Copyright
©The Author(s) 2022.
World J Gastroenterol. Jun 7, 2022; 28(21): 2251-2281
Published online Jun 7, 2022. doi: 10.3748/wjg.v28.i21.2251
Published online Jun 7, 2022. doi: 10.3748/wjg.v28.i21.2251
Table 1 Hepatocellular carcinoma incidence and risk factors
| Location | Chronic HBV infection | Chronic HCV infection | Alcoholic liver disease | Non-alcoholic steatohepatitis | ||||
| NC | CC | NC | CC | NC | CC | NC | CC | |
| Europe | 0.12 | 2.2 | 0-1.8 | 3.7 | 0.1 | 1.8 | 0.5 | 1.1 |
| East Asia | 0.8 | 4.3 | F0/1 0.4; F2 1.5; F3 5.1 | 7.1 | 0.1 | 1.7 | a | a |
| Risk factors in hepatocellular carcinoma (other than liver cirrhosis) | OR (95%CI) | |
| Strong risk factors (OR > 10) | Europe | |
| Untreated chronic HBV/HCV hepatitis | 191.0 | |
| Untreated chronic HCV hepatitis | 31.2 | |
| Untreated chronic HBV hepatitis | 18.8 | |
| East Asia and Africa | ||
| Untreated chronic HBV/HCV hepatitis | 75.6 | |
| Untreated chronic HBV hepatitis | 20.8 | |
| Untreated chronic HCV hepatitis | 11.5 | |
| Moderate risk factors (OR = 2-10) | Aflatoxin B1 exposure | 5.9 |
| Untreated chronic HDV infection | 3.9 | |
| Diabetes | 3.2 | |
| Asian race | 3.2 | |
| Male gender | 2.8 | |
| Alcohol intake | 2.3 | |
| Severe iron overload | 2.1 | |
| Weak risk factors (OR < 2) | Obesity (BMI > 30 kg/m2) | 1.9 |
| Mild iron overload | 1.6 | |
| Current smoking | 1.6 | |
| HCV genotype 1b | 1.6 | |
| PNPLA3 rs738409 single nucleotide polymorphism | 1.4 | |
Table 3 Molecular pathways of hepatocellular carcinoma carcinogenesis in hepatitis B virus infected patients
| HBx related pathways |
| DNA repair impairment and DNA instability |
| HBx - binds to DDB1 - instability of Scm5/6 - impairment in DNA replication and repair |
| HBx - interacts with TFIIH - impairment in DNA replication and repair |
| HBx - blocks BER pathway - impairment in DNA repair |
| HBx - binds to CRM1 and sequestering it in cytoplasm - aberrant centrosome duplication and chromatin’s segregation - chromosome instability |
| DNA replication increase |
| HBx - upregulates RLF and CDT1 and downregulates geminin - DNA replication |
| HBx - binds to cccDNA - recruiting PCAF - histone H3 acetylation - inhibition of chromatin’s methylation - DNA replication |
| Cell cycle deregulation via signal pathways |
| HBx - binds to p53 - impaired function of p53 - cell cycle dysregulation |
| HBx - induces AFP expression - activation of PTEN and PI3K/mTOR pathway - cell cycle deregulation |
| HBx - activates Notch1 and Notch4 receptor - cell cycle progression |
| HBx - upregulates NF-kB, AP-1, AP-2, c-EBP, RNA-polymerase, ATF - altered oncogenes expression and cell cycle deregulation |
| HBx - upregulates NF-kB - upregulation of EGR1 - upregulation of miR-3928v - downregulation of VDAC3 - tumor suppressor inhibition |
| HBx - downregulates SFRP1 and SFRP5 - DNMT1 recruitment - inhibition of WNT/β-catenin pathway - epithelial mesenchymal transition |
| Epigenetic modification impairment |
| HBx - interacts with MBD2 and CBP - P3 and P4 promoters’ activation through hypomethylation - recruitment of IGF2 - oncogenesis |
| HBx - stimulates deacetylation of IGFBP3 gene - upregulation of IGF1 - mitogenic and anti-apoptotic effects |
| HBx - upregulates DNMT1 - hypermethylation of RASSF1A - tumor suppressor inhibition |
| HBx - downregulates DNMT3a/DNMT3L and recruits HDAC1 - hypomethylation of oncogenes promoters including JAK/STAT3 - impairment in cell differentiation |
| HBx - downregulates CD82, MTA1, PCDH10 through hypermethylation - tumor progression |
| HBx - inhibits CDH1 through deacetylation - E-cadherin upregulation - metastasis promotion |
| Apoptosis impairment |
| HBx - upregulates Bcl2 and Mcl1, inhibits Bax - apoptosis inhibition |
| HBx - upregulates Foxo4 - increased resistance to ROS damage, avoiding cell death and apoptosis |
| HBx - upregulates NF-kB - increase of DR5 - TRAIL induced apoptosis |
| HBx - inhibits caspase-8 inhibitor A 20 - TRAIL induced apoptosis |
| mi/lnc RNA related pathways |
| HBx - impairs miRNA regulation and synthesis - cell cycle deregulation |
| HBx - impairs lncRNA regulation and synthesis - cell cycle deregulation |
| Oxidative stress |
