiangang Li, Mohammad Nazmul Hasan, Lijie Gu
Bile acids are physiological detergents and signalling molecules that are critically implicated in liver health and diseases. Dysregulation of bile acid homeostasis alters cell function and causes cell injury in chronic liver diseases. Therapeutic agents targeting bile acid synthesis, transport and signalling hold great potential for treatment of chronic liver diseases. The broad cellular and physiological impacts of pharmacological manipulations of bile acid metabolism are still incompletely understood. Recent research has discovered new links of bile acid signalling to the regulation of autophagy and lysosome biology, redox homeostasis and endoplasmic reticulum stress. These are well-conserved mechanisms that allow cells to adapt to nutrient and organelle stresses and play critical roles in maintaining cellular integrity and promoting survival. However, dysregulation of these cellular pathways is often observed in chronic liver diseases, which exacerbates cellular dysfunction to contribute to disease pathogenesis. Therefore, identification of these novel links has significantly advanced our knowledge of bile acid biology and physiology, which is needed to understand the contributions of bile acid dysregulation in disease pathogenesis, establish bile acids as diagnostic markers and develop bile acid-based pharmacological interventions. In this review, we will first discuss the roles of bile acid dysregulation in the pathogenesis of chronic liver diseases, and then discuss the recent findings on the crosstalk of bile acid signalling and cellular stress responses. Future investigations are needed to better define the roles of these crosstalks in regulating cellular function and disease processes.
{"title":"Bile acids regulation of cellular stress responses in liver physiology and diseases.","authors":"Tiangang Li, Mohammad Nazmul Hasan, Lijie Gu","doi":"10.1136/egastro-2024-100074","DOIUrl":"10.1136/egastro-2024-100074","url":null,"abstract":"<p><p>Bile acids are physiological detergents and signalling molecules that are critically implicated in liver health and diseases. Dysregulation of bile acid homeostasis alters cell function and causes cell injury in chronic liver diseases. Therapeutic agents targeting bile acid synthesis, transport and signalling hold great potential for treatment of chronic liver diseases. The broad cellular and physiological impacts of pharmacological manipulations of bile acid metabolism are still incompletely understood. Recent research has discovered new links of bile acid signalling to the regulation of autophagy and lysosome biology, redox homeostasis and endoplasmic reticulum stress. These are well-conserved mechanisms that allow cells to adapt to nutrient and organelle stresses and play critical roles in maintaining cellular integrity and promoting survival. However, dysregulation of these cellular pathways is often observed in chronic liver diseases, which exacerbates cellular dysfunction to contribute to disease pathogenesis. Therefore, identification of these novel links has significantly advanced our knowledge of bile acid biology and physiology, which is needed to understand the contributions of bile acid dysregulation in disease pathogenesis, establish bile acids as diagnostic markers and develop bile acid-based pharmacological interventions. In this review, we will first discuss the roles of bile acid dysregulation in the pathogenesis of chronic liver diseases, and then discuss the recent findings on the crosstalk of bile acid signalling and cellular stress responses. Future investigations are needed to better define the roles of these crosstalks in regulating cellular function and disease processes.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141725196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1136/egastro-2023-100042
S. Burgess, H. T. Cronjé
Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes. However, if performed without critical thought, we may simply have replaced one set of implausible assumptions (no unmeasured confounding or reverse causation) with another set of implausible assumptions (no pleiotropy or other instrument invalidity). The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables. Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy; in general, a biologically motivated strategy is preferred. In this review, we discuss various ways of implementing a biologically motivated selection strategy: using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels, using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy. In some cases, a genome-wide analysis can provide important complementary evidence, even when its reliability is questionable. In other cases, a biologically-motivated analysis may not be possible. The choice of genetic variants must be informed by biological and functional considerations where possible, requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.
