Table 1.

Etiological causes and background of HCC development.

Etiological Causes	Background of HCC Development
Metabolic Syndrome	Chronic InflammationFat accumulation in Hepatocytes Insulin ResistanceDiabetes MellitusObesityHypertension Fat accumulation in Hepatocytes Insulin Resistance Diabetes Mellitus Obesity Hypertension
NAFLD	TNF αIL6LeptinResistin IL6 Leptin Resistin
HBV	DNA integrationGenomic InstabilityChronic InflammationTissue DamageEpigenetic AlterationRegeneration, Scarring and Stellate Cell ActivationFibrosis Genomic Instability Chronic Inflammation Tissue Damage Epigenetic Alteration Regeneration, Scarring and Stellate Cell Activation Fibrosis
HCV	Chronic inflammationNecrosisTissue damageEpigenetic AlterationRegeneration, Scarring and Stellate Cell ActivationFibrosis [66] Necrosis Tissue damage Epigenetic Alteration Regeneration, Scarring and Stellate Cell Activation Fibrosis [66]
Autoimmune disease	Epigenetic Variants Predisposition HLAD AllelesRegulatory mRNAs ExpressionsRisk Allele SH2B3CTLA4 VariantsFAS/FASL mutationsFOXp3 generationsAIRE mutationsGATA2 dysfunctionAltered immune mechanism Impaired CD4+ cellsCD8 + cytotoxic damageActivation of NK cellsB cell DifferentiationAutoantibodiesComplement activationSecreted cytokinesInterferon cell induced liver damageDefectous T regIL signaling in liver damage [67] Predisposition HLAD Alleles Regulatory mRNAs Expressions Risk Allele SH2B3 CTLA4 Variants FAS/FASL mutations FOXp3 generations AIRE mutations GATA2 dysfunction Altered immune mechanism Impaired CD4+ cells CD8 + cytotoxic damage Activation of NK cells B cell Differentiation Autoantibodies Complement activation Secreted cytokines Interferon cell induced liver damage Defectous T reg IL signaling in liver damage [67]
Nutritional carcinogen	Aflatoxin B1Chronic injuryGenetic and epigenetic alteration [68] Chronic injury Genetic and epigenetic alteration [68]
Alcoholic Liver Disease	NecrosisInflammationRegeneration, Scarring and StellateCell ActivationEpigenetic AlterationFibrosisGenetic Features TERT promoter MutationCTNNB1 MutationSignalling Pathways IL6-JAK STAT (more in steatotic Type) Wnt Beta catenin Signalling (more Cholestatic type)Chromosome Stability Chromosome 7 amplificationSteatotic type CRP+ Cholestatic TypeNuclear beta CateninCluster B/S3/iCluster 2G4 glass- InterferonPoly 7 subtypes WNT/Beta Catenine, CTTNNB1 Type -G5 G6 ClassIL6 -JAK STAT (more in Steatotic type) Wnt-Beta Catetine signaling (more in cholestatic type) Inflammation Regeneration, Scarring and Stellate Cell Activation Epigenetic Alteration Fibrosis Genetic Features TERT promoter Mutation CTNNB1 Mutation Signalling Pathways IL6-JAK STAT (more in steatotic Type) Wnt Beta catenin Signalling (more Cholestatic type) Chromosome Stability Chromosome 7 amplification Steatotic type CRP+ Cholestatic Type Nuclear beta Catenin Cluster B/S3/iCluster 2 G4 glass- Interferon Poly 7 subtypes WNT/Beta Catenine, CTTNNB1 Type -G5 G6 Class IL6 -JAK STAT (more in Steatotic type) Wnt-Beta Catetine signaling (more in cholestatic type)
Age	Up to 7-fold increased risk of HCC > 55Genetic Predisposition [69] Genetic Predisposition [69]
Overweight and Obesity	8-fold increase risk of HCC