| HBx - downregulates NQO1 - mitochondrial injury - ROS production |
| C-terminal truncated HBx - mitochondrial DNA damage - ROS production |
| Neoangiogenesis |
| HBx - upregulates VEGF, HIF1 and ANG2 - neoangiogenesis |
| Unknown mechanism |
| HBx - binds to HSP60 and HSP70 - unknown function but involved in HCC carcinogenesis |
| Pre-S/S related pathways |
| pre-S2 - retention of HBV proteins in ER - ROS increase - cell DNA damages |
| pre-S2 - retention of HBV proteins in ER - upregulation of CCNA - chromosome instability and centrosome overduplication |
| pre-S2 - interacts with JAB1 - RB tumor suppressor inhibition |
| HBsAg related pathways |
| HBsAg - binds to ECHS1 - ROS increase - cell DNA damages |
| HBsAg - binds to JTB - decreased apoptosis and increased cell mobility |
| HBeAg related pathways |
| HBeAg - stimulates upregulation of miR-106b - RB tumor suppressor inhibition |
| HBV DNA related pathways |
| cccDNA - triggers DNA repair pathways - histone degradation and cell cycle checkpoints activation - enhanced DNA recombination rate |
| HBV DNA - genome integration - oncogene activation or tumor suppressor inhibition with evidence of fusion proteins |
| HBV DNA - genome integration - genetic instability - clonal proliferation |
| Inflammatory pathways |
| Increased cytokines production (TGF-β, IL-4, IL-10, IL-12, IL-13) - JAK/STAT3 activation - cell proliferation |
| CD4+ T follicular helper decrease - loss of growth inhibition and death control of cancer cells |
| CD8+ cell dysfunction - impaired growth inhibition and death control of cancer cells |
| Functional exhausted CD8+TIM-3+ T cells - increased viral replication - increased viral factors in HCC development |
| NK cells - increase in IL-4 and IL-13 - activation of HSCs - increased cytokines production - cell cycle deregulation |
| NK cells - miR-146a increase - reduced cytotoxicity and decreased IFN-γ production - reduction in immunosurveillance |
| Tregs - PD1 and CTLA4 overexpression - C |
| Gut microbiota-related pathways |
| HBV related dysbiosis - circulating LPS - TLR4 activation - cytokines production - JAK/STAT3 activation - cell proliferation |
Table 4 Hepatocellular carcinoma surveillance in hepatitis B virus infected patients
| HCC surveillance in HBV-infected patients | ||
| Western medical societies | ||
| EASL, 2017 | High-risk-patients: (1) HBV cirrhotic patients; (2) HBV and F3 fibrosis; and (3) HBsAg-positive patient on NA treatment with a PAGE-B of ≥ 18 at the onset of therapy. Medium risk-patients: HBsAg-positive patient on NA treatment with a PAGE-B of 10 - 17 at the onset of therapy | Screening with US examination with or without AFP every 6 mo for medium and high-risk patients. No specific HCC screening needed for low-risk patients |
| AASLD, 2018 | High-risk patients: (1) HBV cirrhotic patients; (2) Special population of HBsAg-positive adults: Asian or African men (> 40 yr) and Asian women (> 50 yr), first-degree family member with a history of HCC, HDV coinfected; and (3) HBsAg-positive children/adolescents with advanced F3 or cirrhosis and first-degree family member with HCC | Screening with US examination with or without AFP every 6 mo; if in areas where US is not readily available, screening with AFP every 6 mo |
| Eastern medical societies | ||
| JSH, 2014-2021 | Extremely-high-risk patients: HBV cirrhotic patients. High-risk patients: Special population of HBsAg positive patients: age ≥ 40, male, alcohol consumption, high HBV load, family history of HCC, HCV/HDV/HIV coinfection, F3 fibrosis, low platelet count associated with advanced fibrosis, genotype C, and core promoter mutation | Screening with US and tumor marker measurements (AFP, protein induced by vitamin K absence or antagonist-II and AFP-lectin fraction 3) every 3-4 mo in the super-high-risk population. A 6-12 mo dynamic CT scan or dynamic MRI should be performed. Screening every 6 mo in high-risk populations |
| APASL, 2016 | High-risk patients: All patients with HBV-related cirrhosis. HBsAg-positive without cirrhosis, based on the economic situation of each country and on the available risk scores | Surveillance by US and AFP should be performed every 6 mo and preferably every 3-4 mo in cirrhotic patients and those at high risk of HCC |