{"title":"Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principles","authors":"S. Burgess, H. T. Cronjé","doi":"10.1136/egastro-2023-100042","DOIUrl":"https://doi.org/10.1136/egastro-2023-100042","url":null,"abstract":"Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes. However, if performed without critical thought, we may simply have replaced one set of implausible assumptions (no unmeasured confounding or reverse causation) with another set of implausible assumptions (no pleiotropy or other instrument invalidity). The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables. Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy; in general, a biologically motivated strategy is preferred. In this review, we discuss various ways of implementing a biologically motivated selection strategy: using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels, using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy. In some cases, a genome-wide analysis can provide important complementary evidence, even when its reliability is questionable. In other cases, a biologically-motivated analysis may not be possible. The choice of genetic variants must be informed by biological and functional considerations where possible, requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139638552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1136/egastro-2023-100006
R. Little, Thisun Jayawardana, Sabrina Koentgen, Fan Zhang, Susan J Connor, Alex Boussioutas, M. Ward, Peter R. Gibson, Miles P Sparrow, Georgina L Hold
The pathogenesis of inflammatory bowel disease (IBD) is complex and multifactorial. Undertreated disease has substantial individual and societal consequences. Current patient classification and subsequent positioning of IBD therapy are based on crude, readily accessible clinical data. These broad parameters are unlikely to reflect underlying molecular profiles and may account for the observed heterogeneity in treatment response. Precision medicine offers identification and integration of molecular profiles into clinical decision-making. Despite several promising scientific and technological advances, the pathogenesis and targetable molecular drivers of IBD remain incompletely understood. Precision medicine therefore remains aspirational. This comprehensive narrative review describes our current understanding of IBD pathophysiology, highlights preliminary genetic, immunological and microbial predictors of treatment response and outlines the role of ‘big data’ and machine learning in the path towards precision medicine.
{"title":"Pathogenesis and precision medicine for predicting response in inflammatory bowel disease: advances and future directions","authors":"R. Little, Thisun Jayawardana, Sabrina Koentgen, Fan Zhang, Susan J Connor, Alex Boussioutas, M. Ward, Peter R. Gibson, Miles P Sparrow, Georgina L Hold","doi":"10.1136/egastro-2023-100006","DOIUrl":"https://doi.org/10.1136/egastro-2023-100006","url":null,"abstract":"The pathogenesis of inflammatory bowel disease (IBD) is complex and multifactorial. Undertreated disease has substantial individual and societal consequences. Current patient classification and subsequent positioning of IBD therapy are based on crude, readily accessible clinical data. These broad parameters are unlikely to reflect underlying molecular profiles and may account for the observed heterogeneity in treatment response. Precision medicine offers identification and integration of molecular profiles into clinical decision-making. Despite several promising scientific and technological advances, the pathogenesis and targetable molecular drivers of IBD remain incompletely understood. Precision medicine therefore remains aspirational. This comprehensive narrative review describes our current understanding of IBD pathophysiology, highlights preliminary genetic, immunological and microbial predictors of treatment response and outlines the role of ‘big data’ and machine learning in the path towards precision medicine.","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139631601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1136/egastro-2023-100036
