graph LR
Hepatic_Stellate_Cell_Activation["Hepatic Stellate Cell Activation"]
Lactulose["Lactulose"]
Jaundice["Jaundice"]
IL_11_Signalling_in_Hepatic_Stellate_Cells["IL-11 Signalling in Hepatic Stellate Cells"]
Alcohol_Consumption["Alcohol Consumption"]
Hepatic_Pro_Inflammatory_Mediator_Release["Hepatic Pro-Inflammatory Mediator Release"]
Gastrointestinal_Hemorrhage["Gastrointestinal Hemorrhage"]
Excessive_Hepatic_ECM_Deposition["Excessive Hepatic ECM Deposition"]
Liver_Transplantation["Liver Transplantation"]
Reactive_Metabolite_Formation_and_Covalent_Protein_Adduction["Reactive Metabolite Formation and Covalent Protein Adduction"]
Coagulopathy["Coagulopathy"]
Synthetic_Dysfunction["Synthetic Dysfunction"]
Hepatocyte_Injury_and_Death["Hepatocyte Injury and Death"]
Antiviral_Therapy["Antiviral Therapy"]
Increased_Intrahepatic_Vascular_Resistance["Increased Intrahepatic Vascular Resistance"]
Kupffer_Cell_Activation["Kupffer Cell Activation"]
Esophageal_Varices["Esophageal Varices"]
Ascites["Ascites"]
TGF_beta_Signaling_in_Fibrogenesis["TGF-beta Signaling in Fibrogenesis"]
Portal_Hypertension["Portal Hypertension"]
Akura_Twin_384_well_liver_fibrosis_microphysiological_system_HepaRG_THP_1_and_hTERT_HSC_microtissues["Akura Twin 384-well liver fibrosis microphysiological system (HepaRG/THP-1 and hTERT-HSC microtissues)"]
Carbon_Tetrachloride_Exposure["Carbon Tetrachloride Exposure"]
Splanchnic_Vasodilation_and_Hyperdynamic_Circulation["Splanchnic Vasodilation and Hyperdynamic Circulation"]
Splenomegaly["Splenomegaly"]
Beta_Blockers["Beta Blockers"]
Hepatic_Encephalopathy["Hepatic Encephalopathy"]
Diuretics["Diuretics"]
Cirrhotic_Architectural_Distortion["Cirrhotic Architectural Distortion"]
Reactive_Metabolite_Formation_and_Covalent_Protein_Adduction --> Hepatocyte_Injury_and_Death
Hepatocyte_Injury_and_Death --> Kupffer_Cell_Activation
IL_11_Signalling_in_Hepatic_Stellate_Cells --> Hepatic_Stellate_Cell_Activation
Hepatic_Stellate_Cell_Activation --> Excessive_Hepatic_ECM_Deposition
Excessive_Hepatic_ECM_Deposition --> Cirrhotic_Architectural_Distortion
Cirrhotic_Architectural_Distortion --> Increased_Intrahepatic_Vascular_Resistance
Cirrhotic_Architectural_Distortion --> Synthetic_Dysfunction
Cirrhotic_Architectural_Distortion --> Jaundice
Increased_Intrahepatic_Vascular_Resistance --> Portal_Hypertension
TGF_beta_Signaling_in_Fibrogenesis --> Hepatic_Stellate_Cell_Activation
TGF_beta_Signaling_in_Fibrogenesis --> IL_11_Signalling_in_Hepatic_Stellate_Cells
Kupffer_Cell_Activation --> Hepatic_Pro_Inflammatory_Mediator_Release
Hepatic_Pro_Inflammatory_Mediator_Release --> Hepatic_Stellate_Cell_Activation
Hepatic_Pro_Inflammatory_Mediator_Release --> TGF_beta_Signaling_in_Fibrogenesis
Splanchnic_Vasodilation_and_Hyperdynamic_Circulation --> Portal_Hypertension
Portal_Hypertension --> Esophageal_Varices
Portal_Hypertension --> Ascites
Portal_Hypertension --> Hepatic_Encephalopathy
Portal_Hypertension --> Splenomegaly
Synthetic_Dysfunction --> Coagulopathy
