肝细胞与其他肝非实质细胞之间的组织和相互作用在维持正常肝功能和结构方面起着关键作用。虽然肿瘤微环境内的空间异质性被证实是癌症进展的基本特征，但肝组织拓扑结构和微环境因素在慢性感染引起的肝损伤中的作用尚未广泛研究。我们从一组慢性乙型肝炎患者的110个核心穿刺活检中获得了图像，这些患者的纤维化程度根据METAVIR评分而有所不同。组织切片被免疫荧光染色并成像，以确定免疫细胞CD45阳性和HBsAg阴性、HBsAg阳性肝细胞在组织中的位置。我们应用了生态学中采用的几种描述性技术，包括Getis-Ord、Shannon指数和Morisita-Horn指数，来量化免疫细胞和不同类型肝细胞在组织活检中的共定位程度。此外，我们使用联合对数高斯Cox过程对不同细胞类型的空间分布进行建模，并提出了多种特征来量化空间异质性。然后，我们使用线性判别分析方法将这些度量与患者纤维化程度相关联。我们的分析发现，HBsAg阴性肝细胞与免疫细胞的共定位以及HBsAg阳性肝细胞与免疫细胞的共定位是解释慢性乙型肝炎患者METAVIR评分的同等重要因素。此外，我们发现，如果允许METAVIR评分误差为1，我们能够达到约80%的精确度。通过这项研究，我们展示了从生态学采用并应用于肝组织微环境的方法可以用于量化异质性，以及这些方法在肝拓扑结构的生物标志分析中的价值。版权所有 © 2023 Elsevier Ltd. 保留所有权利。

The organization and interaction between hepatocytes and other hepatic non-parenchymal cells plays a pivotal role in maintaining normal liver function and structure. Although spatial heterogeneity within the tumor micro-environment has been proven to be a fundamental feature in cancer progression, the role of liver tissue topology and micro-environmental factors in the context of liver damage in chronic infection has not been widely studied yet. We obtained images from 110 core needle biopsies from a cohort of chronic hepatitis B patients with different fibrosis stages according to METAVIR score. The tissue sections were immunofluorescently stained and imaged to determine the locations of CD45 positive immune cells and HBsAg-negative and HBsAg-positive hepatocytes within the tissue. We applied several descriptive techniques adopted from ecology, including Getis-Ord, the Shannon Index and the Morisita-Horn Index, to quantify the extent to which immune cells and different types of liver cells co-localize in the tissue biopsies. Additionally, we modeled the spatial distribution of the different cell types using a joint log-Gaussian Cox process and proposed several features to quantify spatial heterogeneity. We then related these measures to the patient fibrosis stage by using a linear discriminant analysis approach. Our analysis revealed that the co-localization of HBsAg-negative hepatocytes with immune cells and the co-localization of HBsAg-positive hepatocytes with immune cells are equally important factors for explaining the METAVIR score in chronic hepatitis B patients. Moreover, we found that if we allow for an error of 1 on the METAVIR score, we are able to reach an accuracy of around 80%. With this study we demonstrate how methods adopted from ecology and applied to the liver tissue micro-environment can be used to quantify heterogeneity and how these approaches can be valuable in biomarker analyses for liver topology.Copyright © 2023 Elsevier Ltd. All rights reserved.