B. Chang, Hui Tian, Ang Huang, Xingran Zhai, Qiaoling Wang, Lin Han, Xueyuan Jin, Li Gao, Qing-xiang Liang, Baosen Li, Yinying Lu, Huan Xie, Dong Ji, Zhengsheng Zou
To explore the incidence of alcohol-related hepatocellular carcinoma (HCC), evaluate possible synergisms between alcohol and well-known risk factors associated with HCC and establish a nomogram to predict alcohol-associated liver disease (ALD)-related HCC risk.A database of 136 571 inpatients in the Fifth Medical Center of Chinese PLA General Hospital from 2002 to 2018 with chronic liver disease was established. Data were collected by medical records review. Multivariate logistic regression was used to identify the independent high-risk factors associated with HCC, and then were incorporated into a novel nomogram. Afterward, the new established model was validated using external cohort by receiver operating characteristic curves analysis. For external cohort, 1646 patients with ALD admitted to our hospital from 2019 to 2021 were included. ALD was diagnosed on the basis of a history of sustained heavy alcohol intake greater than 40 g/day for men and 20 g/day for women for >5 years, clinical evidence of liver disease and supporting laboratory abnormalities.Over the last 17 years, trends showed obviously increases in ALD. ALD-related HCC experienced a significant increase from 5.8% to 30.7%, whereas hepatitis B virus (HBV)-related HCC declined from 77.6% to 52.0%. In patients with ALD-related HCC (5119), 3816 (74.54%) cases had HBV infection, 493 (9.63%) cases had hepatitis C virus (HCV) infection, 71 (1.39%) cases were coinfected with both HBV and HCV, and 739 (14.44%) cases had neither HBV nor HCV infection. Drinking years (OR 1.009, 95% CI (1.000 to 1.017)), age (OR 1.060, 95% CI (1.051 to 1.069)), diabetes mellitus (OR 1.314, 95% CI (1.123 to 1.538)), HBV infection (OR 4.905, 95% CI (4.242 to 5.671)), liver cirrhosis (OR 4.922, 95% CI (3.887 to 6.232)) and male sex (OR 17.011, 95%CI (2.296 to 126.013)) were associated with increased risk of HCC in patients with ALD. A nomogram had a concordance index of 0.786 (95% CI 0.773 to 0.799) and had well-fitted calibration curves. These results were successfully validated both in the internal cohort and external cohort.The prevalence of ALD and ALD-related HCC has been increased dramatically. The nomogram model established here with its high accuracy and easy-to-use features achieved an optimal prediction of HCC development in patients with ALD, which can help clinicians to develop an individualised and precise treatment strategy.
{"title":"Prevalence and prediction of hepatocellular carcinoma in alcohol-associated liver disease: a retrospective study of 136 571 patients with chronic liver diseases","authors":"B. Chang, Hui Tian, Ang Huang, Xingran Zhai, Qiaoling Wang, Lin Han, Xueyuan Jin, Li Gao, Qing-xiang Liang, Baosen Li, Yinying Lu, Huan Xie, Dong Ji, Zhengsheng Zou","doi":"10.1136/egastro-2023-100036","DOIUrl":"https://doi.org/10.1136/egastro-2023-100036","url":null,"abstract":"To explore the incidence of alcohol-related hepatocellular carcinoma (HCC), evaluate possible synergisms between alcohol and well-known risk factors associated with HCC and establish a nomogram to predict alcohol-associated liver disease (ALD)-related HCC risk.A database of 136 571 inpatients in the Fifth Medical Center of Chinese PLA General Hospital from 2002 to 2018 with chronic liver disease was established. Data were collected by medical records review. Multivariate logistic regression was used to identify the independent high-risk factors associated with HCC, and then