Esophageal_Varices --> Gastrointestinal_Hemorrhage
Alcohol_Consumption --> Hepatocyte_Injury_and_Death
Carbon_Tetrachloride_Exposure --> Reactive_Metabolite_Formation_and_Covalent_Protein_Adduction
Antiviral_Therapy --> Excessive_Hepatic_ECM_Deposition
Diuretics --> Ascites
Beta_Blockers --> Splanchnic_Vasodilation_and_Hyperdynamic_Circulation
Lactulose --> Hepatic_Encephalopathy
Liver_Transplantation --> Cirrhotic_Architectural_Distortion
Akura_Twin_384_well_liver_fibrosis_microphysiological_system_HepaRG_THP_1_and_hTERT_HSC_microtissues --> Hepatic_Stellate_Cell_Activation
Akura_Twin_384_well_liver_fibrosis_microphysiological_system_HepaRG_THP_1_and_hTERT_HSC_microtissues --> Kupffer_Cell_Activation
Akura_Twin_384_well_liver_fibrosis_microphysiological_system_HepaRG_THP_1_and_hTERT_HSC_microtissues --> Hepatic_Pro_Inflammatory_Mediator_Release
Akura_Twin_384_well_liver_fibrosis_microphysiological_system_HepaRG_THP_1_and_hTERT_HSC_microtissues --> Hepatocyte_Injury_and_Death
Akura_Twin_384_well_liver_fibrosis_microphysiological_system_HepaRG_THP_1_and_hTERT_HSC_microtissues --> TGF_beta_Signaling_in_Fibrogenesis
style Hepatic_Stellate_Cell_Activation fill:#dbeafe
style Lactulose fill:#fce7f3
style Jaundice fill:#fef3c7
style IL_11_Signalling_in_Hepatic_Stellate_Cells fill:#dbeafe
style Alcohol_Consumption fill:#dcfce7
style Hepatic_Pro_Inflammatory_Mediator_Release fill:#dbeafe
style Gastrointestinal_Hemorrhage fill:#fef3c7
style Excessive_Hepatic_ECM_Deposition fill:#dbeafe
style Liver_Transplantation fill:#fce7f3
style Reactive_Metabolite_Formation_and_Covalent_Protein_Adduction fill:#dbeafe
style Coagulopathy fill:#fef3c7
style Synthetic_Dysfunction fill:#dbeafe
style Hepatocyte_Injury_and_Death fill:#dbeafe
style Antiviral_Therapy fill:#fce7f3
style Increased_Intrahepatic_Vascular_Resistance fill:#dbeafe
style Kupffer_Cell_Activation fill:#dbeafe
style Esophageal_Varices fill:#fef3c7
style Ascites fill:#fef3c7
style TGF_beta_Signaling_in_Fibrogenesis fill:#dbeafe
style Portal_Hypertension fill:#dbeafe
style Akura_Twin_384_well_liver_fibrosis_microphysiological_system_HepaRG_THP_1_and_hTERT_HSC_microtissues fill:#ccfbf1
style Carbon_Tetrachloride_Exposure fill:#dcfce7
style Splanchnic_Vasodilation_and_Hyperdynamic_Circulation fill:#dbeafe
style Splenomegaly fill:#fef3c7
style Beta_Blockers fill:#fce7f3
style Hepatic_Encephalopathy fill:#fef3c7
style Diuretics fill:#fce7f3
style Cirrhotic_Architectural_Distortion fill:#dbeafe
graph LR
Enhanced_Hepatocyte_Proliferation["Enhanced Hepatocyte Proliferation"]
Chronic_hepatitis_B_or_C_infection["Chronic hepatitis B or C infection"]
Impaired_Mitochondrial_Oxidative_Phosphorylation["Impaired Mitochondrial Oxidative Phosphorylation"]
Telomere_Dysfunction_and_Genomic_Instability["Telomere Dysfunction and Genomic Instability"]
Atezolizumab_plus_Bevacizumab["Atezolizumab plus Bevacizumab"]
Portal_Vein_Invasion_and_Tumor_Thrombus["Portal Vein Invasion and Tumor Thrombus"]
TAGLN2_Mediated_CSNK1E_Stabilization["TAGLN2-Mediated CSNK1E Stabilization"]
