Fibroscan and fibrosis-4 in recovered hepatitis C patients

Abstract

The management of chronic hepatitis C, particularly focusing on patient follow-up after hepatitis C virus (HCV) cure, has been extensively documented. da Silva et al recently evaluated the prognostic value of liver stiffness measurements and the fibrosis-4 index at baseline and 1 year after HCV therapy with direct-acting antiviral. They aimed to predict hepatocellular carcinoma occurrence in patients with compensated advanced chronic liver disease who achieved a sustained viral response. This editorial comments on an article by da Silva et al published in a recent issue of the World Journal of Gastroenterology. We discuss da Silva et al’s work in the context of patients who have recovered from hepatitis C, highlighting the current knowledge in the field and providing guidance. Articles from the Google Scholar database, PubMed, European Association for the Study of Liver and American Association for the Study of Liver Diseases guidelines, and other relevant databases and studies were used in this study.

Key Words: Fibroscan; Fibrosis-4; Non-invasive tests; Hepatitis C recovered patients; Hepatitis C sustained viral response; Direct-acting antiviral therapy; Patients follow-up; Hepatocellular cancer prediction

Core Tip: This editorial comments on the work of da Silva et al to expand knowledge in the related research field on three subtopics: The concept of hepatitis C recovered patients, the place of non-invasive tests (NITs), including fibroscan and fibrosis-4, in the management of these patients, and future research directions. While this editorial comments on the interesting work of da Silva et al, it relies on the concept of patients recovering after direct-acting antiviral treatment, the relevance of NITs, and the pathobiology of the hepatitis C virus in the management of this disease. The latter supports the concept of patients recovering after hepatitis C virus eradication because the disappearance of the hepatitis C virus does not rule out the progression of liver fibrosis or hepatocellular carcinoma.

This editorial refers to “Transient elastography and fibrosis-4 index as predictors of hepatocellular carcinoma in hepatitis C virus patients with sustained virological response” by da Silva et al, 2025; http://doi.org/10.3748/wjg.v31.i45.112318.

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INTRODUCTION

The management of chronic hepatitis C has been well documented by the European Association for the Study of Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD)[1-3]. The EASL has extensively documented patient monitoring after hepatitis C virus (HCV) cure or HCV sustained viral response (HCV-SVR)[1].

Achieving SVR is the endpoint of HCV treatment. The end of treatment (EOT) was determined by a viral response, which was achieved when HCV RNA became undetectable using a sensitive molecular technique (lower limit of detection = 15 IU/mL). SVR is defined as undetectable HCV RNA in the serum or plasma 12 weeks (SVR12) or 24 weeks (SVR24) after EOT[4].

SVR in patients with HCV does not preclude the occurrence of hepatocellular carcinoma (HCC). Hence, refining HCC prediction in this growing population may be an unmet medical need[1,3]. In a recent issue of the World Journal of Gastroenterology, da Silva et al[5] in line with the EASL and AASLD perspectives, an interesting study was conducted.

Compensated advanced chronic liver disease (cACLD) is a potential risk factor for HCC even after HCV-SVR, and patients with cACLD before SVR are at high risk for HCC[5]. Non-invasive tests (NITs), including liver stiffness measurement (LSM) by transient elastography or biomarkers such as fibrosis-4 (FIB-4), are used for cACLD diagnosis. NITs are currently used to monitor patients with clinically significant portal hypertension (CSPH). The use of NITs is recommended to improve outcomes in patients with portal hypertension. The AASLD and Baveno VII recognize the crucial importance of stratifying the risk of decompensation in patients with cACLD using NITs. CSPH is the main risk factor for decompensation[6]. Although measuring the hepatic venous pressure gradient is the diagnostic standard for CSPH, its invasiveness limits its widespread use. Both guidelines recommend the use of LSM via transient elastography in combination with platelet counts to diagnose CSPH. While any of these combinations can be used for CSPH diagnosis, according to AASLD, Baveno VII recommends using LSM > 25 kPa to confirm CSPH. LSM values between 15 kPa and 25 kPa are considered indeterminate, representing 40%-60% of cACLD patients who would require further testing, such as the hepatic venous pressure gradient and endoscopy. Studies have shown that spleen stiffness measurement improves the diagnostic accuracy of CSPH when combined with LSM and platelet count, decreasing the number of patients with undetermined results and, most importantly, reducing decompensation events in the gray zone of the Baveno VII[6].

