Fibroscan and fibrosis-4 in recovered hepatitis C patients

Table 1 Biology of liver fibrosis and fibrogenic profiles

Topic	Mechanisms of fibrogenesis, progression, and non-invasive prediction tools	Ref.
Definition of liver fibrosis	Liver fibrosis is defined by the excessive accumulation of extracellular matrix proteins such as collagen, laminin, elastin, and fibronectin. It is currently considered a wound-healing response to chronic liver injury	Sebastiani et al[29]; Bataller and Brenner[30]
Viral implication
HCV-infected liver cells	HCV core and NS5A proteins can disrupt lipid metabolism and signaling in infected hepatocytes, triggering reactive oxygen species and the production of profibrogenic mediators such as TGF-β1	Schuppan et al[31]
	Chronic inflammation from HCV-related liver injury promotes lymphocytic infiltration of the hepatic parenchyma. Some hepatocytes undergo apoptosis, while activated Kupffer cells release fibrogenic mediators	Bataller and Brenner[30]
	Inflammatory cytokines such as TNF-α, IL-1β, IL-23, and IL-6, released during chronic inflammation, are associated with hepatocellular carcinoma development	Dash et al[32]
HCV genotype	HCV genotype 3 infection has been reported as a risk factor involved in carcinogenesis	Yang et al[15]
Multifactorial contribution after HCV cure
Liver, portal, and bone marrow cells	Hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin are the main collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines including TGF-β1, angiotensin II, and leptin, which promotes extracellular matrix proteins	Bataller and Brenner[30]
Cirrhosis	Antiviral treatment is not sufficient to completely reverse cirrhosis; therefore, the risk of HCC remains. In patients with cirrhosis after HCV cure, the incidence of HCC decreased over time and was lower in younger patients and those with less advanced fibrosis and no prior decompensation. Advanced age and ≥ F3/F4 fibrosis are the most important risk factors directly or indirectly contributing to HCC occurrence after antiviral therapy	Yang et al[15]
	The cirrhotic microenvironment favors the recruitment and expansion of committed regulatory T cells, establishing a state of immune tolerance that may contribute to progression from cirrhosis to cancer. While HCV-specific CD8+ T cells multiply rapidly after HCV clearance, there is a significant reduction in programmed cell death protein 1 on their surface, suggesting that the exhausted state of CD8+ T cells is only partially restored. However, Treg cells are not affected by direct-acting antiviral treatment, which may compromise tumor surveillance	Yang et al[15]; Dash et al[32]
Inflammation	A high proportion of patients have ongoing hepatic inflammation despite HCV eradication, which has potential implications for the management of approximately one third of patients after sustained virologic response	Welsch et al[33]
History of HCC	A history of prior HCC and larger tumor size are associated with early HCC recurrence	Yang et al[15]
Immunological, epigenetic, and host factors	HCV-induced HCC remains incompletely understood, and the mechanisms underlying HCC occurrence after DAA therapy are not fully resolved. Proposed mechanisms include immune cell dysfunction during HCV infection, cytokine network imbalance, epigenetic alterations, and host factors	Yang et al[15]; Elbahrawy et al[19]; Hamdane et al[20]
	Persistent immune dysregulation has been suggested even after an HCV cure	Choi et al[34]
	High baseline NKG2D expression in lymphoid cells has been reported in patients with early HCC occurrence after therapy	Hsu et al[16]
	Epigenetic changes can promote open chromatin and increase the expression of cancer-specific genes, thereby supporting HCC development. In cirrhosis, reduced hepatocyte proliferation may activate a stem-cell compartment via epigenetic programming. Stress signaling can also reprogram cellular responses away from cell death and toward proliferation, facilitating the emergence of malignancies such as HCC	Yang et al[15]; Dash et al[32]
	Alcohol exposure, metabolic disorders such as nonalcoholic steatohepatitis, or coinfections with HIV or Schistosoma mansoni have been reported as risk factors for HCC	Schuppan et al[31]
	Male gender, hepatic steatosis, diabetes, and high GGT and AFP levels have been reported as risk factors for HCC	Yang et al[15]
Genetic factors	Genes reported as genetic risk factors for HCC include hereditary hemochromatosis, angiotensinogen, TGF-β1, TNF-α, apolipoprotein E, microsomal epoxide hydrolase, monocyte chemotactic protein-1, monocyte chemotactic protein-2, and factor V (Leiden)	Bataller and Brenner[30]
	Interferon gene expression in the host can be downregulated after DAA treatment, which may promote cell proliferation in the absence of proper immune surveillance, and contribute to tumor development	Yang et al[15]
	Elevated genetic risk scores have been reported as a risk factor for HCC	Yang et al[15]
Overlapping injury	Concomitant liver disease due to nonviral etiologies accelerates HCV-induced liver disease, including the development of cirrhosis and HCC	Dash et al[32]
Fibrosis staging	Non-invasive tests are essential for staging liver fibrosis, a key determinant of patient management and prognosis	Sebastiani et al[29]
	Non-invasive tests have demonstrated predictive and prognostic value for HCC risk even after HCV eradication. A decrease in the FIB-4 score from ≥ 3.25 before SVR to < 3.25 after SVR was associated with an approximately 50% reduction in HCC risk. However, the absolute HCC risk remained above 2% per year and persisted for at least 10 years in patients who achieved SVR	Yang et al[15]
	Although liver stiffness and fibrosis indices improved substantially after SVR, hepatic steatosis paradoxically became more prevalent, underscoring a shift from virus-induced injury to metabolic dysfunction–associated steatotic liver disease	Rattanapito et al[35]

HCV: Hepatitis C virus; TGF: Transforming growth factor; TNF: Tumor necrosis factor; IL: Interleukin; HCC: Hepatocellular carcinoma; CD: Cluster of differentiation; DAA: Direct-acting antiviral; NKG2D: Natural killer group 2 member D; HIV: Human immunodeficiency virus; GGT: Gamma-glutamyltransferase; AFP: Alpha fetoprotein; FIB-4: Fibrosis-4; SVR: Sustained viral response.