Long_term_Western_diet_feeding["Long-term Western diet feeding"]
Aerobic_Glycolytic_Shift_in_MASLD_Associated_HCC["Aerobic Glycolytic Shift in MASLD-Associated HCC"]
Accumulation_of_Driver_Mutations["Accumulation of Driver Mutations"]
Lenvatinib["Lenvatinib"]
Aerobic_Glycolysis_and_Metabolic_Reprogramming["Aerobic Glycolysis and Metabolic Reprogramming"]
MMP9_Upregulation["MMP9 Upregulation"]
Angiogenesis_and_VEGF_Signaling["Angiogenesis and VEGF Signaling"]
Sorafenib["Sorafenib"]
YAP_Nuclear_Translocation["YAP Nuclear Translocation"]
Immune_Evasion_and_Immunosuppressive_Microenvironment["Immune Evasion and Immunosuppressive Microenvironment"]
WNT_Beta_Catenin_Pathway_Activation["WNT/Beta-Catenin Pathway Activation"]
PI3K_AKT_mTOR_Pathway_Activation["PI3K/AKT/mTOR Pathway Activation"]
Necroptosis_Independent_MLKL_Function["Necroptosis-Independent MLKL Function"]
Chronic_Liver_Injury_and_Cirrhosis["Chronic Liver Injury and Cirrhosis"]
Hepatocyte_MLKL_Upregulation["Hepatocyte MLKL Upregulation"]
Durvalumab_plus_Tremelimumab["Durvalumab plus Tremelimumab"]
TAGLN2_Driven_Epithelial_Mesenchymal_Transition["TAGLN2-Driven Epithelial-Mesenchymal Transition"]
Monomethyl_phthalate_exposure["Monomethyl phthalate exposure"]
MFN2_Suppression_and_Impaired_Mitochondrial_Fusion["MFN2 Suppression and Impaired Mitochondrial Fusion"]
Alcohol_and_aflatoxin_exposure["Alcohol and aflatoxin exposure"]
Chronic_Liver_Injury_and_Cirrhosis --> Telomere_Dysfunction_and_Genomic_Instability
Chronic_Liver_Injury_and_Cirrhosis --> Accumulation_of_Driver_Mutations
Telomere_Dysfunction_and_Genomic_Instability --> WNT_Beta_Catenin_Pathway_Activation
Accumulation_of_Driver_Mutations --> PI3K_AKT_mTOR_Pathway_Activation
WNT_Beta_Catenin_Pathway_Activation --> Enhanced_Hepatocyte_Proliferation
WNT_Beta_Catenin_Pathway_Activation --> Portal_Vein_Invasion_and_Tumor_Thrombus
Hepatocyte_MLKL_Upregulation --> Necroptosis_Independent_MLKL_Function
Hepatocyte_MLKL_Upregulation --> MFN2_Suppression_and_Impaired_Mitochondrial_Fusion
MFN2_Suppression_and_Impaired_Mitochondrial_Fusion --> Impaired_Mitochondrial_Oxidative_Phosphorylation
Impaired_Mitochondrial_Oxidative_Phosphorylation --> Aerobic_Glycolytic_Shift_in_MASLD_Associated_HCC
Aerobic_Glycolytic_Shift_in_MASLD_Associated_HCC --> Enhanced_Hepatocyte_Proliferation
PI3K_AKT_mTOR_Pathway_Activation --> Enhanced_Hepatocyte_Proliferation
PI3K_AKT_mTOR_Pathway_Activation --> Immune_Evasion_and_Immunosuppressive_Microenvironment
PI3K_AKT_mTOR_Pathway_Activation --> Aerobic_Glycolysis_and_Metabolic_Reprogramming
Angiogenesis_and_VEGF_Signaling --> Immune_Evasion_and_Immunosuppressive_Microenvironment
Aerobic_Glycolysis_and_Metabolic_Reprogramming --> Enhanced_Hepatocyte_Proliferation
MMP9_Upregulation --> Portal_Vein_Invasion_and_Tumor_Thrombus
MMP9_Upregulation --> Enhanced_Hepatocyte_Proliferation
TAGLN2_Mediated_CSNK1E_Stabilization --> YAP_Nuclear_Translocation
YAP_Nuclear_Translocation --> TAGLN2_Driven_Epithelial_Mesenchymal_Transition
