Hepatitis C

Infectious Disease MONDO:0005231 Pathograph 6 Show in embeddings browser Viral Hepatitis Liver Disease

Hepatitis C is a liver infection caused by the hepatitis C virus (HCV). It is primarily transmitted through blood-to-blood contact, including injection drug use, unsafe medical practices, and rarely through sexual transmission. Acute infection is often asymptomatic but progresses to chronic infection in 75-85% of cases. Chronic hepatitis C can lead to liver cirrhosis, hepatocellular carcinoma, and liver failure. Direct-acting antiviral therapies have revolutionized treatment, with cure rates exceeding 95%.

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5
Pathophys.
12
Phenotypes
6
Pathograph
1
Genes
3
Medical Actions
2
Subtypes
7
Datasets
2
Deep Research
◆

Subtypes

2
Acute Hepatitis C
Initial HCV infection within the first 6 months, often asymptomatic but may present with jaundice and elevated transaminases.
Chronic Hepatitis C
Persistent HCV infection beyond 6 months, affecting 75-85% of infected individuals and leading to progressive liver damage.
⚙

Pathophysiology

5
Viral Replication and Hepatocyte Injury
HCV is a positive-sense single-stranded RNA virus that replicates primarily in hepatocytes. Viral replication causes direct cytopathic effects and triggers immune-mediated hepatocyte destruction. The virus evades immune clearance through high mutation rates and quasispecies diversity.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
viral life cycle GO:0019058 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves viral life cycle (GO:0019058). GO:0019058 is a biological process from the Gene Ontology.
Chronic Inflammation and Fibrosis
Persistent HCV infection induces chronic hepatic inflammation with infiltration of lymphocytes and activation of hepatic stellate cells. This leads to progressive fibrosis through excessive collagen deposition, ultimately resulting in cirrhosis.
hepatic stellate cell CL:0000632 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatic stellate cell (CL:0000632). CL:0000632 is a cell type from the Cell Ontology. T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
chronic inflammatory response GO:0002544 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves chronic inflammatory response (GO:0002544). GO:0002544 is a biological process from the Gene Ontology. hepatic stellate cell activation GO:0035733 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves hepatic stellate cell activation (GO:0035733). GO:0035733 is a biological process from the Gene Ontology. collagen biosynthetic process GO:0032964 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves collagen biosynthetic process (GO:0032964). GO:0032964 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:26569658 SUPPORT
"patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis"
Study specifically targets HCV patients with decompensated cirrhosis, confirming progression of chronic inflammation to advanced liver damage.
Immune Evasion
HCV employs multiple strategies to evade host immune responses, including interference with interferon signaling, rapid viral mutation generating escape variants, and exhaustion of HCV-specific T cells.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
symbiont-mediated suppression of host type I interferon-mediated signaling pathway GO:0039502 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves symbiont-mediated suppression of host type I interferon-mediated signaling pathway (GO:0039502). GO:0039502 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:16127453 SUPPORT In Vitro
"'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection"
In-vitro siRNA-knockdown study demonstrates the RIG-I/IPS-1(MAVS) interferon-induction pathway that HCV NS3/4A disrupts to evade interferon signaling; general virology, not HCV-specific.
Hepatocellular Carcinoma Development
Chronic inflammation, oxidative stress, and direct viral effects on cell signaling pathways contribute to hepatocarcinogenesis. Cirrhosis is the major risk factor, but HCC can occur in non-cirrhotic livers.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Show evidence (2 references)
PMID:22537432 SUPPORT Human Clinical
"The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%, depending on etiology (it is highest in individuals with HCV infection)"
Epidemiologic review establishing cirrhosis as the dominant HCC risk factor, with the highest cumulative HCC risk among HCV-infected patients.
PMID:19759533 SUPPORT Human Clinical
"Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma"
Documents the natural-history progression from persistent HCV infection to cirrhosis and hepatocellular carcinoma.
Cryoglobulin Immune Complex Deposition
Chronic HCV antigenaemia drives production of cryoprecipitable immunoglobulin complexes that deposit in small vessels and glomerular capillary walls. This single immune-complex mechanism accounts for the cryoglobulinemia-spectrum extrahepatic manifestations, which affect skin and kidney rather than liver.
immune complex formation GO:0097281 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased immune complex formation (GO:0097281). GO:0097281 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Mixed Cryoglobulinemia Cryoprecipitable immune complexes are the defining constituent of the mixed cryoglobulinemia syndrome.
Leukocytoclastic Vasculitis Immune complexes deposited in dermal small vessels produce the cutaneous leukocytoclastic vasculitis.
Membranoproliferative Glomerulonephritis Immune complexes deposited in glomerular capillary walls produce membranoproliferative glomerulonephritis.
Show evidence (1 reference)
PMID:22919404 SUPPORT Other
"Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney."
Histomorphologic review states that immune complex deposition in small vessels and glomerular capillaries is the mechanism producing the cutaneous and renal manifestations, establishing this node as their shared upstream cause.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hepatitis C Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Cardiovascular 1
Sicca Syndrome Keratoconjunctivitis sicca HP:0001097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratoconjunctivitis sicca (HP:0001097). HP:0001097 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22919404 SUPPORT Other
"Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."
Review of HCV extrahepatic manifestations lists sicca syndrome among the HCV-associated entities.
PMID:16510035 SUPPORT Other
"Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes."
Confirms sicca syndrome as one of the non-cryoglobulin HCV-associated extrahepatic syndromes with a less definite relationship to infection.
Digestive 4
Jaundice FREQUENT HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Cirrhosis FREQUENT HP:0001394 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cirrhosis (HP:0001394). HP:0001394 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26569658 SUPPORT
"patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis"
Study specifically targets HCV patients with cirrhosis, confirming cirrhosis as a major complication.
PMID:24725239 SUPPORT
"Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis"
Large HCV trial confirms cirrhosis prevalence among chronic HCV patients.
Hepatocellular Carcinoma OCCASIONAL HP:0001402 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatocellular carcinoma (HP:0001402). HP:0001402 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22537432 SUPPORT Human Clinical
"most cases of HCC (approximately 80%) are associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections"
Establishes chronic HCV infection as a leading cause of hepatocellular carcinoma.
Integument 1
Porphyria Cutanea Tarda Cutaneous photosensitivity HP:0000992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Porphyria cutanea tarda, annotated with Cutaneous photosensitivity (HP:0000992). HP:0000992 is a phenotype from the Human Phenotype Ontology.
No HPO term exists for porphyria cutanea tarda itself (confirmed via OAK search of sqlite:obo:hp); bound to the closest broader phenotype, Cutaneous photosensitivity, with a more specific preferred_term, following the same pattern used for SSPE in Measles.yaml. MONDO:0015104 is the disease-level term for porphyria cutanea tarda.
Show evidence (2 references)
PMID:22919404 SUPPORT Other
"Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."
Review of HCV extrahepatic manifestations lists porphyria cutanea tarda among the HCV-associated entities beyond the cryoglobulinemia spectrum.
PMID:16510035 SUPPORT Other
"Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes."
Confirms porphyria cutanea tarda as one of the non-cryoglobulin HCV-associated extrahepatic syndromes with a less definite relationship to infection.
Metabolism 1
Elevated Transaminases VERY_FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Constitutional 1
Fatigue VERY_FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16510035 SUPPORT Other
"Although nonspecific, fatigue and arthralgias are very common in those with chronic hepatitis C."
Review of HCV extrahepatic manifestations establishes fatigue as a very common symptom of chronic hepatitis C (not a treatment adverse event).
Other 4
Mixed Cryoglobulinemia HP:0100778 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryoglobulinemia (HP:0100778). HP:0100778 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16510035 SUPPORT Other
"The most prevalent extrahepatic diseases with the highest degree of association with HCV are the essential mixed cryoglobulins with skin, neurologic, renal, and rheumatologic complications."
Review of HCV extrahepatic manifestations identifies mixed cryoglobulinemia as the most prevalent and most strongly HCV-associated extrahepatic syndrome.
Leukocytoclastic Vasculitis HP:0034786 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukocytoclastic vasculitis (HP:0034786). HP:0034786 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22919404 SUPPORT Other
"immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"
Review of HCV extrahepatic pathology identifies immune-complex-mediated leukocytoclastic vasculitis in the skin as a morphologic manifestation of HCV-associated cryoglobulinemia.
Membranoproliferative Glomerulonephritis HP:0000793 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Membranoproliferative glomerulonephritis (HP:0000793). HP:0000793 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22919404 SUPPORT Other
"immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"
Review of HCV extrahepatic pathology identifies immune-complex-mediated membranoproliferative glomerulonephritis in the kidney as the renal manifestation of HCV-associated cryoglobulinemia.
B-Cell Non-Hodgkin Lymphoma B-cell lymphoma HP:0012191 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is B-cell non-Hodgkin lymphoma, annotated with B-cell lymphoma (HP:0012191). HP:0012191 is a phenotype from the Human Phenotype Ontology.
HPO has no combined "B-cell non-Hodgkin lymphoma" term. HP:0012191 B-cell lymphoma is a descendant of HP:0012539 Non-Hodgkin lymphoma, so the narrower lineage term is bound here and the non-Hodgkin sense is entailed.
Show evidence (1 reference)
PMID:22919404 SUPPORT Other
"Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."
Review of HCV extrahepatic manifestations lists B-cell non-Hodgkin lymphomas among the HCV-associated entities.
🧬

