Zgjim Osmani, Willem Pieter Brouwer, Dwin G.B. Grashof, Youkyung Lim, Michael Doukas, Harry L.A. Janssen, Harmen J.G. van de Werken, Andre Boonstra
{"title":"代谢功能障碍相关性脂肪性肝炎降低了慢性乙型肝炎患者的干扰素和巨噬细胞肝基因特征","authors":"Zgjim Osmani, Willem Pieter Brouwer, Dwin G.B. Grashof, Youkyung Lim, Michael Doukas, Harry L.A. Janssen, Harmen J.G. van de Werken, Andre Boonstra","doi":"10.1016/j.jhep.2024.10.032","DOIUrl":null,"url":null,"abstract":"<h3>Background & Aims</h3>Chronic HBV patients with concomitant metabolic dysfunction-associated steatohepatitis (MASH) have been shown to develop more advanced fibrosis faster with more severe liver disease as compared to patients with chronic HBV alone. However, our understanding of the underlying mechanisms is limited. Here we study how MASH co-morbidity impact immune activity in the liver of patients with chronic HBV infection.<h3>Methods</h3>Bulk RNA sequencing was performed on liver biopsies from patients with only MASH (n=10), only HBeAg-negative chronic HBV (ENEG; n=11), combined MASH/ENEG (n=9) and healthy controls (n=9). Biopsies with no or minimal fibrosis (≤F2) were selected to avoid confounding effects of fibrosis. We compared whole transcriptome data from patients with MASH/ENEG to those with ENEG alone to determine the impact of MASH co-morbidity on chronic hepatitis B.<h3>Results</h3>There is a high degree of overlap of liver gene expression profiles in patients with only ENEG versus those with only MASH compared to healthy controls, suggesting a largely shared mechanism of liver dysfunction and immune activity for these distinct conditions. In patients with ENEG, MASH co-morbidity significantly reduced interferon pathway activity (NES=2.03, p.adj=0.0251), the expression of ISGs (e.g., <em>IFIT2</em>, <em>IFI27</em>, <em>IFITM1</em>, <em>IFI6</em>), and macrophage gene signatures (e.g., <em>MARCO</em>, <em>CD163</em>, <em>CD5L</em>, <em>CD63</em>), when compared to patients with ENEG alone.<h3>Conclusions</h3>Transcriptomic profiling of the liver suggests that MASH negatively impacts ISGs expression in the liver of patients with ENEG, which may affect antiviral immune pathways, viral replication and inflammatory responses resulting in an increased risk of advanced fibrosis in patients with chronic hepatitis B. Our study provides valuable insights for guiding future research aimed at developing effective, tailored strategies for managing patients with both conditions.<h3>Impact and implications</h3>In recent decades, obesity and associated health issues have reached epidemic levels, with steatotic liver disease affecting up to 30% of adults in developed countries, and this trend is also observed among chronic hepatitis B patients. Given the high and rising prevalence of steatotic liver disease and its frequent co-occurrence in chronic hepatitis B patients, it is essential to understand how conditions such as metabolic dysfunction-associated steatohepatitis (MASH) impact immune responses in the liver. This study provides unique insights into the impact of MASH on HBV antiviral immune activity in the liver of patients with chronic hepatitis B. The rising number of patients with both conditions affects treatment outcomes and highlights the urgent need for novel, tailored therapeutic strategies. Our study holds significant relevance for guiding future research on developing treatment strategies for patients with both MASH and chronic hepatitis B.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":null,"pages":null},"PeriodicalIF":26.8000,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Metabolic dysfunction-associated steatohepatitis reduces interferon and macrophage liver gene signatures in patients with chronic hepatitis B\",\"authors\":\"Zgjim Osmani, Willem Pieter Brouwer, Dwin G.B. Grashof, Youkyung Lim, Michael Doukas, Harry L.A. Janssen, Harmen J.G. van de Werken, Andre Boonstra\",\"doi\":\"10.1016/j.jhep.2024.10.032\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3>Background & Aims</h3>Chronic HBV patients with concomitant metabolic dysfunction-associated steatohepatitis (MASH) have been shown to develop more advanced fibrosis faster with more severe liver disease as compared to patients with chronic HBV alone. However, our understanding of the underlying mechanisms is limited. Here we study how MASH co-morbidity impact immune activity in the liver of patients with chronic HBV infection.<h3>Methods</h3>Bulk RNA sequencing was performed on liver biopsies from patients with only MASH (n=10), only HBeAg-negative chronic HBV (ENEG; n=11), combined MASH/ENEG (n=9) and healthy controls (n=9). Biopsies with no or minimal fibrosis (≤F2) were selected to avoid confounding effects of fibrosis. We compared whole transcriptome data from patients with MASH/ENEG to those with ENEG alone to determine the impact of MASH co-morbidity on chronic hepatitis B.<h3>Results</h3>There is a high degree of overlap of liver gene expression profiles in patients with only ENEG versus those with only MASH compared to healthy controls, suggesting a largely shared mechanism of liver dysfunction and immune activity for these distinct conditions. In patients with ENEG, MASH co-morbidity significantly reduced interferon pathway activity (NES=2.03, p.adj=0.0251), the expression of ISGs (e.g., <em>IFIT2</em>, <em>IFI27</em>, <em>IFITM1</em>, <em>IFI6</em>), and macrophage gene signatures (e.g., <em>MARCO</em>, <em>CD163</em>, <em>CD5L</em>, <em>CD63</em>), when compared to patients with ENEG alone.