TAGLN2_Driven_Epithelial_Mesenchymal_Transition --> Portal_Vein_Invasion_and_Tumor_Thrombus
Chronic_hepatitis_B_or_C_infection --> Chronic_Liver_Injury_and_Cirrhosis
Alcohol_and_aflatoxin_exposure --> Chronic_Liver_Injury_and_Cirrhosis
Long_term_Western_diet_feeding --> Hepatocyte_MLKL_Upregulation
Monomethyl_phthalate_exposure --> MMP9_Upregulation
Atezolizumab_plus_Bevacizumab --> Immune_Evasion_and_Immunosuppressive_Microenvironment
Atezolizumab_plus_Bevacizumab --> Angiogenesis_and_VEGF_Signaling
Durvalumab_plus_Tremelimumab --> Immune_Evasion_and_Immunosuppressive_Microenvironment
Sorafenib --> Angiogenesis_and_VEGF_Signaling
Lenvatinib --> Angiogenesis_and_VEGF_Signaling
style Enhanced_Hepatocyte_Proliferation fill:#dbeafe
style Chronic_hepatitis_B_or_C_infection fill:#dcfce7
style Impaired_Mitochondrial_Oxidative_Phosphorylation fill:#dbeafe
style Telomere_Dysfunction_and_Genomic_Instability fill:#dbeafe
style Atezolizumab_plus_Bevacizumab fill:#fce7f3
style Portal_Vein_Invasion_and_Tumor_Thrombus fill:#dbeafe
style TAGLN2_Mediated_CSNK1E_Stabilization fill:#dbeafe
style Long_term_Western_diet_feeding fill:#dcfce7
style Aerobic_Glycolytic_Shift_in_MASLD_Associated_HCC fill:#dbeafe
style Accumulation_of_Driver_Mutations fill:#dbeafe
style Lenvatinib fill:#fce7f3
style Aerobic_Glycolysis_and_Metabolic_Reprogramming fill:#dbeafe
style MMP9_Upregulation fill:#dbeafe
style Angiogenesis_and_VEGF_Signaling fill:#dbeafe
style Sorafenib fill:#fce7f3
style YAP_Nuclear_Translocation fill:#dbeafe
style Immune_Evasion_and_Immunosuppressive_Microenvironment fill:#dbeafe
style WNT_Beta_Catenin_Pathway_Activation fill:#dbeafe
style PI3K_AKT_mTOR_Pathway_Activation fill:#dbeafe
style Necroptosis_Independent_MLKL_Function fill:#dbeafe
style Chronic_Liver_Injury_and_Cirrhosis fill:#dbeafe
style Hepatocyte_MLKL_Upregulation fill:#dbeafe
style Durvalumab_plus_Tremelimumab fill:#fce7f3
style TAGLN2_Driven_Epithelial_Mesenchymal_Transition fill:#dbeafe
style Monomethyl_phthalate_exposure fill:#dcfce7
style MFN2_Suppression_and_Impaired_Mitochondrial_Fusion fill:#dbeafe
style Alcohol_and_aflatoxin_exposure fill:#dcfce7
name: com_Liver_Cirrhosis__Hepatocellular_Carcinoma
creation_date: "2026-08-08T00:00:00Z"
curation_status: CANDIDATE
notes: >-
Split out of the former `kb/disorders/Metastatic_HCC.yaml`'s `environmental:` block
(since folded into `Hepatocellular_Carcinoma`, design decisions §3a)
(dismech#8185): that entry listed `Cirrhosis` as an "exposure" acting on the
disease's own "Chronic Liver Disease Substrate" pathophysiology node, but
cirrhosis is one of the chronic liver injury states that node itself
enumerates rather than something external to the organism acting on it, and
it is a first-class `Disease` entry in its own right
(`kb/disorders/Liver_Cirrhosis.yaml`). Modeling the relationship here as a
disease-disease comorbidity instead makes it queryable and avoids the
near-tautological pathograph edge. Directionality is A_BEFORE_B: cirrhosis
is the premalignant substrate that precedes HCC development, not the
reverse.