Genetic Associations

1
IL28B Polymorphisms (Susceptibility)
Show evidence (2 references)
PMID:19759533 SUPPORT Human Clinical
"the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry"
Genome-wide association evidence that the IL28B rs12979860 C/C genotype favors spontaneous clearance of HCV.
PMID:19684573 SUPPORT Human Clinical
"a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment"
Landmark GWAS linking the IL28B polymorphism to response to interferon-based HCV therapy.
💊

Medical Actions

3
Direct-Acting Antivirals (DAAs)
Action: antiviral therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antiviral therapy (NCIT:C16119). NCIT:C16119 is a clinical intervention from the NCI Thesaurus. Ontology label: Antiviral Therapy NCIT:C16119
Oral medications targeting viral proteins (NS3/4A protease, NS5A, NS5B polymerase) with cure rates exceeding 95%. Regimens include sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, and others.
Show evidence (3 references)
PMID:24725239 SUPPORT
"Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection."
Landmark trial demonstrating near-universal cure rates with DAA therapy.
PMID:26569658 SUPPORT
"Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis."
Study confirms high efficacy of DAAs even in patients with decompensated cirrhosis.
PMID:36891719 SUPPORT Other
"More and more direct antiviral agents, especially pan genotypic agents including those developed and produced by domestic enterprises, have been included in the national basic medical insurance directory."
The 2022 hepatitis C prevention-and-treatment guideline reflects expanding availability of pangenotypic direct-acting antiviral agents as standard therapy.
Liver Transplantation
Action: Liver TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liver Transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. NCIT:C15271
Treatment option for decompensated cirrhosis or hepatocellular carcinoma. DAA therapy post-transplant prevents graft reinfection.
Hepatocellular Carcinoma Surveillance
Action: surveillance for malignanciesNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surveillance for malignancies, annotated with Cancer Screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
Regular ultrasound and AFP monitoring in cirrhotic patients for early detection of hepatocellular carcinoma.
Show evidence (1 reference)
PMID:15042359 SUPPORT Human Clinical
"biannual screening reduced HCC mortality by 37%"
Landmark randomized controlled trial demonstrating that biannual AFP plus ultrasound surveillance reduces HCC mortality in at-risk chronic-hepatitis patients.
🌍

Environmental Factors

4
Injection Drug Use
injection drug use ECTO:6000007 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is injection drug use, annotated with exposure to substance abuse (ECTO:6000007). ECTO:6000007 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Major route of HCV transmission through sharing of needles and drug preparation equipment
Show evidence (2 references)
PMID:24923487 SUPPORT Human Clinical
"The highest detected risk was intravenous drug users (IDUs) (OR = 9.6)"
Meta-analysis of HCV risk factors: injecting drug use carries the single largest odds ratio of any exposure assessed, which is what makes it the major transmission route rather than merely one of several.
PMID:39066277 SUPPORT Human Clinical
"injection drug use has become the major route of HCV transmission, especially in high-income countries, and it is emerging even in rural areas"
Historical worldwide review of HCV transmission modes identifies injection drug use as the current major transmission route.
Unsafe Medical Practices
Transmission through contaminated medical equipment, blood transfusions (pre-1992), and organ transplants
Show evidence (2 references)
PMID:18657711 SUPPORT Human Clinical
"unsafe blood products and medical practices continue to increase transmission of HCV in many developing countries"
States the iatrogenic transmission route this annotation records, and notes the geographic split: transfusion-related transmission has declined in developed countries while unsafe medical practice continues to drive it elsewhere.
PMID:25516637 SUPPORT Human Clinical
"the more important risk is represented by unsafe practices regarding injections, notably with the improper use of multidose vials used for multiple patients"
Review of health care-associated HCV infection identifies unsafe injection practices, including improper multidose-vial use, as the leading contamination route.
Occupational Exposure
Healthcare workers at risk through needlestick injuries
Show evidence (2 references)
PMID:15018469 SUPPORT Human Clinical
"Of 4,403 exposed HCW, 14 seroconverted (0.31%; 95% CI 0.15-0.48)"
Quantifies the per-exposure risk in 4,403 exposed healthcare workers. The same study found the risk concentrated in hollow-bore blood-filled needle injuries (0.74%) and raised sixfold by deep injury, so the annotation's needlestick framing is the right one.
PMID:16231252 SUPPORT Human Clinical
"All case patients were exposed to HCV-infected fluids through percutaneous injuries"
European case-control study of HCV seroconversion in health care workers confirms percutaneous (needlestick) injury as the occupational exposure route.
Tattoos and Body Piercing
Both are established HCV risk factors; non-sterile equipment is the presumed route but is not itself evidenced by the cited studies
Show evidence (2 references)
PMID:20678951 SUPPORT Human Clinical
"The pooled odds ratio (OR) and 95% confidence interval (CI) of the association of tattooing and hepatitis C from all studies was 2.74"
Meta-analysis of 83 studies; the association is strongest in non-injection drug users (OR 5.74), which matters because it separates tattooing from confounding by injecting. PARTIAL because it covers the tattooing half of this exposure only -- piercing is evidenced by the item below -- and because it measures association rather than the sterility mechanism the note names.
PMID:24923487 SUPPORT Human Clinical
"Other significant risk factors included poor education, older age, sharing sharp or blunt objects, MSM, tattooing, hijama, body piercing, minor operations and medical procedures"
Covers the body-piercing half of this exposure, which the tattooing meta-analysis above does not. PARTIAL because the source lists piercing among significant risk factors without a per-factor odds ratio, so it establishes that piercing is a risk factor without quantifying it.
🔬