were incorporated into a novel nomogram. Afterward, the new established model was validated using external cohort by receiver operating characteristic curves analysis. For external cohort, 1646 patients with ALD admitted to our hospital from 2019 to 2021 were included. ALD was diagnosed on the basis of a history of sustained heavy alcohol intake greater than 40 g/day for men and 20 g/day for women for >5 years, clinical evidence of liver disease and supporting laboratory abnormalities.Over the last 17 years, trends showed obviously increases in ALD. ALD-related HCC experienced a significant increase from 5.8% to 30.7%, whereas hepatitis B virus (HBV)-related HCC declined from 77.6% to 52.0%. In patients with ALD-related HCC (5119), 3816 (74.54%) cases had HBV infection, 493 (9.63%) cases had hepatitis C virus (HCV) infection, 71 (1.39%) cases were coinfected with both HBV and HCV, and 739 (14.44%) cases had neither HBV nor HCV infection. Drinking years (OR 1.009, 95% CI (1.000 to 1.017)), age (OR 1.060, 95% CI (1.051 to 1.069)), diabetes mellitus (OR 1.314, 95% CI (1.123 to 1.538)), HBV infection (OR 4.905, 95% CI (4.242 to 5.671)), liver cirrhosis (OR 4.922, 95% CI (3.887 to 6.232)) and male sex (OR 17.011, 95%CI (2.296 to 126.013)) were associated with increased risk of HCC in patients with ALD. A nomogram had a concordance index of 0.786 (95% CI 0.773 to 0.799) and had well-fitted calibration curves. These results were successfully validated both in the internal cohort and external cohort.The prevalence of ALD and ALD-related HCC has been increased dramatically. The nomogram model established here with its high accuracy and easy-to-use features achieved an optimal prediction of HCC development in patients with ALD, which can help clinicians to develop an individualised and precise treatment strategy.","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139636209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1136/egastro-2023-100035
F. Åberg, Mitja Lääperi, V. Männistö
Steatotic liver disease (SLD) is a growing global concern. The Chronic Liver Disease (CLivD) risk score predicts liver-related outcomes in the general population using easily accessible variables with or without laboratory tests (CLivDlaband CLivDnon-lab). We assessed CLivD’s associations with liver steatosis, fibrosis and its combined performance with fibrosis-4 (FIB-4) for advanced fibrosis detection.Using the National Health and Nutrition Examination Survey data (2017–2020), 3603 participants aged 40–70 years with valid liver stiffness measurements (LSMs) were included. Advanced fibrosis was defined as LSM ≥12 kPa, and SLD as controlled attenuation parameter ≥288 dB/m.Significant associations were found between CLivD and SLD and advanced fibrosis. CLivDlabhad an area under the curve (AUC) for advanced fibrosis of 0.72 (95% CI 0.68 to 0.77), while CLivDnon-labhad an AUC of 0.68 (95% CI 0.64 to 0.72), both slightly higher than FIB-4 (AUC 0.66, 95% CI 0.60 to 0.72). Among participants without obesity, AUC of CLivDlabwas 0.82 (95% CI 0.76 to 0.88) and AUC of CLivDnon-labwas 0.72 (95% CI 0.65 to 0.79). The CLivD score improved FIB-4’s AUC for advanced fibrosis detection from <0.5 at minimal CLivD scores to >0.8 at high CLivD scores. A sequential CLivD→FIB-4 strategy outperformed universal FIB-4 testing, enhancing specificity from 72% to 83%, with sensitivity at 51%–53%. This strategy identified a subgroup with a 55% prevalence of advanced fibrosis, while 47% had minimal-risk CLivD scores, eliminating the need for FIB-4 testing.The CLivD score, designed for predicting liver-related outcomes, effectively identifies liver steatosis and advanced fibrosis in the general population. Combining CLivD with FIB-4 enhances advanced fibrosis detection accuracy. The CLivD score could enhance population-based liver fibrosis screening, optimising resource allocation.