| KLCSG, 2014-18 | High-risk patients: HBV cirrhotic patients; chronic hepatitis B patients | Screening with US examination with or without AFP every 6 mo. If liver US cannot be performed properly, liver dynamic CT or dynamic contrast-enhanced MRI can be performed |
Table 5 Molecular pathways of hepatocellular carcinoma carcinogenesis in hepatitis D virus infected patients
| Cell cycle deregulation via signal pathways |
| L-HDAg - Smad 3 activation - TGFβ upregulation - cells growth and dedifferentiation |
| L-HDAg - antagonizes c-Jun inhibitory effect over TGFβ - TGFβ upregulation - cells growth and epithelial-mesenchymal transition |
| L-HDAg - TNF-α stimulation - NF-κB activation - inflammation and proliferation |
| L-HDAg - activates STAT3 downstream protein - JAK/STAT pathway activation - cell growth |
| L-HDAg - stimulates c-Fos activation - cells growth and dedifferentiation |
| L-HDAg - downregulates GSTP1 - tumor oncosuppressor inhibition |
| Oxidative stress |
| L-HDAg - NF-κB and STAT3 activation - ROS production - DNA damage |
| L-HDAg - activates promoters of GRP78 and GRP94 - ROS production - DNA damage |
| L-HDAg - activates TGFβ1 - Nox4 activity - ROS production - DNA damage |
| S-HDAg and L-HDAg - increase in TRAF2 - inflammation and ROS production |
| S-HDAg and L-HDAg - bind to SRE - targeting proinflammatory genes - inflammation and ROS production |
| Epigenetic mechanisms |
| S-HDAg and L-HDAg - increased activity of histone acetyltransferases and CBP - histone H3 acetylation of clusterin promoter - increased clusterin expression - prolonged cell survival |
| S-HDAg - stimulates Histone H1e acetylation - clusterin promoter activation - prolonged cell survival |
| HDV - DNMT1 and 3b increased activity - tumor suppressor inhibition |
| S-HDAg and L-HDAg - hypermethylation of E2F1 promoter - cell cycle dysregulation |
Table 6 Molecular pathways of hepatocellular carcinoma carcinogenesis in hepatitis C virus infected patients
| HCV core protein-related pathways |
| Signaling pathways |
| HCV core protein - binds p53, p73 and RB - tumor suppressors inactivation |
| HCV core protein - increased TERT gene activity – oncogenesis |
| HCV core protein - induces expression of cyclin E/CDK2 - G1/S transition |
| HCV core protein - inhibits CKI1 - cell cycle deregulation |
| HCV core protein - induces RAF/MAPK pathway – oncogenesis |
| HCV core protein - inhibits E-cadherin expression and SFRP1 via histone modification - activation of WNT/β-catenin signaling - epithelial mesenchymal transition |
| HCV core protein - interacts with TBR1 - inhibit TGFβ signaling and prevent translocation of Smad - cell spreading, cell growth regulation |
| Oxidative stress and mitochondrial impairment |
| HCV core protein - impairs lipid β-oxidation - reduces mitochondrial electron transport chain - ROS production |
| HCV core protein - impairs mitophagy - mitochondrial damage - ROS production |
| HCV core protein -interacts with HSP60 - ROS production and inhibition of TNFα induced apoptosis |
| Angiogenesis |
| HCV core protein - stimulate an increasing in HIF1α and AP-1 - upregulation of VEGF expression - angiogenesis |
| HCV core protein - activates PI3K/Akt and JAK/STAT - AR activation - angiogenesis |
| HCV core protein - activates COX2, MMP-2 and MMP-9 – angiogenesis |
| Inflammation |
| HCV core protein - suppresses of NF-kB pathways - impaired immune response |
| HCV core protein - upregulates cytokines and deregulates HSCs activity - impaired immune response |
| E2 protein-related pathways |
| E2 protein - interacts with CD81 - impaired host immune system |
| E2 protein - activates MAPK/ERK pathway - promoting cell proliferation |
| E2 protein - inhibits PKR - inhibition of protein synthesis |
| NS2 protein-related pathways |
| NS2 - activates cyclinD/CDK4 - induces expression of cyclin E/CDK2 - G1/S transition |
| NS2 - binds p53 - tumor suppressors inactivation |
| NS3-related pathways |
| NS3 - inhibits p53 - tumor suppressor inactivation |
| NS3 - inhibits ATM - tumor suppressor inactivation |
| NS3 - suppresses of NF-kB pathways - impaired immune response |