Biochemical Markers

4
HCV RNA (Detected)
Context: Confirms active viral infection; quantitative levels guide treatment monitoring
Anti-HCV Antibodies (Detected)
Context: Indicates current or past infection; does not distinguish active from resolved infection
Elevated ALT (Elevated)
Context: Marker of hepatocyte injury, though may be normal in some chronic infections
Elevated Bilirubin (Elevated)
Context: Indicates impaired hepatic function, especially in acute infection or decompensated cirrhosis
🦠

Infectious Agent

1
Hepatitis C virus
Hepacivirus hominis NCBITaxon:3052230 NCBI Taxonomy (NCBITaxon)
📊

Related Datasets

7
Hepatitis C Virus-induced Differential Transcriptional Traits in Host Cells After Persistent Infection Elimination by Direct-Acting Antivirals In Cell Culture geo:GSE267834
Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct acting antiviral (DAA) drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection.
human BULK RNA SEQ n=28
PMID:38988177
Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Longitudinal transcriptomic characterization of the immune response to acute hepatitis C virus infection geo:GSE119117
Most individuals exposed to hepatitis C virus (HCV) become persistently infected while a minority spontaneously eliminate the virus. Although early immune events influence infection outcome, the cellular composition, molecular effectors, and timeframe of the host response active shortly after viral exposure remain incompletely understood. Employing specimens collected from people who inject drugs (PWID) with high risk of HCV exposure, we utilized RNA-Seq to characterize immune function in peripheral blood before, during, and after acute HCV infection resulting in spontaneous resolution.
human BULK RNA SEQ n=53
PMID:30222771
Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
The human liver circadian transcriptome and its carcinogenic perturbation by hepatitis C virus infection (RNA-Seq I) geo:GSE200809
Chronic liver disease and cancer are global health challenges. The role of the circadian clock (CC) as a regulator of physiology and disease is well established in animal models. However, in human liver the identity of circadian genes and their epigenetic regulation is unknown. Here, we unraveled the circadian transcriptome and epigenome of human hepatocytes using a human liver chimeric mouse model. We identified genes coding for transcription factors, chromatin modifiers, and critical enzymes which are expressed rhythmically in human hepatocytes, and which differ from the mouse liver circadian transcriptome.
human BULK RNA SEQ n=6
PMID:39209804
Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort ega:EGAS00001000096
The hepatitis C virus infects nearly 3% of the World’s population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B SNPs, rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of hepatitis C virus infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (>1%) haplotypes for IL28B, one tagged by rs8099917 minor allele, four tagged by rs12979860.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Hepatitis C"); description-level mentions were not accepted. EGA study_type: Resequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Genome-to-genome analysis highlights the impact of the human innate and adaptive immune systems on the hepatitis C virus ega:EGAS00001002324
Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. We use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals chronically infected with HCV, predominately genotype 3. We show that both HLA alleles and interferon lambda innate immune system genes drive viral genome polymorphism, and that IFNL4 genotypes determine HCV viral load through a mechanism that is dependent on a specific polymorphism in the HCV polyprotein. We highlight the interplay between innate immune responses and the viral genome in HCV control.
human
PMID:28394351
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Hepatitis C"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) dbgap:phs000430
Reprinted from http://www.haltctrial.org/ Purpose The H epatitis C A ntiviral L ong-term T reatment against C irrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C
Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Hepatitis C"). Retrieved 2026-08-02.
Site specific glycan analysis of hepatitis C virus E1E2 glycoprotein complex massive:MSV000088553
Dataset for N-linked glycosylation analysis contained within "Structure of the hepatitis C virus E1E2 glycoprotein complex"
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Hepatitis C"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Hepatitis C
creation_date: '2026-01-09T05:44:55Z'
category: Infectious Disease
description: >
  Hepatitis C is a liver infection caused by the hepatitis C virus (HCV). It is primarily
  transmitted through blood-to-blood contact, including injection drug use, unsafe medical
  practices, and rarely through sexual transmission. Acute infection is often asymptomatic
  but progresses to chronic infection in 75-85% of cases. Chronic hepatitis C can lead to
  liver cirrhosis, hepatocellular carcinoma, and liver failure. Direct-acting antiviral
  therapies have revolutionized treatment, with cure rates exceeding 95%.
disease_term:
  preferred_term: hepatitis C virus infection
  term:
    id: MONDO:0005231
    label: hepatitis C virus infection
parents:
- Viral Hepatitis
- Liver Disease
infectious_agent:
- name: Hepatitis C virus
  infectious_agent_term:
    preferred_term: Hepacivirus hominis
    term:
      id: NCBITaxon:3052230
      label: Hepacivirus hominis
has_subtypes:
- name: Acute Hepatitis C
  description: Initial HCV infection within the first 6 months, often asymptomatic but may present with jaundice and elevated transaminases.
- name: Chronic Hepatitis C
  description: Persistent HCV infection beyond 6 months, affecting 75-85% of infected individuals and leading to progressive liver damage.
pathophysiology:
- name: Viral Replication and Hepatocyte Injury
  description: >
    HCV is a positive-sense single-stranded RNA virus that replicates primarily in
    hepatocytes. Viral replication causes direct cytopathic effects and triggers
    immune-mediated hepatocyte destruction. The virus evades immune clearance through
    high mutation rates and quasispecies diversity.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: viral life cycle
    term:
      id: GO:0019058
      label: viral life cycle
- name: Chronic Inflammation and Fibrosis
  description: >
    Persistent HCV infection induces chronic hepatic inflammation with infiltration
    of lymphocytes and activation of hepatic stellate cells. This leads to progressive
    fibrosis through excessive collagen deposition, ultimately resulting in cirrhosis.
  cell_types:
  - preferred_term: hepatic stellate cell
    term:
      id: CL:0000632
      label: hepatic stellate cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: chronic inflammatory response
    term:
      id: GO:0002544
      label: chronic inflammatory response
  - preferred_term: hepatic stellate cell activation
    term:
      id: GO:0035733
      label: hepatic stellate cell activation
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
  evidence:
  - reference: PMID:26569658
    reference_title: "Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis."
    supports: SUPPORT
    snippet: "patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis"
    explanation: Study specifically targets HCV patients with decompensated cirrhosis, confirming progression of chronic inflammation to advanced liver damage.
- name: Immune Evasion
  description: >
    HCV employs multiple strategies to evade host immune responses, including
    interference with interferon signaling, rapid viral mutation generating escape
    variants, and exhaustion of HCV-specific T cells.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: symbiont-mediated suppression of host type I interferon-mediated signaling pathway
    term:
      id: GO:0039502
