graph LR
Hepatocyte_Injury_and_Death["Hepatocyte Injury and Death"]
Kupffer_Cell_and_Inflammatory_Response["Kupffer Cell and Inflammatory Response"]
Hepatic_Stellate_Cell_Activation["Hepatic Stellate Cell Activation"]
IL_11_Signalling_in_Hepatic_Stellate_Cells["IL-11 Signalling in Hepatic Stellate Cells"]
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)"]
TGF_beta_Signaling_in_Fibrogenesis["TGF-beta Signaling in Fibrogenesis"]
IL_11_Signalling_in_Hepatic_Stellate_Cells --> Hepatic_Stellate_Cell_Activation
TGF_beta_Signaling_in_Fibrogenesis --> Hepatic_Stellate_Cell_Activation
TGF_beta_Signaling_in_Fibrogenesis --> IL_11_Signalling_in_Hepatic_Stellate_Cells
Kupffer_Cell_and_Inflammatory_Response --> Hepatic_Stellate_Cell_Activation
Kupffer_Cell_and_Inflammatory_Response --> TGF_beta_Signaling_in_Fibrogenesis
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_and_Inflammatory_Response
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 Hepatocyte_Injury_and_Death fill:#dbeafe
style Kupffer_Cell_and_Inflammatory_Response fill:#dbeafe
style Hepatic_Stellate_Cell_Activation fill:#dbeafe
style IL_11_Signalling_in_Hepatic_Stellate_Cells fill:#dbeafe
style Akura_Twin_384_well_liver_fibrosis_microphysiological_system_HepaRG_THP_1_and_hTERT_HSC_microtissues fill:#ccfbf1
style TGF_beta_Signaling_in_Fibrogenesis fill:#dbeafe
graph LR
Chronic_hepatitis_B_or_C_infection["Chronic hepatitis B or C infection"]
Durvalumab_plus_Tremelimumab["Durvalumab plus Tremelimumab"]
Telomere_Dysfunction_and_Genomic_Instability["Telomere Dysfunction and Genomic Instability"]
Accumulation_of_Driver_Mutations["Accumulation of Driver Mutations"]
Aerobic_Glycolysis_and_Metabolic_Reprogramming["Aerobic Glycolysis and Metabolic Reprogramming"]
Sorafenib["Sorafenib"]
PI3K_AKT_mTOR_Pathway_Activation["PI3K/AKT/mTOR Pathway Activation"]
Lenvatinib["Lenvatinib"]
Portal_Vein_Invasion_and_Tumor_Thrombus["Portal Vein Invasion and Tumor Thrombus"]
Chronic_Liver_Injury_and_Cirrhosis["Chronic Liver Injury and Cirrhosis"]
WNT_Beta_Catenin_Pathway_Activation["WNT/Beta-Catenin Pathway Activation"]
Enhanced_Hepatocyte_Proliferation["Enhanced Hepatocyte Proliferation"]
Immune_Evasion_and_Immunosuppressive_Microenvironment["Immune Evasion and Immunosuppressive Microenvironment"]
Angiogenesis_and_VEGF_Signaling["Angiogenesis and VEGF Signaling"]
Alcohol_and_aflatoxin_exposure["Alcohol and aflatoxin exposure"]
Atezolizumab_plus_Bevacizumab["Atezolizumab plus Bevacizumab"]
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
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
Chronic_hepatitis_B_or_C_infection --> Chronic_Liver_Injury_and_Cirrhosis
Alcohol_and_aflatoxin_exposure --> Chronic_Liver_Injury_and_Cirrhosis
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 Chronic_hepatitis_B_or_C_infection fill:#dcfce7
style Durvalumab_plus_Tremelimumab fill:#fce7f3
style Telomere_Dysfunction_and_Genomic_Instability fill:#dbeafe
style Accumulation_of_Driver_Mutations fill:#dbeafe
style Aerobic_Glycolysis_and_Metabolic_Reprogramming fill:#dbeafe
style Sorafenib fill:#fce7f3
style PI3K_AKT_mTOR_Pathway_Activation fill:#dbeafe
style Lenvatinib fill:#fce7f3
style Portal_Vein_Invasion_and_Tumor_Thrombus fill:#dbeafe
style Chronic_Liver_Injury_and_Cirrhosis fill:#dbeafe
style WNT_Beta_Catenin_Pathway_Activation fill:#dbeafe
style Enhanced_Hepatocyte_Proliferation fill:#dbeafe
style Immune_Evasion_and_Immunosuppressive_Microenvironment fill:#dbeafe
style Angiogenesis_and_VEGF_Signaling fill:#dbeafe
style Alcohol_and_aflatoxin_exposure fill:#dcfce7
style Atezolizumab_plus_Bevacizumab fill:#fce7f3
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.