脂肪肝（SLD）是全球日益关注的问题。慢性肝病（CLivD）风险评分利用易于获取的变量，通过或不通过实验室检测（CLivDlab 和 CLivDnon-lab）预测普通人群中与肝脏相关的结果。我们评估了CLivD与肝脏脂肪变性、肝纤维化的关联，以及其与纤维化-4（FIB-4）联合检测晚期肝纤维化的性能。利用美国国家健康与营养调查数据（2017-2020年），纳入了3603名年龄在40-70岁之间、具有有效肝脏硬度测量值（LSM）的参与者。晚期肝纤维化的定义为 LSM ≥12 kPa，SLD 为受控衰减参数 ≥288 dB/m.研究发现 CLivD 和 SLD 与晚期肝纤维化之间存在显著关联。CLivDlab的晚期纤维化曲线下面积（AUC）为0.72（95% CI 0.68至0.77），而CLivDnon-lab的AUC为0.68（95% CI 0.64至0.72），均略高于FIB-4（AUC 0.66，95% CI 0.60至0.72）。在无肥胖症的参与者中，CLivDlab的AUC为0.82（95% CI 0.76至0.88），CLivDnon-lab的AUC为0.72（95% CI 0.65至0.79）。CLivD评分提高了FIB-4的晚期纤维化检测AUC，CLivD高分时AUC为0.8。CLivD→FIB-4连续检测策略优于FIB-4全面检测，特异性从72%提高到83%，灵敏度为51%-53%。CLivD评分是为预测肝脏相关结果而设计的，能有效识别普通人群中的肝脏脂肪变性和晚期纤维化。将CLivD与FIB-4结合可提高晚期肝纤维化检测的准确性。CLivD评分可加强基于人群的肝纤维化筛查，优化资源分配。
{"title":"CLivD score modifies FIB-4 performance in liver fibrosis detection in the US general population","authors":"F. Åberg, Mitja Lääperi, V. Männistö","doi":"10.1136/egastro-2023-100035","DOIUrl":"https://doi.org/10.1136/egastro-2023-100035","url":null,"abstract":"Steatotic liver disease (SLD) is a growing global concern. The Chronic Liver Disease (CLivD) risk score predicts liver-related outcomes in the general population using easily accessible variables with or without laboratory tests (CLivDlaband CLivDnon-lab). We assessed CLivD’s associations with liver steatosis, fibrosis and its combined performance with fibrosis-4 (FIB-4) for advanced fibrosis detection.Using the National Health and Nutrition Examination Survey data (2017–2020), 3603 participants aged 40–70 years with valid liver stiffness measurements (LSMs) were included. Advanced fibrosis was defined as LSM ≥12 kPa, and SLD as controlled attenuation parameter ≥288 dB/m.Significant associations were found between CLivD and SLD and advanced fibrosis. CLivDlabhad an area under the curve (AUC) for advanced fibrosis of 0.72 (95% CI 0.68 to 0.77), while CLivDnon-labhad an AUC of 0.68 (95% CI 0.64 to 0.72), both slightly higher than FIB-4 (AUC 0.66, 95% CI 0.60 to 0.72). Among participants without obesity, AUC of CLivDlabwas 0.82 (95% CI 0.76 to 0.88) and AUC of CLivDnon-labwas 0.72 (95% CI 0.65 to 0.79). The CLivD score improved FIB-4’s AUC for advanced fibrosis detection from <0.5 at minimal CLivD scores to >0.8 at high CLivD scores. A sequential CLivD→FIB-4 strategy outperformed universal FIB-4 testing, enhancing specificity from 72% to 83%, with sensitivity at 51%–53%. This strategy identified a subgroup with a 55% prevalence of advanced fibrosis, while 47% had minimal-risk CLivD scores, eliminating the need for FIB-4 testing.The CLivD score, designed for predicting liver-related outcomes, effectively identifies liver steatosis and advanced fibrosis in the general population. Combining CLivD with FIB-4 enhances advanced fibrosis detection accuracy. The CLivD score could enhance population-based liver fibrosis screening, optimising resource allocation.","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139016090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1136/egastro-2023-100017
F. Mokhtari-Esbuie, Bryan C Szeglin, Mohsen Rouhani Ravari, Mark Duncan, John W Harmon
Worldwide, gastric cancer results in significant morbidity and mortality. Ten per cent of patients with gastric cancer have a strong family history of the disease.CDH1(E-cadherin) has been identified as a key gene whose mutation leads to hereditary diffuse gastric cancer. We overviewed 33 articles with prophylactic total gastrectomy and assessed the outcomes and benefits. Families with mutations inCDH1may benefit from early prophylactic total gastrectomy. Dr Mark Duncan has applied his experience as a high-volume gastric cancer surgeon to treat not only individual patients, but several generations of patients within a family. This use of prophylactic total gastrectomy is well tolerated by patients and prevents the future development of gastric cancer.