      label: symbiont-mediated suppression of host type I interferon-mediated signaling pathway
  evidence:
  - reference: PMID:16127453
    reference_title: "IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection"
    explanation: In-vitro siRNA-knockdown study demonstrates the RIG-I/IPS-1(MAVS) interferon-induction pathway that HCV NS3/4A disrupts to evade interferon signaling; general virology, not HCV-specific.
- name: Hepatocellular Carcinoma Development
  description: >
    Chronic inflammation, oxidative stress, and direct viral effects on cell signaling
    pathways contribute to hepatocarcinogenesis. Cirrhosis is the major risk factor,
    but HCC can occur in non-cirrhotic livers.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:22537432
    reference_title: "Epidemiology of viral hepatitis and hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%, depending on etiology (it is highest in individuals with HCV infection)"
    explanation: Epidemiologic review establishing cirrhosis as the dominant HCC risk factor, with the highest cumulative HCC risk among HCV-infected patients.
  - reference: PMID:19759533
    reference_title: "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma"
    explanation: Documents the natural-history progression from persistent HCV infection to cirrhosis and hepatocellular carcinoma.
- name: Cryoglobulin Immune Complex Deposition
  description: >
    Chronic HCV antigenaemia drives production of cryoprecipitable
    immunoglobulin complexes that deposit in small vessels and glomerular
    capillary walls. This single immune-complex mechanism accounts for the
    cryoglobulinemia-spectrum extrahepatic manifestations, which affect skin
    and kidney rather than liver.
  biological_processes:
  - preferred_term: immune complex formation
    term:
      id: GO:0097281
      label: immune complex formation
    modifier: INCREASED
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney."
    explanation: Histomorphologic review states that immune complex deposition in small vessels and glomerular capillaries is the mechanism producing the cutaneous and renal manifestations, establishing this node as their shared upstream cause.
  downstream:
  - target: Mixed Cryoglobulinemia
    description: Cryoprecipitable immune complexes are the defining constituent of the mixed cryoglobulinemia syndrome.
    causal_link_type: DIRECT
  - target: Leukocytoclastic Vasculitis
    description: Immune complexes deposited in dermal small vessels produce the cutaneous leukocytoclastic vasculitis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22919404
      reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin"
      explanation: States the small-vessel deposition to cutaneous leukocytoclastic vasculitis link directly.
  - target: Membranoproliferative Glomerulonephritis
    description: Immune complexes deposited in glomerular capillary walls produce membranoproliferative glomerulonephritis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22919404
      reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"
      explanation: States the glomerular capillary deposition to membranoproliferative glomerulonephritis link directly.
phenotypes:
- name: Fatigue
  category: Constitutional
  frequency: VERY_FREQUENT
  description: Chronic fatigue is the most common symptom, often persisting even after viral clearance.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:16510035
    reference_title: "Extrahepatic manifestations of hepatitis C virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although nonspecific, fatigue and arthralgias are very common in those with chronic hepatitis C."
    explanation: Review of HCV extrahepatic manifestations establishes fatigue as a very common symptom of chronic hepatitis C (not a treatment adverse event).
- name: Jaundice
  category: Hepatic
  frequency: FREQUENT
  description: Yellow discoloration of skin and sclera due to elevated bilirubin, more common in acute infection.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
- name: Hepatomegaly
  category: Hepatic
  frequency: FREQUENT
  description: Enlarged liver due to inflammation and/or fatty infiltration.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
- name: Elevated Transaminases
  category: Laboratory
  frequency: VERY_FREQUENT
  description: Elevated ALT and AST indicating hepatocyte injury, though levels may fluctuate in chronic infection.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  reports_on:
  - target: Viral Replication and Hepatocyte Injury
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Serum ALT and AST measure hepatocyte injury from HCV replication and immune-mediated destruction.
- name: Cirrhosis
  category: Hepatic
  frequency: FREQUENT
  description: End-stage liver fibrosis developing in 15-30% of chronically infected patients over 20-30 years.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  evidence:
  - reference: PMID:26569658
    reference_title: "Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis."
    supports: SUPPORT
    snippet: "patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis"
    explanation: Study specifically targets HCV patients with cirrhosis, confirming cirrhosis as a major complication.
  - reference: PMID:24725239
    reference_title: "Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection."
    supports: SUPPORT
    snippet: "Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis"
    explanation: Large HCV trial confirms cirrhosis prevalence among chronic HCV patients.
- name: Hepatocellular Carcinoma
  category: Neoplastic
  frequency: OCCASIONAL
  description: Primary liver cancer developing in 1-5% of cirrhotic patients annually.
  phenotype_term:
    preferred_term: Hepatocellular carcinoma
    term:
      id: HP:0001402
      label: Hepatocellular carcinoma
  evidence:
  - reference: PMID:22537432
    reference_title: "Epidemiology of viral hepatitis and hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most cases of HCC (approximately 80%) are associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections"
    explanation: Establishes chronic HCV infection as a leading cause of hepatocellular carcinoma.
- name: Mixed Cryoglobulinemia
  category: Immunologic
  description: >
    Immune-complex syndrome with skin, neurologic, renal, and rheumatologic
    complications; the most prevalent and most strongly HCV-associated
    extrahepatic manifestation.
  phenotype_term:
    preferred_term: Cryoglobulinemia
    term:
      id: HP:0100778
      label: Cryoglobulinemia
  evidence:
  - reference: PMID:16510035
    reference_title: "Extrahepatic manifestations of hepatitis C virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most prevalent extrahepatic diseases with the highest degree of association with HCV are the essential mixed cryoglobulins with skin, neurologic, renal, and rheumatologic complications."
    explanation: Review of HCV extrahepatic manifestations identifies mixed cryoglobulinemia as the most prevalent and most strongly HCV-associated extrahepatic syndrome.
- name: Leukocytoclastic Vasculitis
  category: Dermatologic
  description: >
    Cutaneous small-vessel vasculitis from immune-complex deposition, the
    dermatologic manifestation of HCV-associated mixed cryoglobulinemia.
  phenotype_term:
    preferred_term: Leukocytoclastic vasculitis
    term:
      id: HP:0034786
      label: Leukocytoclastic vasculitis
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"
    explanation: Review of HCV extrahepatic pathology identifies immune-complex-mediated leukocytoclastic vasculitis in the skin as a morphologic manifestation of HCV-associated cryoglobulinemia.
- name: Membranoproliferative Glomerulonephritis
  category: Renal
  description: >
    Immune-complex glomerulonephritis, the classic renal manifestation of
    HCV-associated mixed cryoglobulinemia.
  phenotype_term:
    preferred_term: Membranoproliferative glomerulonephritis
    term:
      id: HP:0000793
      label: Membranoproliferative glomerulonephritis