Side B is `Hepatocellular_Carcinoma`, not `Metastatic_HCC`. The cited
evidence establishes cirrhosis as the background from which HCC arises and
measures incident HCC in a cirrhosis cohort; none of it addresses
*metastatic* HCC specifically, and the relationship between cirrhosis and
stage at presentation runs the other way if anything, since HCC arising in
non-cirrhotic liver is not caught by surveillance and tends to present
larger and later. Attaching a directed RISK edge to the metastatic entity
would assert more than the sources support (review of dismech#8195).
disease_a:
slug: Liver_Cirrhosis
preferred_term: cirrhosis of liver
term:
id: MONDO:0005155
label: cirrhosis of liver
disease_b:
slug: Hepatocellular_Carcinoma
preferred_term: hepatocellular carcinoma
term:
id: MONDO:0007256
label: hepatocellular carcinoma
directionality: A_BEFORE_B
effect_direction: RISK
hypotheses:
- description: >-
Cirrhosis provides the premalignant inflammatory and regenerative context
for most hepatocellular carcinoma: sustained hepatocyte injury and
regeneration in the cirrhotic liver create the genomic instability and
proliferative pressure from which HCC arises.
evidence:
- reference: PMID:41567639
reference_title: Identification of novel germline and somatic mutations associated with hepatocellular carcinoma by next-generation sequencing.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HCC typically arises in patients with chronic liver disease, including hepatitis, cirrhosis, and non-alcoholic fatty liver diseases."
explanation: >-
Establishes cirrhosis as one of the chronic liver disease backgrounds
from which HCC typically arises.
association_signals:
- source: LITERATURE
method: LITERATURE_ASSOCIATION
population: >-
Brazilian cirrhosis outpatient cohort under six-monthly HCC surveillance
(n=453; hepatitis C virus and heavy alcohol use the main etiologies),
Porto Alegre, 2005-2014, 10-year retrospective cohort with Kaplan-Meier
estimation of incident HCC.
directionality: A_BEFORE_B
effect_direction: RISK
statistics:
metrics:
- metric_type: INCIDENCE_RATE
metric_value: 2.6
notes: >-
Kaplan-Meier cumulative incidence of HCC at 1 year among patients who
had cirrhosis at cohort entry, expressed as a percentage; 15.4% at 5
years and 28.8% at 10 years, with 75 of 453 patients (16.6%)
developing HCC over the study period. Chosen over a within-case
prevalence figure because the denominator here is the cirrhosis
population followed forward, which is what a directed A_BEFORE_B risk
signal requires.
evidence:
- reference: PMID:28028370
reference_title: "Incidence of hepatocellular carcinoma in outpatients with cirrhosis in Brazil: A 10-year retrospective cohort study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HCC was diagnosed in 75 patients (16.6%), with an estimated cumulative incidence of 2.6% in the 1st year, 15.4% in the 5th year, and 28.8% in the 10th year."
explanation: >-
Measures incident HCC prospectively in a defined cirrhosis cohort,
supporting cirrhosis as an antecedent risk state for HCC rather than
merely a frequent co-finding among HCC cases.