| NS3 - blocks TLR3 and RIG-I - impaired immune response |
| NS5A-related pathways: Signaling pathways |
| NS5A - inhibits p53 - tumor suppression inactivation |
| NS5A - interacts with TGFBR1 - inhibit TGFβ signaling and prevent translocation of Smad 3/4 - cell spreading, cell growth regulation |
| NS5A - increases phosphorylation of GSK3β - activates β-catenin - upregulates c-Myc - cell growth |
| NS5A - activates Akt pathway – oncogenesis |
| NS5A - interacts with PI3K p85 subunit - upregulates cell survival cascade |
| NS5A - activates Twist 2 - epithelial mesenchymal transition |
| NS5A - activates RAS - enhance tumor cell invasiveness |
| NS5A - inhibits JAK/STAT pathway - blockage of IFN signaling |
| NS5A - inhibits PKR - inhibition of protein synthesis |
| NS5A - activates TLR4 - amplified NANOG - Twist 1 induction - oncogenesis and epithelial mesenchymal transition |
| NS5A-related pathways: Apoptosis |
| NS5A - inhibits TNFα mediated apoptosis - cell immortalization |
| NS5A - inactivates caspase 3 - inhibition of apoptosis |
| NS5A - inhibits proteolytic cleavage of death substrates (PARPs pathway) - impaired DNA repair and apoptosis |
| NS5A-related pathways: Oxidative stress |
| NS5A - induces of WNT/β-catenin signaling - upregulation of c-Myc - ROS production |
| NS5A - increases calcium release from ER - mitochondrial calcium uptake - ROS production |
| Epigenetic modifications |
| HCV - alters histone mark H3K27ac - TNFα and IL2 pathways - cell growth deregulation and epithelial mesenchymal transition |
| HCV - upregulates DNMT1 and SMYD3 - increased methylation of CDKN2A, GSTP1, APC, SOCS1, RASSF1A - tumor suppressors inhibition |
| HCV - increases miR-141 - inhibition of DLC1 - tumor suppressor inhibition |
| Inflammatory pathways |
| HCV - activates CCL20-CCR6 - endothelial cell invasion and angiogenesis |
| Switch from Th1 to Th2 - increasing in IL4-5-8-10 - loss of death control on cancer cells |
| Switch from Th1 to Th2 - decreasing in IL1-2-12-15 - loss of death control on cancer cells |
| Gut microbiota-related pathways |
| HCV-related dysbiosis - circulating LPS - TLR4 activation - cytokines production - JAK/STAT3 activation - cell proliferation |
Table 7 Hepatocellular carcinoma surveillance in hepatitis C virus infected patients
| HCC surveillance in HCV infected patients | ||
| Western medical societies | ||
| EASL, 2018 | High-risk patients: HCV-related cirrhosis. Chronic hepatitis C and stage | Screening with US examination with or without AFP every 6 mo for high-risk patients (incidence > 1.5%/yr) |
| AASLD, 2018 | High-risk patients: HCV-related cirrhosis. Chronic hepatitis C and stage 3 fibrosis | Screening with US examination with or without AFP every 6 mo for high-risk group (incidence > 1.5%/yr) |
| Eastern medical societies | ||
| JSH, 2017-2021 | Extremely-high-risk patients: All patients with HCV-related cirrhosis. High-risk patients: Patients with chronic hepatitis C | Screening with US and tumor marker measurements (AFP, PIVKA-II and AFP-L3) every 3-4 mo in the super-high-risk population. A 6-12 mo dynamic CT scan, dynamic MRI should be performed or Sonazoid CEUS. Screening every 6 mo in high-risk populations |
| APASL, 2017 | High-risk patients: All patients with HCV-related cirrhosis. SVR patients with chronic hepatitis C with advanced liver fibrosis, independently of the histologic response to therapy. SVR patients with chronic hepatitis C with any histologic stage of HCV with comorbidities, such as alcohol abuse and DM | Surveillance by US and AFP should be performed every 6 mo and preferably every 3-4 mo in cirrhotic patients and those at high risk of HCC |
| KLCSG, 2014-2018 | High-risk patients: All patients with HCV-related cirrhosis. Patients with chronic hepatitis C and advanced fibrosis | Screening with US examination with or without AFP every 6 mo. If liver US cannot be performed properly, liver dynamic CT or dynamic contrast-enhanced MRI can be performed as an alternative |
- Citation: Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28(21): 2251-2281
- URL: https://www.wjgnet.com/1007-9327/full/v28/i21/2251.htm
- DOI: https://dx.doi.org/10.3748/wjg.v28.i21.2251