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"
    explanation: Review of HCV extrahepatic pathology identifies immune-complex-mediated membranoproliferative glomerulonephritis in the kidney as the renal manifestation of HCV-associated cryoglobulinemia.
- name: Porphyria Cutanea Tarda
  category: Dermatologic
  description: >
    Cutaneous porphyria presenting with photosensitivity and skin fragility;
    an HCV-associated extrahepatic entity with a less definite (non-cryoglobulin)
    relationship to infection than cryoglobulinemia.
  phenotype_term:
    preferred_term: Porphyria cutanea tarda
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  notes: >-
    No HPO term exists for porphyria cutanea tarda itself (confirmed via OAK
    search of sqlite:obo:hp); bound to the closest broader phenotype,
    Cutaneous photosensitivity, with a more specific preferred_term, following
    the same pattern used for SSPE in Measles.yaml. MONDO:0015104 is the
    disease-level term for porphyria cutanea tarda.
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."
    explanation: Review of HCV extrahepatic manifestations lists porphyria cutanea tarda among the HCV-associated entities beyond the cryoglobulinemia spectrum.
  - reference: PMID:16510035
    reference_title: "Extrahepatic manifestations of hepatitis C virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes."
    explanation: Confirms porphyria cutanea tarda as one of the non-cryoglobulin HCV-associated extrahepatic syndromes with a less definite relationship to infection.
- name: Sicca Syndrome
  category: Immunologic
  description: >
    Sjogren-like sicca complex reported as an HCV-associated extrahepatic
    manifestation, distinct from classic autoimmune Sjogren syndrome.
  phenotype_term:
    preferred_term: Keratoconjunctivitis sicca
    term:
      id: HP:0001097
      label: Keratoconjunctivitis sicca
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."
    explanation: Review of HCV extrahepatic manifestations lists sicca syndrome among the HCV-associated entities.
  - reference: PMID:16510035
    reference_title: "Extrahepatic manifestations of hepatitis C virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes."
    explanation: Confirms sicca syndrome as one of the non-cryoglobulin HCV-associated extrahepatic syndromes with a less definite relationship to infection.
- name: B-Cell Non-Hodgkin Lymphoma
  category: Neoplastic
  description: >
    Lymphoproliferative outcome at the far end of the same chronic B-cell
    stimulation continuum as HCV-associated mixed cryoglobulinemia.
  phenotype_term:
    preferred_term: B-cell non-Hodgkin lymphoma
    term:
      id: HP:0012191
      label: B-cell lymphoma
  notes: >-
    HPO has no combined "B-cell non-Hodgkin lymphoma" term. HP:0012191 B-cell
    lymphoma is a descendant of HP:0012539 Non-Hodgkin lymphoma, so the
    narrower lineage term is bound here and the non-Hodgkin sense is entailed.
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."
    explanation: Review of HCV extrahepatic manifestations lists B-cell non-Hodgkin lymphomas among the HCV-associated entities.
biochemical:
- name: HCV RNA
  presence: Detected
  context: Confirms active viral infection; quantitative levels guide treatment monitoring
- name: Anti-HCV Antibodies
  presence: Detected
  context: Indicates current or past infection; does not distinguish active from resolved infection
- name: Elevated ALT
  presence: Elevated
  context: Marker of hepatocyte injury, though may be normal in some chronic infections
- name: Elevated Bilirubin
  presence: Elevated
  context: Indicates impaired hepatic function, especially in acute infection or decompensated cirrhosis
genetic:
- name: IL28B Polymorphisms
  association: Susceptibility
  notes: IL28B (IFNL3) variants influence spontaneous clearance and response to interferon-based therapy
  evidence:
  - reference: PMID:19759533
    reference_title: "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry"
    explanation: Genome-wide association evidence that the IL28B rs12979860 C/C genotype favors spontaneous clearance of HCV.
  - reference: PMID:19684573
    reference_title: "Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment"
    explanation: Landmark GWAS linking the IL28B polymorphism to response to interferon-based HCV therapy.
environmental:
- name: Injection Drug Use
  exposure_term:
    preferred_term: injection drug use
    term:
      id: ECTO:6000007
      label: exposure to substance abuse
  notes: Major route of HCV transmission through sharing of needles and drug preparation equipment
  evidence:
  - reference: PMID:24923487
    reference_title: "A comprehensive hepatitis C virus risk factors meta-analysis (1989-2013): do they differ in Egypt?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The highest detected risk was intravenous drug users (IDUs) (OR = 9.6)"
    explanation: "Meta-analysis of HCV risk factors: injecting drug use carries the single largest odds ratio of any exposure assessed, which is what makes it the major transmission route rather than merely one of several."
  - reference: PMID:39066277
    reference_title: "Prevalence and Modes of Transmission of Hepatitis C Virus Infection: A Historical Worldwide Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "injection drug use has become the major route of HCV transmission, especially in high-income countries, and it is emerging even in rural areas"
    explanation: Historical worldwide review of HCV transmission modes identifies injection drug use as the current major transmission route.
- name: Unsafe Medical Practices
  notes: Transmission through contaminated medical equipment, blood transfusions (pre-1992), and organ transplants
  evidence:
  - reference: PMID:18657711
    reference_title: "Acute hepatitis C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "unsafe blood products and medical practices continue to increase transmission of HCV in many developing countries"
    explanation: "States the iatrogenic transmission route this annotation records, and notes the geographic split: transfusion-related transmission has declined in developed countries while unsafe medical practice continues to drive it elsewhere."
  - reference: PMID:25516637
    reference_title: "Health care-associated hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the more important risk is represented by unsafe practices regarding injections, notably with the improper use of multidose vials used for multiple patients"
    explanation: Review of health care-associated HCV infection identifies unsafe injection practices, including improper multidose-vial use, as the leading contamination route.
- name: Occupational Exposure
  notes: Healthcare workers at risk through needlestick injuries
  evidence:
  - reference: PMID:15018469
    reference_title: "Risk of hepatitis C virus transmission following percutaneous exposure in healthcare workers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 4,403 exposed HCW, 14 seroconverted (0.31%; 95% CI 0.15-0.48)"
    explanation: "Quantifies the per-exposure risk in 4,403 exposed healthcare workers. The same study found the risk concentrated in hollow-bore blood-filled needle injuries (0.74%) and raised sixfold by deep injury, so the annotation's needlestick framing is the right one."
  - reference: PMID:16231252
    reference_title: "Risk factors for hepatitis C virus transmission to health care workers after occupational exposure: a European case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All case patients were exposed to HCV-infected fluids through percutaneous injuries"
    explanation: European case-control study of HCV seroconversion in health care workers confirms percutaneous (needlestick) injury as the occupational exposure route.
- name: Tattoos and Body Piercing
  notes: Both are established HCV risk factors; non-sterile equipment is the
    presumed route but is not itself evidenced by the cited studies
  evidence:
