Hepatocellular Carcinoma Prevention: Comparison
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The hepatitis C virus (HCV), a single-stranded RNA virus belonging to the Flaviviridae family, is a major cause of hepatocellular carcinoma (HCC) worldwide. Tumors caused by HCC have an increased mortality rate globally, which is more accentuated in Western countries. The carcinogenic potential of this virus is mediated through a wide range of mechanisms, spanning from the induction of chronic inflammation to oxidative stress and deregulation of cellular pathways by viral proteins.

  • hepatitis C virus
  • direct-acting antiviral therapy
  • sustained virological response
  • hepatocellular carcinoma
  • surveillance

1. Mechanisms of Liver Cell Carcinogenesis by Hepatitis C Virus

The pathogenesis of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is a multifactorial process where the crucial mechanism is persisting liver cell inflammation, as documented by the clear association that exists between HCC and cirrhosis. In certain clinical contexts, however, liver inflammation has been shown to translate into a favorable histologic biomarker of HCC outcome, largely depending on the ability that cell infiltrates retain to circumvent immunotolerance and dispose of transformed hepatocytes [1]. The inflammatory stimuli resulting from persistent replication of HCV are elicited by the virus, being able to evade the virus’ neutralizing response of the host immunity, thus allowing HCV to hijack the homeostatic mechanisms of the liver cells, an event that in parallel stimulates the restless deposition of fibrotic tissue and promotes the neoplastic transformation of the hepatic parenchyma [1][2][3].
The pillar of HCV-induced liver inflammation is an immune cell-mediated attack on the infected liver cells, which accounts for the release of reactive oxygen species (ROS) and pro-inflammatory cytokines by both liver and immune cells, including natural killer cells and T cells [1]. On their own, the resulting inflammation and necrosis of the liver cells act as a potent stimulus to hepatocyte regeneration and wound healing, with significant consequences on the process of oxidative stress in the liver, which leads to the induction of epigenetic and oncogenic alterations, telomere shortening, and, in the end, to genomic instability [3]. The process of fibrotic remodeling of the liver has important prognostic implications as it partners with the process of liver carcinogenesis driven by specific viral proteins like core proteins and the non-structural NS5A protein that are able to subvert liver cell homeostasis [4][5][6][7]. The core proteins are involved in the dysregulation of lifesaving functions of the liver cell such as growth, differentiation, apoptosis, transcription, and angiogenesis. The bridge between those dysregulations and HCV is the activation of the MAPK, Wnt/beta-catenin, TGF-alfa, PI3K/Akt/mTOR, NF-kB, IL-6/STAT3, and androgen receptor signaling, whereas the protective apoptotic signaling becomes suppressed. Partnering with the oncogenic activity of the core protein of HCV is the NS5A protein that engages with such relevant pro-oncogenic pathways as beta-catenin, PI3K/AKT/mTOR, NF-kB, and p53. The final consequences of all those interactions are the remodeling of the chromatin structure, a shelter for the nuclear DNA, coupled with a reshuffle of cell gene expressions leading to altered epigenetic regulation and the production of microRNAs [8].
These epigenetic events include the increase in DNA methyltransferase activity and histone deacetylation, whereas the HCV-induced increase in the expression of the pro-oncogenic microRNA miR-155 leads to activation of the Wnt signaling implicated in the accelerated proliferation and neoplastic transformation of the liver cells [9][10]. Other important steps in HCV-induced liver carcinogenesis are the onset of endoplasmic reticulum stress and the interaction with the gut microbiota. At the endoplasmic reticulum level, HCV infection causes an accumulation of misfolded proteins, which activates the unfolded protein response and the release of calcium ions into the cytoplasm. Calcium is released in the cytoplasm and may stimulate ROS production that can induce inflammation, tissue damage, and fibrosis and contribute to the development of HCC [3].
Another cytoplasmic event that may contribute to HCC onset is steatosis, i.e., the accumulation of triglycerides in hepatocytes due to HCV’s core ability to reduce triglyceride transfer protein activity and cause oxidative stress that contributes to the oncogenic process [11]. The altered composition of the gut microbiota has been involved in HCV-related HCC following studies with whole-genome sequencing of fecal DNA from patients with HCV-related HCC and the demonstration that the transplantation of microbiota from patients with HCC into mice amplified liver cancer incidence as compared with mice with transplanted microbiota from healthy donors [12].