在世界范围内，胃癌的发病率和死亡率都很高。10%的胃癌患者有强烈的胃癌家族史，cdh1 (e -钙粘蛋白)已被确定为一个关键基因，其突变导致遗传性弥漫性胃癌。我们回顾了33篇关于预防性全胃切除术的文章，并评估了结果和益处。有incdh1突变的家庭可能从早期预防性全胃切除术中获益。马克·邓肯医生运用他作为胃癌外科医生的经验，不仅治疗单个病人，而且治疗一个家庭中几代人的病人。这种预防性全胃切除术的使用被患者很好地耐受，并防止胃癌的未来发展。
{"title":"Pioneering use of genetic analysis forCDH1to identify candidates for prophylactic total gastrectomy to prevent hereditary diffuse gastric cancer","authors":"F. Mokhtari-Esbuie, Bryan C Szeglin, Mohsen Rouhani Ravari, Mark Duncan, John W Harmon","doi":"10.1136/egastro-2023-100017","DOIUrl":"https://doi.org/10.1136/egastro-2023-100017","url":null,"abstract":"Worldwide, gastric cancer results in significant morbidity and mortality. Ten per cent of patients with gastric cancer have a strong family history of the disease.CDH1(E-cadherin) has been identified as a key gene whose mutation leads to hereditary diffuse gastric cancer. We overviewed 33 articles with prophylactic total gastrectomy and assessed the outcomes and benefits. Families with mutations inCDH1may benefit from early prophylactic total gastrectomy. Dr Mark Duncan has applied his experience as a high-volume gastric cancer surgeon to treat not only individual patients, but several generations of patients within a family. This use of prophylactic total gastrectomy is well tolerated by patients and prevents the future development of gastric cancer.","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138616658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-01DOI: 10.1136/egastro-2023-100029
Lanlan Chen, Guoyue Lv
Recent studies have decoded the human Y chromosome sequencing with predominant precision and coverage, offering promising prospects in human genetics and clinical translation. Such an achievement is facilitated by third-generation sequencing technologies including Oxford Nanopore Technology and Pacific Biosciences, which can overcome the limitations of next-generation sequencing. In the context of digestive diseases, these advancements hold significant potential as they can help address the ‘missing heritability’ problem and detect various genomic variants in genetic association analyses, beyond single nucleotide polymorphisms, hoping to reveal ‘major’ genes for complex diseases. Besides, the completion of the Y chromosome enables research into sex-specific genetic effects on diseases and this knowledge can lead to sex-specific therapeutic targets and a better understanding of molecular mechanisms behind gender disparities. In summary, the recent decoding of the Y chromosome, coupled with third-generation sequencing, offers new opportunities to address heritability gaps, discover major disease genes and investigate sex-specific effects in digestive diseases, providing valuable insights for clinicians in delivering precise healthcare services.
{"title":"New horizons of human genetics in digestive diseases","authors":"Lanlan Chen, Guoyue Lv","doi":"10.1136/egastro-2023-100029","DOIUrl":"https://doi.org/10.1136/egastro-2023-100029","url":null,"abstract":"Recent studies have decoded the human Y chromosome sequencing with predominant precision and coverage, offering promising prospects in human genetics and clinical translation. Such an achievement is facilitated by third-generation sequencing technologies including Oxford Nanopore Technology and Pacific Biosciences, which can overcome the limitations of next-generation sequencing. In the context of digestive diseases, these advancements hold significant potential as they can help address the ‘missing heritability’ problem and detect various genomic variants in genetic association analyses, beyond single nucleotide polymorphisms, hoping to reveal ‘major’ genes for complex diseases. Besides, the completion of the Y chromosome enables research into sex-specific genetic effects on diseases and this knowledge can lead to sex-specific therapeutic targets and a better understanding of molecular mechanisms behind gender disparities. In summary, the recent decoding of the Y chromosome, coupled with third-generation sequencing, offers new opportunities to address heritability gaps, discover major disease genes and investigate sex-specific effects in digestive diseases, providing valuable insights for clinicians in delivering precise healthcare services.","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135565753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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