<h3>Conclusions</h3>Transcriptomic profiling of the liver suggests that MASH negatively impacts ISGs expression in the liver of patients with ENEG, which may affect antiviral immune pathways, viral replication and inflammatory responses resulting in an increased risk of advanced fibrosis in patients with chronic hepatitis B. Our study provides valuable insights for guiding future research aimed at developing effective, tailored strategies for managing patients with both conditions.<h3>Impact and implications</h3>In recent decades, obesity and associated health issues have reached epidemic levels, with steatotic liver disease affecting up to 30% of adults in developed countries, and this trend is also observed among chronic hepatitis B patients. Given the high and rising prevalence of steatotic liver disease and its frequent co-occurrence in chronic hepatitis B patients, it is essential to understand how conditions such as metabolic dysfunction-associated steatohepatitis (MASH) impact immune responses in the liver. This study provides unique insights into the impact of MASH on HBV antiviral immune activity in the liver of patients with chronic hepatitis B. The rising number of patients with both conditions affects treatment outcomes and highlights the urgent need for novel, tailored therapeutic strategies. Our study holds significant relevance for guiding future research on developing treatment strategies for patients with both MASH and chronic hepatitis B.\",\"PeriodicalId\":15888,\"journal\":{\"name\":\"Journal of Hepatology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":26.8000,\"publicationDate\":\"2024-10-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Hepatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jhep.2024.10.032\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Hepatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jhep.2024.10.032","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Metabolic dysfunction-associated steatohepatitis reduces interferon and macrophage liver gene signatures in patients with chronic hepatitis B
Background & Aims
Chronic HBV patients with concomitant metabolic dysfunction-associated steatohepatitis (MASH) have been shown to develop more advanced fibrosis faster with more severe liver disease as compared to patients with chronic HBV alone. However, our understanding of the underlying mechanisms is limited. Here we study how MASH co-morbidity impact immune activity in the liver of patients with chronic HBV infection.
Methods
Bulk RNA sequencing was performed on liver biopsies from patients with only MASH (n=10), only HBeAg-negative chronic HBV (ENEG; n=11), combined MASH/ENEG (n=9) and healthy controls (n=9). Biopsies with no or minimal fibrosis (≤F2) were selected to avoid confounding effects of fibrosis. We compared whole transcriptome data from patients with MASH/ENEG to those with ENEG alone to determine the impact of MASH co-morbidity on chronic hepatitis B.
Results
There is a high degree of overlap of liver gene expression profiles in patients with only ENEG versus those with only MASH compared to healthy controls, suggesting a largely shared mechanism of liver dysfunction and immune activity for these distinct conditions. In patients with ENEG, MASH co-morbidity significantly reduced interferon pathway activity (NES=2.03, p.adj=0.0251), the expression of ISGs (e.g., IFIT2, IFI27, IFITM1, IFI6), and macrophage gene signatures (e.g., MARCO, CD163, CD5L, CD63), when compared to patients with ENEG alone.
Conclusions
Transcriptomic profiling of the liver suggests that MASH negatively impacts ISGs expression in the liver of patients with ENEG, which may affect antiviral immune pathways, viral replication and inflammatory responses resulting in an increased risk of advanced fibrosis in patients with chronic hepatitis B. Our study provides valuable insights for guiding future research aimed at developing effective, tailored strategies for managing patients with both conditions.
Impact and implications
In recent decades, obesity and associated health issues have reached epidemic levels, with steatotic liver disease affecting up to 30% of adults in developed countries, and this trend is also observed among chronic hepatitis B patients. Given the high and rising prevalence of steatotic liver disease and its frequent co-occurrence in chronic hepatitis B patients, it is essential to understand how conditions such as metabolic dysfunction-associated steatohepatitis (MASH) impact immune responses in the liver. This study provides unique insights into the impact of MASH on HBV antiviral immune activity in the liver of patients with chronic hepatitis B. The rising number of patients with both conditions affects treatment outcomes and highlights the urgent need for novel, tailored therapeutic strategies. Our study holds significant relevance for guiding future research on developing treatment strategies for patients with both MASH and chronic hepatitis B.
期刊介绍:
The Journal of Hepatology is the official publication of the European Association for the Study of the Liver (EASL). It is dedicated to presenting clinical and basic research in the field of hepatology through original papers, reviews, case reports, and letters to the Editor. The Journal is published in English and may consider supplements that pass an editorial review.