Abstract / Summary
Chronic liver disease is characterised not only by persistent injury and fibrosis, but also by a progressive shift from adaptive hepatocyte-driven repair toward maladaptive tissue remodelling. Although liver regeneration is often discussed as a compensatory response, chronic injury may render this process structurally and functionally dysregulated, thereby promoting architectural distortion, fibrosis progression, and a microenvironment permissive for hepatocarcinogenesis. In this narrative review, we propose that this transition can be interpreted through three interconnected, histopathology-anchored endpoints: ductular reaction, extracellular matrix remodelling, and parenchymal extinction. We discuss ductular reaction as a progenitor niche phenotype that emerges when effective hepatocyte regeneration is impaired and becomes increasingly linked to portal inflammation, fibrogenic signalling, and altered cell–matrix interactions. We then examine extracellular matrix remodelling as a central tissue-level process involving activated stellate cells, portal fibroblasts, macrophages, cholangiocytes, and dysfunctional endothelial cells, resulting in collagen accumulation, increased stiffness, fibrous septa formation, and progressive reorganization of the hepatic microenvironment. Finally, we address parenchymal extinction as a morphological endpoint of often-irreversible or incompletely reversible hepatocyte loss accompanied by microvascular injury, ischaemia, and fibrotic replacement, contributing directly to architectural collapse and disease advancement. Rather than representing isolated phenomena, these three processes form a biologically integrated remodelling axis that links failed regeneration with fibrosis progression and malignant transformation. By framing chronic liver disease through these assessable histologic endpoints, this review aims to provide a more coherent pathology-oriented model of progression and to highlight mechanisms that may improve tissue-based risk stratification and future translational research.