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.

中文翻译：

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代谢功能障碍相关的脂肪性肝炎可降低慢性乙型肝炎患者的干扰素和巨噬细胞肝脏基因特征

 背景和目标

与单纯慢性 HBV 患者相比，慢性 HBV 患者伴有代谢功能障碍相关脂肪性肝炎 （MASH） 的患者发展得更快，肝病更严重。然而，我们对潜在机制的理解是有限的。在这里，我们研究了 MASH 合并症如何影响慢性 HBV 感染患者肝脏中的免疫活性。

 方法

对仅 MASH （n=10）、仅 HBeAg 阴性慢性 HBV （ENEG;n=11）、联合 MASH/ENEG （n=9） 和健康对照 （n=9） 患者的肝活检进行大量 RNA 测序。选择无纤维化或轻微纤维化 （≤F2） 的活检以避免纤维化的混杂效应。我们将 MASH/ENEG 患者与单独 ENEG 患者的全转录组数据进行了比较，以确定 MASH 合并症对慢性乙型肝炎的影响。

 结果

与健康对照相比，仅 ENEG 患者与仅 MASH 患者的肝脏基因表达谱高度重叠，这表明这些不同情况的肝功能障碍和免疫活性机制在很大程度上相同。在 ENEG 患者中，MASH 合并症显著降低干扰素通路活性 （NES=2.03，p.adj=0.0251）、ISG 表达 （例如 IFIT2、IFI27、IFITM1、IFI6） 和巨噬细胞基因特征 （例如，MARCO、CD163、CD5L、CD63），与单独的 ENEG 患者相比。

 结论

肝脏的转录组学分析表明，MASH 对 ENEG 患者肝脏中的 ISGs 表达产生负面影响，这可能会影响抗病毒免疫途径、病毒复制和炎症反应，从而导致慢性乙型肝炎患者发生晚期纤维化的风险增加。我们的研究为指导未来的研究提供了有价值的见解，旨在开发有效的、量身定制的策略来管理这两种疾病的患者。

 影响和影响

近几十年来，肥胖和相关健康问题已达到流行水平，脂肪性肝病影响了发达国家高达 30% 的成年人，这种趋势在慢性乙型肝炎患者中也观察到。鉴于脂肪性肝病的高患病率和不断上升，以及它在慢性乙型肝炎患者中经常同时发生，了解代谢功能障碍相关脂肪性肝炎 （MASH） 等疾病如何影响肝脏的免疫反应至关重要。这项研究为 MASH 对慢性乙型肝炎患者肝脏中 HBV 抗病毒免疫活性的影响提供了独特的见解。患有这两种疾病的患者人数不断增加会影响治疗结果，并凸显了对新颖、量身定制的治疗策略的迫切需求。我们的研究对于指导未来为 MASH 和慢性乙型肝炎患者制定治疗策略的研究具有重要意义。