2. Recommended Strategies of Hepatocellular Carcinoma Surveillance

Secondary prevention based on semi-annual surveillance is associated with improvements in early tumor detection and reduced HCC mortality [13][14]. Although it is highly operator-dependent and has worse performance in patients with obesity, ultrasound is the standard of care imaging modality recommended for HCC surveillance by all liver societies [14][15][16] (Table 1). EASL recommends semi-annual abdominal ultrasound exams, without determination of serum AFP level, not only for HCV patients with cirrhosis but also for those with the METAVIR F3 stage of fibrosis. The same holds true for patients with cured HCV infection and a similar disease stage [14]. AASLD recommends against surveillance of patients with advanced fibrosis but without cirrhosis [15]. Though insufficient as a standalone biomarker for HCC screening, AFP has a role in conjunction with other tests for the early detection of HCC [14][15][16].
Table 1. Recommendations of the International Liver Societies for HCC surveillance [17][18][19].
Recommendation EASL 2018 AASLD 2023 APASL 2017
Screening interval Six months Six months Six months
Imaging US US, contrast US
    enhanced MR/CT when  
    US visualization limited  
Serum AFP No Yes Yes
Liver biopsy Non-cirrhotics Non-cirrhotics Unsolved >/= 1 cm
    Unsolved nodules  
    LI-RADs 4 and 5 in trials  
Diagnosis of HCC CT/MRI/CEUS CT/MRI CT/MRI/CEUS
Includes <1 cm nodule US every 4 months in the first year. Alternative imaging/CT/MRI every 3–6 months. If size unchanged, resume 6 months contrast medium.
Along these lines, ILCA recommends delivering surveillance with ultrasound not only to those with cirrhosis but also to those with METAVIR stage F3 fibrosis and high scores of GALAD, a phase III validated biomarker that includes gender, age, AFP-L3, AFP, and des-gamma—carboxy prothrombin (DCP) level [20][21][22]. However, further translational studies are required before GALAD is endorsed as the ideal biomarker for risk-stratified surveillance of HCV patients. Bi-annual examination with abdominal ultrasounds is widely recognized to confer significant clinical benefits in virtue of its ability to identify liver cancer at a curable stage. In a meta-analysis and systemic review of 59 studies comparing 41,052 patients with an HCC detected by surveillance and 104,344 patients with an incident HCC, surveillance was associated with an odds ratio gain of 1.86 (95% CI 1.73–1.98) in terms of early-stage detection, 1.83 (95% CI 1.69–1.97) in terms of receipt of curative therapy, and 0.67 (95% CI 0.61–0.72) in terms of reduced mortality. Interestingly, all those clinical benefits came at the expense of mild-severity harms that affected 8.8–27.8% of the individuals [23]. In a previous meta-analysis of 32 studies with 13,367 patients, the same group reported ultrasound alone to have a satisfactory specificity of 91% (95% CI 86–94%) for T1/T2 HCC but quite a low diagnostic sensitivity of 47% (95% CI 33–61%) only, that however could be inflated to 63% (95% CI 48–75%) with the combined determination of serum AFP level [24]. Though associated with superior survival compared to annual surveillance (40.3 vs. 30 months, p = 0.03), semi-annual surveillance is not further improved with quarterly surveillance [25][26]. Noticeably, the recommendations of the international societies are not fully aligned with each other, and they show nuances with respect to the use of liver biopsy and second-level imaging techniques to achieve the final diagnosis of HCC (Table 1). Surveillance is not recommended in patients with clinical decompensation when liver transplantation is not an option. However, a large grey area between these two recommendations is represented by aged patients with comorbidities, where the lack of data prevents the adoption of any specific recommendation and decisions are taken on individualized bases. In one modeling study among HCV-cured patients with advanced fibrosis, bi-annual HCC surveillance with ultrasound and AFP was considered cost-effective up to the age of 60, because it added 23 quality-adjusted life years and detected 24 potentially curable HCCs per 1000 patients [27]. This fuels the debate with respect to the growing population of aged patients with a cured hepatitis C, where HCV eradication is associated with a reduced (not abolished) risk of HCC coupled with an increase in longevity due to a significant reduction in mortality from liver decompensation and extrahepatic complications of HCV [28].

3. Overcoming the Underuse and Low Diagnostic Accuracy of Currently Available Screening Tests

Apart from the inadequate risk stratification of the patients, working against the effectiveness of HCC surveillance are several other hurdles that include the underuse of surveillance and the suboptimal accuracy of currently available screening tests. To overcome the underuse of screening, one intervention aiming to increase patients’ compliance with screening was the development of programs of mail outreach coupled with specific training of nurses and dedicated pathways to screening that have proven to be of some efficacy [29]. Two-phase CT and contrast-enhanced MRI can yield superior sensitivity for early-stage HCC detection compared to ultrasound (86% vs. 29%, respectively), but their use as surveillance tests is limited by concerns about cost, radiologic capacity, and potential adverse effects by contrast and/or radiation exposure [30][31]. Abbreviated magnetic resonance imaging (AMRI) is a user-friendly approach that allows to overcome the low sensitivity of ultrasound for early tumor detection and its suboptimal specificity, leading to screening-related harms. AMRI might better serve certain subgroups of patients, including obese individuals, patients with nonalcoholic steatohepatitis, and those with Child–Pugh B or C cirrhosis. In a meta-analysis of 15 studies involving more than 2800 patients (917 with HCC), AMRI showed a sensitivity of 86% for any size tumor and of 69% for tumors < 2 cm in size [32]. In that systemic review, the sensitivity of ultrasound was definitively lower than that of AMRI, whereas the specificity (94%) of non-contrast AMRI was comparable to that of contrast-enhanced AMRI. While the great appeal of non-contrast AMRI is built on low invasiveness, low cost, and repeatability, all those pros are counterbalanced by technical constraints like the lower Contrast-to-Noise Ratio (CNR) and dependence on Diffusion-Weighted Imaging (DWI) that may challenge the identification of HCC nodules [33][34]. In a recent analysis of privately insured patients, those with cirrhosis were likely to incur both out-of-pocket and opportunity costs from HCC screening [35]. This was particularly true for patients undergoing second-level imaging techniques and, in general, for low-risk patients, in whom potential harms related to increases in overdiagnosis offset the minimal benefits of screening.

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