Screening for HCC in F3 patients has a low cost-effectiveness ratio; however, evidence remains limited to exclude these patients from surveillance. Lifelong ultrasound monitoring is recommended for patients with cirrhosis (F4)[5]. Hence, there is a need to use simple and cost-effective NITs to predict HCC incidence in patients with HCV-SVR. Therefore, da Silva et al[5] aimed to evaluate the prognostic value of LSM and FIB-4 at baseline and 1 year after HCV treatment to predict HCC occurrence in patients with cACLD and HCV-SVR. The authors used a retrospective cohort study design to analyze the data of 425 eligible patients with cACLD and HCV-SVR. They demonstrated that LSM ≥ 20 and FIB-4 > 3.25 are independent predictors of HCC in patients with HCV-SVR. Hence, they suggested that these findings be considered a cost-saving model for HCC surveillance.

The authors assessed the prognostic value of NITs in predicting HCC incidence in a pretreatment cohort of cACLD patients (defined as LSM ≥ 10 kPa) who achieved SVR after direct-acting antiviral (DAA) therapy. They demonstrated the good performance of the LSM and FIB-4 index as predictors of HCC for four years. Furthermore, they highlighted that the difference in liver stiffness measured by NIT before and after treatment (after EOT, i.e., 1-year-EOT) is not a good marker for HCC-risk stratification. This finding corroborates that of Semmler et al[7], who, after evaluating the Baveno VII criteria in a large cohort of patients, concluded that a variation in LSM did not provide significant prognostic value in patients with follow-up LSM values between 10 kPa and 19.9 kPa. Similar to the LSM, the pre- and post-treatment FIB-4 index dynamics did not predict HCC, as reported by da Silva et al[5].

The FIB-4 index score is useful for predicting HCC in patients with SVR who have undergone DAA therapy. In line with Ciancio et al[8] and many other authors[9,10], da Silva et al[5] demonstrated that among patients with a 1-year EOT FIB-4 index of less than 3.25, a higher cumulative survival free of HCC was observed. Thus, they demonstrated that a pretreatment FIB-4 cut-off value of 3.25 was associated with the development of HCC.

As suggested by da Silva et al[5], their findings may be applied to similar cohorts, as their study represents a large real-world cohort from two centers with homogeneous treatment and monitoring procedures and a well-defined LSM interval. However, the retrospective nature of their work means that these findings should be replicated through other investigations, including prospective designs.

We hereby contribute to da Silva et al’s study[5] through an editorial to expand the knowledge in this related research field. Thus, this editorial comments on the work of da Silva et al[5] on three main subtopics: Concept of hepatitis C recovered patients (HCV-RP), the place of NITs (including Fibroscan and FIB-4) in HCV-RP management, and research perspectives.

THE CONCEPT OF HCV-RP AND ITS SUGGESTED DEFINITION OR CLASSIFICATION

The debate about people who are cured vs those who are recovered shapes our understanding of addiction and influences therapeutic approaches to it. Describing a patient as ‘cured’ can imply an endpoint that underestimates a process that may last a lifetime. In contrast, the term ‘recovery’ acknowledges and admits a complex process marked by improvement and progression. Presenting healing as a journey rather than a destination resonates deeply with many individuals[11]. Moreover, in the oncology field, when administering a treatment with a curative goal, patients and clinicians are faced with a fundamental question: Is the cancer cured?

Regarding the limitations of surveillance tools, it is not evident that all tumor cells have been eradicated; therefore, the disease is not cured. Even patients who respond to treatment require post-therapy prognostic factors to predict their outcomes[12].

However, it remains unclear whether the risk of HCC declines over time after HCV eradication. Patients with cirrhosis (before SVR to treatment for HCV infection) continue to have a high risk of HCC (> 2%/year) for many years, even if their FIB-4 score decreases, and should continue to be under surveillance. Patients without cirrhosis but with FIB-4 scores ≥ 3.25 have a high enough risk to merit HCC surveillance, especially if the FIB-4 score remains ≥ 3.25 after SVR[13,14].

HCV cure is defined as viral eradication or SVR[1-3]. Liver disease may evolve into HCC even after HCV cure. The absence of fibrosis regression is associated with a high risk of HCC after HCV clearance[15]. From our perspective, chronic HCV-RP can be divided into two groups: (1) Presumed-recovered patients; and (2) Completely recovered patients.

Presumed-recovered patients are those who can develop liver fibrosis/cirrhosis or other complications, requiring lifetime HCC surveillance. The concept of presumed HCV-recovered patients, similar to that of HCV cure, does not preclude the occurrence of HCC.

However, HCV-completely recovered patients may refer to people who do not progress to HCV-related liver disease or extrahepatic complications after SVR and are discharged for HCC surveillance after SVR. Patients who completely recovered were defined as having both virological clearance and pathobiological resolution.