  - reference: PMID:20678951
    reference_title: "Tattooing and the risk of transmission of hepatitis C: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled odds ratio (OR) and 95% confidence interval (CI) of the association of tattooing and hepatitis C from all studies was 2.74"
    explanation: "Meta-analysis of 83 studies; the association is strongest in non-injection drug users (OR 5.74), which matters because it separates tattooing from confounding by injecting. PARTIAL because it covers the tattooing half of this exposure only -- piercing is evidenced by the item below -- and because it measures association rather than the sterility mechanism the note names."
  - reference: PMID:24923487
    reference_title: "A comprehensive hepatitis C virus risk factors meta-analysis (1989-2013): do they differ in Egypt?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other significant risk factors included poor education, older age, sharing sharp or blunt objects, MSM, tattooing, hijama, body piercing, minor operations and medical procedures"
    explanation: "Covers the body-piercing half of this exposure, which the tattooing meta-analysis above does not. PARTIAL because the source lists piercing among significant risk factors without a per-factor odds ratio, so it establishes that piercing is a risk factor without quantifying it."
treatments:
- name: Direct-Acting Antivirals (DAAs)
  description: >
    Oral medications targeting viral proteins (NS3/4A protease, NS5A, NS5B polymerase)
    with cure rates exceeding 95%. Regimens include sofosbuvir/velpatasvir,
    glecaprevir/pibrentasvir, and others.
  treatment_term:
    preferred_term: antiviral therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
  evidence:
  - reference: PMID:24725239
    reference_title: "Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection."
    supports: SUPPORT
    snippet: "Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection."
    explanation: Landmark trial demonstrating near-universal cure rates with DAA therapy.
  - reference: PMID:26569658
    reference_title: "Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis."
    supports: SUPPORT
    snippet: "Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis."
    explanation: Study confirms high efficacy of DAAs even in patients with decompensated cirrhosis.
  - reference: PMID:36891719
    reference_title: "Guideline for the prevention and treatment of hepatitis C (2022 version)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More and more direct antiviral agents, especially pan genotypic agents including those developed and produced by domestic enterprises, have been included in the national basic medical insurance directory."
    explanation: The 2022 hepatitis C prevention-and-treatment guideline reflects expanding availability of pangenotypic direct-acting antiviral agents as standard therapy.
- name: Liver Transplantation
  description: >
    Treatment option for decompensated cirrhosis or hepatocellular carcinoma.
    DAA therapy post-transplant prevents graft reinfection.
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
- name: Hepatocellular Carcinoma Surveillance
  description: >
    Regular ultrasound and AFP monitoring in cirrhotic patients for early
    detection of hepatocellular carcinoma.
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:15042359
    reference_title: "Randomized controlled trial of screening for hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biannual screening reduced HCC mortality by 37%"
    explanation: Landmark randomized controlled trial demonstrating that biannual AFP plus ultrasound surveillance reduces HCC mortality in at-risk chronic-hepatitis patients.
datasets:
- accession: geo:GSE267834
  title: Hepatitis C Virus-induced Differential Transcriptional Traits in Host Cells After Persistent Infection Elimination by Direct-Acting Antivirals In Cell Culture
  description: Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct acting antiviral (DAA) drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 28
  publication: PMID:38988177
  notes: Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE119117
  title: Longitudinal transcriptomic characterization of the immune response to acute hepatitis C virus infection
  description: Most individuals exposed to hepatitis C virus (HCV) become persistently infected while a minority spontaneously eliminate the virus. Although early immune events influence infection outcome, the cellular composition, molecular effectors, and timeframe of the host response active shortly after viral exposure remain incompletely understood. Employing specimens collected from people who inject drugs (PWID) with high risk of HCV exposure, we utilized RNA-Seq to characterize immune function in peripheral blood before, during, and after acute HCV infection resulting in spontaneous resolution.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 53
  publication: PMID:30222771
  notes: Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE200809
  title: The human liver circadian transcriptome and its carcinogenic perturbation by hepatitis C virus infection (RNA-Seq I)
  description: Chronic liver disease and cancer are global health challenges. The role of the circadian clock (CC) as a regulator of physiology and disease is well established in animal models. However, in human liver the identity of circadian genes and their epigenetic regulation is unknown. Here, we unraveled the circadian transcriptome and epigenome of human hepatocytes using a human liver chimeric mouse model. We identified genes coding for transcription factors, chromatin modifiers, and critical enzymes which are expressed rhythmically in human hepatocytes, and which differ from the mouse liver circadian transcriptome.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:39209804
  notes: Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001000096
  title: Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort
  description: The hepatitis C virus infects nearly 3% of the World’s population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B SNPs, rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of hepatitis C virus infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (>1%) haplotypes for IL28B, one tagged by rs8099917 minor allele, four tagged by rs12979860.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Hepatitis C"); description-level mentions were not accepted. EGA study_type: Resequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001002324
  title: Genome-to-genome analysis highlights the impact of the human innate and adaptive immune systems on the hepatitis C virus
  description: Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. We use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals chronically infected with HCV, predominately genotype 3. We show that both HLA alleles and interferon lambda innate immune system genes drive viral genome polymorphism, and that IFNL4 genotypes determine HCV viral load through a mechanism that is dependent on a specific polymorphism in the HCV polyprotein. We highlight the interplay between innate immune responses and the viral genome in HCV control.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:28394351
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Hepatitis C"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: dbgap:phs000430
  title: Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C)
  description:  Reprinted from http://www.haltctrial.org/    Purpose    The  H epatitis C  A ntiviral  L ong-term  T reatment against  C irrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Hepatitis C"). Retrieved 2026-08-02.
- accession: massive:MSV000088553
  title: Site specific glycan analysis of hepatitis C virus E1E2 glycoprotein complex
  description: Dataset for N-linked glycosylation analysis contained within "Structure of the hepatitis C virus E1E2 glycoprotein complex"
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Hepatitis C"). Retrieved 2026-08-02.
📚

