Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment

Abstract

Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.

Keywords: Cirrhosis; Hepatitis B virus; Hepatitis C virus; Hepatitis D virus; Hepatocellular carcinoma; Liver.

Figure 1

Molecular pathways in hepatitis B virus and hepatitis D virus carcinogenesis. Created with BioRender.com. HBV: Hepatitis B virus; HDV: Hepatitis D virus; EGFR: Epidermal growth factor receptor; JTB: Jumping translocation breakpoint; HBsAg: Hepatitis B virus surface antigen; VEGFR: Vascular endothelial growth factor receptor; TGF: Transforming growth factor; PI3K: Phosphatidylinositol 3-kinase; Akt: AKT serine/threonine kinase; RAS: Rat sarcoma virus gene; RAF: Rapidly accelerated fibrosarcoma; mTOR: Mechanistic target of rapamycin kinase; JAK: Janus kinase; STAT3: Signal transducer and activator of transcription 3; Smad3: Mothers against decapentaplegic homolog 3; lncRNA: Long non coding RNA; NF-kB: Nuclear factor-kappa B; ROS: Reactive oxygen species; HSP: Heat shock protein; ECSH1: Enoyl-CoA hydratase short chain 1; VDAC: Voltage dependent anion channel; CCND3: Cytoplasmatic Cyclin D3; RB: Retinoblastoma; Bcl2: B-cell lymphoma 2; Bax: Bcl2 associated X; ER: Endoplasmic reticulum; HIF: Hypoxia-inducible factor; AP: Activator protein; DDB: Damage specific DNA binding protein; Scm5/6: Structural maintenance of chromosomes 5/6; PCAF: P300/CBP-associated factor; TFIIH: Transcription factor II H.

Figure 2

Molecular pathways in hepatitis C virus carcinogenesis. Created with BioRender.com. HCV: Hepatitis C virus; EGFR: Epidermal growth factor receptor; WNT: Wingless-related integration site; TGF: Transforming growth factor; PI3K: Phosphatidylinositol 3-kinase; Akt: AKT serine/threonine kinase; RAS: Rat sarcoma virus gene; RAF: Rapidly accelerated fibrosarcoma; mTOR: Mechanistic target of rapamycin kinase; JAK: Janus kinase; STAT3: Signal transducer and activator of transcription 3; Smad3: Mothers against decapentaplegic homolog 3; NS5A: Non-structural protein 5A; NF-kB: Nuclear factor-kappa B; ROS: Reactive oxygen species; RIG1: Retinoic acid-inducible gene 1; ERK: Extracellular signal-regulated kinases; NANOG: Nanog homeobox; ATM: Ataxia telangiectasia mutated; RB: Retinoblastoma; ER: Endoplasmic reticulum; DNMT1: DNA methyltransferase 1; TERT: Telomerase reverse transcriptase; DLC: Deleted in liver cancer; CK1/2: Casein kinase 1/2; GSK: Glycogen synthase kinase.