PLACE OF NITS IN THE MANAGEMENT OF HCV-RP

A negligible HCC occurrence risk is documented in about 90% of HCV patients with baseline LSM ≥ 9.5 kPa ≤ 14.5 kPa plus FIB-4 < 3.25 and aspartate aminotransferase to platelet ratio index (APRI) < 1.5, who achieved SVR. In that subpopulation of patients, FIB-4 and APRI scores were accurate and cost-saving tools for discriminating patients who could be discharged from lifelong HCC surveillance[8]. However, further clinical investigations are needed to identify an aggressive phenotype with a higher risk of HCC after DAA treatment[16].

Individuals with chronic hepatitis C and advanced fibrosis are at risk of HCC after achieving SVR and require lifelong follow-up. Owing to the heterogeneous risk of HCC, which decreases with the regression of the fibrotic process, NITs may be useful for HCV management[10].

Liver stiffness reduction after SVR results partially from the resolution of inflammation but not necessarily from fibrosis regression. However, a lower LSM after EOT provides a better prognosis[5].

As far as advanced chronic liver disease is concerned, the annual global incidence of HCC in patients who have achieved SVR is between 0.2% and 2.5% and is similar to that observed in patients with cirrhosis due to controlled hepatitis B virus infection or non-viral causes, whether related to alcohol or metabolic dysfunction-associated steatotic liver disease[1]. Age is a reported predictor of HCC. Setting an age threshold to exclude HCV-SVR patients from HCC surveillance requires further research[1]. There is no established age threshold for HCC risk stratification, which is likely linked to demographic, genetic, and socioeconomic differences between cohorts, as reported by da Silva et al[5].

The age-male-albumin-bilirubin-platelets score, which includes age, male sex, albumin-bilirubin, and platelets, was shown to be a relevant prognostic marker. This is a discriminatory and calibration marker for assessing the 5-year HCC risk across various cohorts, regardless of etiology and ethnicity[17].

Some guidelines (including those of the EASL) place a heavy burden on cirrhotic patients or those with advanced fibrosis due to lifelong HCC screening every six months[18].

Older age, male sex, low albumin levels, and high LSM values are associated with HCC risk after HCV-SVR in patients with advanced fibrosis or cirrhosis. Therefore, the authors established a nomogram using these predictors to classify patients with hepatitis C according to their risk of developing HCC[18].

There is a controversial view regarding international guidelines on advanced fibrosis (F3), likely reflecting the challenges of accurate fibrosis staging and unclear cost-effectiveness rationales for HCC screening in this subgroup, which may explain the lower HCC incidence. While the EASL guidelines recommend including bridging fibrosis (or advanced fibrosis) in screening programs, the AASLD does not endorse this approach. This recommendation considers the potential risk of misclassifying cirrhosis using NITs, which may reflect an underestimation of the risk of HCC. However, in a cohort of patients with F3/F4 and without nodules characterized on ultrasound, no HCC was detected in F3 patients after a median follow-up of 52.4 months. An approach tailored to post-SVR monitoring using NIT models requires further research to establish a reliable correlation with variations in HCC incidence[1].

FUTURE RESEARCH DIRECTION

In addition to the interest in NITs experiments to predict HCC among HCV-SVR, it is pertinent to comprehensively investigate the pathobiological and therapeutic profiles of HCV infection, allowing us to understand HCV-related liver disease progression even after SVR following DAA therapy and to develop relevant therapeutic options.

The mechanism underlying HCC development after DAA therapy remains unclear. However, pathobiological routes (including immune cell dysfunction during HCV infection, cytokine network imbalance, and epigenetic and gene expression alterations) and host-related factors are conditions that trigger carcinogenesis after DAA treatment[15,19,20].

Given the variability in the natural progression of chronic liver diseases and the diversity of antifibrotic therapeutic options capable of reversing the progression to cirrhosis at an early stage, accurate and reliable diagnosis and monitoring of fibrosis are required[21,22]. This underscores the need for more refined and effective non-invasive techniques for the dynamic evaluation of fibrogenesis and fibrinolysis[22]. The assignment of the personalized screening method could be guided by HCC risk stratification, which considers certain associated characteristics (including age, body mass index, waist circumference, alcohol consumption, and coinfection status) and molecular factors that may evolve[1]. The non-invasive diagnosis of liver fibrosis should align with personalized medicine, offering effective management strategies tailored to patients with liver disorders[21,22].

This transition to precision medicine in hepatology promises to reduce complications and enable effective care for patients with chronic liver disease[23].

The integration of artificial intelligence into diagnostics using NITs (including the multi-omic model) enables high-resolution molecular profiling, paving the way for a revolution in the monitoring and treatment of fibrosis, which may allow both predictive algorithms and biomarker discovery[22,24].