References & Deep Research

Deep Research

2
Disorder ▸

Disorder

  • Name: Hepatitis C
  • Category: Infectious
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 20

Key Pathophysiology Nodes

  • Viral Replication and Hepatocyte Injury
  • Chronic Inflammation and Fibrosis
  • Immune Evasion
  • Hepatocellular Carcinoma Development
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1073/pnas.2403392121
  • DOI:10.1186/s12985-024-02359-1
  • DOI:10.14274/moola-archana_phd2023
  • DOI:10.3389/fimmu.2024.1305157
  • DOI:10.3389/fmicb.2024.1418301
  • DOI:10.3390/ijms25137191
  • DOI:10.3390/ijms25147873
  • DOI:10.3390/microorganisms12061035
  • DOI:10.3390/pathogens13040278
  • DOI:10.3390/pathogens13040339
  • DOI:10.3390/v16121899
  • DOI:10.37349/edd.2024.00049
  • DOI:10.54014/4vbs-5jpp
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 43 citations 2026-01-08T21:10:55.282499

Disease Pathophysiology Research Report

Target Disease - Disease Name: Hepatitis C (chronic hepatitis C virus infection) - MONDO ID: — (not specified) - Category: Infectious

Pathophysiology description (narrative) HCV is a hepatotropic positive‑sense RNA virus whose nonstructural proteins remodel hepatocyte ER membranes into a membranous web for replication while subverting innate sensing and interferon (IFN) signaling. Key innate antagonism includes cleavage/inactivation of adaptor proteins in RIG‑I–like receptor (RLR) signaling and downstream dampening of IFN responses; autophagy/mitophagy is commandeered to both support replication and degrade innate signaling nodes. Chronic infection sustains ER and oxidative stress, lipid droplet remodeling, and insulin resistance, linking metabolic injury to stellate‑cell activation via TGF‑β/SMAD and other growth‑factor axes. Persistent inflammation and fibrogenic remodeling set the stage for hepatocarcinogenesis driven by viral proteins (Core, NS5A, NS3) and host pathway dysregulation (e.g., EGFR, PI3K–AKT–mTOR, Wnt/β‑catenin), with a residual hepatocellular carcinoma (HCC) risk even after viral eradication—especially in those with advanced fibrosis/cirrhosis (lee2024hcvinducedautophagyand pages 3-5, smirne2024chronichepatitisc pages 6-8).

1) Core pathophysiology: key mechanisms and dysregulated pathways - Innate immune evasion - NS3/4A and RLR signaling: Contemporary work emphasizes RLR–MAVS signalosome integrity as central to IFN induction. MAVS oligomerization on the mitochondrial outer membrane is actively regulated by post‑translational palmitoylation; “MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity,” and Cys508 is also “a cleavage site of hepatitis C virus protease NS3/4A,” highlighting how HCV targets this axis (PNAS, 2024; URL: https://doi.org/10.1073/pnas.2403392121; Aug 2024) (galasso2024inflammatoryresponsein pages 8-9). Reviews of RNA‑virus regulation of cGAS–STING further note HCV proteins (NS3/4A, NS5A) can inhibit assembly of STING–MAVS–TBK1/IKKε complexes, attenuating IFN signaling (Virology Journal, 2024; URL: https://doi.org/10.1186/s12985-024-02359-1; May 2024) (galasso2024inflammatoryresponsein pages 8-9). - Autophagy/mitophagy–IFN crosstalk: HCV co‑opts the autophagy pathway to enhance replication and suppress innate signaling. Direct quote: “HCV uses autophagic membranes to enhance its replication… [and] induces Rubicon to delay autophagosome maturation,” while “autophagy mediates degradation of… IFNAR1… thus suppressing… type I IFN responses” (Frontiers in Immunology, 2024; URL: https://doi.org/10.3389/fimmu.2024.1305157; Feb 2024) (lee2024hcvinducedautophagyand pages 3-5). ER stress and mitochondrial ROS activate p62/Keap1/Nrf2, linking antioxidant responses to autophagy and antiviral signaling modulation (lee2024hcvinducedautophagyand pages 3-5).

  • Hepatocyte injury biology
  • ER and oxidative stress: HCV triggers UPR (IRE1/ATF6/PERK) and mitochondrial ROS, promoting autophagy and survival while contributing to hepatocyte injury; quote: “HCV induces ER stress… increases mitochondrial ROS… [and] autophagy… to attenuate the interferon (IFN) response” (Frontiers in Immunology, 2024; URL above) (lee2024hcvinducedautophagyand pages 3-5). HCV proteins (Core, NS5A) elevate ROS and activate NF‑κB/STAT3 signaling, supporting oncogenic programming (IJMS, 2024; URL: https://doi.org/10.3390/ijms25137191; Jun 2024) (galasso2024inflammatoryresponsein pages 8-9).

  • Lipid droplet remodeling and insulin resistance: NS4B and NS5A remodel ER and promote lipid droplet biogenesis; lipoviral particle assembly on LDs/VLDL intertwines replication with lipid metabolism. Chronic HCV is associated with steatosis and insulin‑signaling defects, including TNF‑α–driven IRS‑1 inhibition; genotype‑specific associations (e.g., Gt3 viral steatosis) are noted (Pathogens, 2024; URL: https://doi.org/10.3390/pathogens13040339; Apr 2024) (mendezsanchez2024chronichepatitisc pages 4-5).

  • Fibrosis biology

  • Stellate‑cell activation and cytokine/growth‑factor signaling: Chronic hepatocyte injury and inflammatory cytokines (e.g., TGF‑β) convert quiescent hepatic stellate cells (HSCs) into matrix‑producing myofibroblasts; “Activation of HSCs, triggered by TGFβ recognition, promotes liver fibrosis by inducing extracellular matrix (ECM) production,” with overexpression of PDGF and EGF family signals in HCV contexts (IJMS, 2024; URL above) (galasso2024inflammatoryresponsein pages 8-9). Reviews of fibrogenesis emphasize the centrality of HSCs, inflammatory macrophages, and the potential for regression when the injury (e.g., HCV) is removed (IJMS, 2024; URL: https://doi.org/10.3390/ijms25147873; Jul 2024) (lee2024hcvinducedautophagyand pages 3-5).

  • Reversibility: State‑of‑the‑art fibrosis reviews document that hepatic fibrosis can regress—“even at advanced stages”—after removal of the injurious stimulus, consistent with post‑SVR improvements observed clinically (IJMS, 2024; URL above) (lee2024hcvinducedautophagyand pages 3-5). Clinical reviews similarly note inflammation and portal pressure improvements post‑eradication, though residual HCC risk persists in advanced fibrosis (Viruses, 2024; URL: https://doi.org/10.3390/v16121899; Dec 2024) (smirne2024chronichepatitisc pages 6-8).