Genetic profiling is promising in the current landscape of personalized medicine. Certain genetic mutations related to patatin-like phospholipase domain-containing 3, transmembrane 6 superfamily member 2, or membrane-bound O-acyl transferase domain containing 7 genes influence the progression of liver fibrosis, guiding more individualized therapeutic approaches and monitoring strategies. Moreover, artificial intelligence offers promising avenues for diagnosis, prognosis, patient stratification, and treatment personalization[23,25]. The Dieta app, which uses artificial intelligence to evaluate stool characteristics, has improved the understanding of lactulose dosage and the Bristol stool scale in the context of cirrhosis. Research focused on fibrosis pathogenesis should be conducted to understand the fibrogenetic process and develop antifibrotic drugs. In the near future, patients with cirrhosis could be treated with targeted anti-inflammatory regimens, allowing both the reduction of portal pressure and serving as antifibrotic or fibrinolytic agents[23].

In addition to hepatic-related morbidities, HCV is associated with diverse extrahepatic manifestations (HCV-EHMs). Extrahepatic disorders occurring during HCV infection include immune dysregulation, neurological manifestations, renal events, cardiovascular and cerebrovascular diseases, and type 2 diabetes. Pathophysiological mechanisms, including HCV replication in extrahepatic cells and increased immune reactions, can trigger systemic effects and chronic inflammation, which may contribute to EHMs[1,26]. Jeong et al[26] demonstrated potential recovery through DAA, which may reduce the risk of various MHEs, and emphasized the need to continue research on its association with the risk of type 2 diabetes. However, HCV-EHMs may increase the complexity of liver disease, resulting in an economic burden and reducing patients’ quality of life and mortality[1].

Addressing extrahepatic diseases may require pluralistic approaches, which may reduce the patient burden and improve their health. Successful results with DAA therapy have been reported, as this regimen is associated with a low risk of many EHMs. Accordingly, EHMs’ preventive approach of EHMs for the early detection and treatment of HCV is recommended[26,27]. However, immunological changes have been correlated with the early occurrence of HCC in patients with chronic hepatitis C treated with DAAs therapy. Natural killer group 2 member D, an activating immune receptor expressed by natural killer cells and effector T cells, plays a potential role in the immunosurveillance of cancer cells[16]. Lymphoid cells are divided into small (T and B cells) and large granular (natural killer) cells. Higher baseline receptor (natural killer group 2 member D) expression in lymphoid cells has been reported in patients with early HCC after DAA treatment[16].

In addition to hepatic-related morbidity and EHMs, food insecurity (limited or uncertain access to adequate food) is a manageable risk factor for liver disease progression that may require targeted approaches. Consequently, further investigations should explore nutritional interventions based on the critical determinants of liver health[28].

In summary, the persistence of fibrosis in the absence of the HCV pathogen is well documented[5,15,18]. The basic mechanisms of fibrogenesis have been documented by Sebastiani and coworkers in a simple and clear manner (Figure 1)[29]. We support the concept of recovery instead of cure after viral eradication, based on the biology of fibrosis and the underlying mechanisms summarized in Table 1[30-35].

Figure 1 Chronic hepatitis C and liver fibrosis[29]. Hepatic stellate cells are retinoid-storing cells that play a key role in liver fibrogenesis. During liver injury, they undergo transformation from a quiescent state to proliferative, contractile myofibroblasts. Activated hepatic stellate cells are the main source of collagen and other extracellular matrix (ECM) proteins. Several molecules and pathways regulate the equilibrium between the deposition and degradation of ECM proteins. HSCs: Hepatic stellate cells; PDGF: Platelet-derived growth factor; EGF: Epidermal growth factor; TGF: Transforming growth factor; VEGF: Vascular endothelial growth factor; CTGF: Connective tissue growth factor; CCN2: Cellular communication network factor 2; ET-1: Endothelin-1; CCR5: C-C chemokine receptor 5; CXCL4: Chemokine (CXC class) ligand 4; MMP: Matrix metalloproteinase. Citation: Sebastiani G, Gkouvatsos K, Pantopoulos K. Chronic hepatitis C and liver fibrosis. World J Gastroenterol 2014; 20: 11033-11053. Copyright ©The Author(s) 2014. Published by Baishideng Publishing Group Inc.

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.

CONCLUSION

This non-conclusive study discusses the value of NITs in predicting HCC among patients with cured compensated advanced chronic hepatitis C by commenting on the interesting work of da Silva et al[5] and prompting reflection on the concept of patients recovering after DAA treatment regarding the management of hepatitis C in general. This study highlights the importance of non-invasive tests in risk stratification after SVR and calls for a more nuanced, personalized approach to managing patients with hepatitis C.