  • Oncogenesis

  • Direct viral and host‑pathway mechanisms: Chronic HCV promotes ER stress, oxidative injury, and dysregulation of tumor‑relevant pathways (TERT, p53–p21–Rb, Wnt/β‑catenin/c‑MYC, EGFR, PI3K–AKT–mTOR), epigenetic remodeling, and angiogenic signaling (VEGF/PDGF), with about 15% of HCV‑related HCC reported without definite cirrhosis (Viruses, 2024; URL above) (smirne2024chronichepatitisc pages 5-6). Mechanistic reviews emphasize NS5A‑induced ROS/Ca2+ signaling and Core‑mediated mitochondrial complex I disruption driving NF‑κB/STAT3 and ROS (IJMS, 2024; URL above) (galasso2024inflammatoryresponsein pages 8-9).

2) Key molecular players - Genes/Proteins (HGNC preferred): - DDX58/RIG‑I; IFIH1/MDA5; MAVS (mitochondrial adaptor targeted by NS3/4A); IFNAR1 (downregulated via autophagy); ATG7, SQSTM1/p62, NFE2L2/NRF2, KEAP1, RUBCN (autophagy control); TGFB1, TGFBR1/2, SMAD2/3 (TGF‑β/SMAD); PDGFRB; EGFR; STAT3; RELA/NF‑κB (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8, smirne2024chronichepatitisc pages 5-6). - Chemical entities (CHEBI/drugs): - Reactive oxygen species; cholesterol/lipid droplets; DAAs (sofosbuvir, velpatasvir) used in pan‑genotypic regimens (lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5, xiong2024keypointsfor pages 1-3, mendezsanchez2024chronichepatitisc pages 1-2). - Cell types (CL): - Hepatocytes (primary HCV host cell); hepatic stellate cells (fibrogenic effector); Kupffer cells (liver macrophages) (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8). - Anatomical locations (UBERON): - Liver (parenchyma), hepatic sinusoids, mitochondrial outer membrane, endoplasmic reticulum, lipid droplet organelles relevant to replication and injury (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, mendezsanchez2024chronichepatitisc pages 4-5).

3) Biological processes for GO annotation - Innate immune signaling and antiviral defense: “RIG‑I‑like receptor signaling,” “type I interferon signaling,” “cGAS–STING signaling,” “NF‑κB signaling” (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Autophagy and mitophagy: “macroautophagy,” “selective autophagy,” “mitophagy,” “ER stress/UPR” (lee2024hcvinducedautophagyand pages 3-5). - Fibrogenesis: “TGF‑β receptor signaling,” “SMAD protein signal transduction,” “extracellular matrix organization,” “response to transforming growth factor beta,” “PDGF receptor signaling,” “epithelial‑to‑mesenchymal transition” (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Metabolic rewiring: “lipid droplet organization,” “cholesterol metabolic process,” “regulation of insulin receptor signaling pathway” (mendezsanchez2024chronichepatitisc pages 4-5). - Oncogenic processes: “positive regulation of cell proliferation via EGFR/PI3K–AKT,” “response to reactive oxygen species,” “angiogenesis” (smirne2024chronichepatitisc pages 5-6, galasso2024inflammatoryresponsein pages 8-9).

4) Cellular components - Mitochondrial outer membrane (MAVS signaling; mitophagy); endoplasmic reticulum (membranous web; UPR); lipid droplets (assembly); autophagosomes and autolysosomes (HCV replication support and innate signal degradation) (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, mendezsanchez2024chronichepatitisc pages 4-5).

5) Disease progression: sequence and stages - Acute infection → innate immune engagement (RLRs, cGAS–STING), but HCV NS proteins suppress adaptor signaling and IFN responses via protease cleavage (MAVS/TRIF) and autophagy‑mediated receptor/adaptor degradation (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Establishment of chronic infection → persistent ER/oxidative stress, autophagy/mitophagy, lipid remodeling, and insulin resistance in hepatocytes (lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5). - Paracrine inflammatory milieu → Kupffer cell cytokines and DAMPs activate HSCs via TGF‑β/PDGF/EGFR signaling, promoting ECM deposition and fibrotic scarring; fibrogenesis is dynamic and may regress after SVR (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Cirrhosis and dysplastic change → oncogenic pathway activation (TERT, p53–Rb, Wnt/β‑catenin, EGFR/PI3K–AKT–mTOR), genomic instability, and angiogenesis culminate in HCC; ~15% of HCV‑related HCC can arise without definite cirrhosis (smirne2024chronichepatitisc pages 5-6).

6) Phenotypic manifestations and extrahepatic disease - Hepatic phenotypes: chronic hepatitis, steatosis, progressive fibrosis → cirrhosis (portal hypertension, decompensation), and HCC (smirne2024chronichepatitisc pages 6-8, smirne2024chronichepatitisc pages 5-6). - Extrahepatic immune‑complex and lymphoproliferative disease: Mixed cryoglobulinemia (MC) with complement activation and renal involvement; chronic antigenic stimulation drives B‑cell clonal expansion and risk of NHL; mechanisms include E2–CD81‑mediated B‑cell activation and core/gC1qR‑driven complement deposition (Pathogens, 2024; URL: https://doi.org/10.3390/pathogens13040339; Apr 2024) (mendezsanchez2024chronichepatitisc pages 4-5). Kidney disease risk (cryoglobulinemic GN, CKD/ESRD) is well‑recognized (Frontiers in Microbiology, 2024; URL: https://doi.org/10.3389/fmicb.2024.1418301; Jun 2024) (mendezsanchez2024chronichepatitisc pages 1-2). - Metabolic manifestations: insulin resistance/T2DM risk and lipid abnormalities are common; eradication can normalize lipid/carbohydrate metabolism, though vascular risk patterns after SVR are nuanced (Pathogens, 2024; URL: https://doi.org/10.3390/pathogens13040278; Mar 2024) (sallam2024contemporaryinsightsinto pages 25-26). - Modification after DAA/SVR: Reviews document improvement or remission of extrahepatic manifestations following SVR (Pathogens, 2024; URL above) and reduced—but not eliminated—HCC risk after SVR, especially in advanced fibrosis/cirrhosis (Viruses, 2024; URL above) (mendezsanchez2024chronichepatitisc pages 1-2, smirne2024chronichepatitisc pages 6-8).

Current applications and real‑world implementations - Pan‑genotypic DAA regimens (e.g., sofosbuvir/velpatasvir) achieve high SVR across patient groups and are expected to reduce HCV complications globally by 2030 (Exploration of Digestive Diseases, 2024; URL: https://doi.org/10.37349/edd.2024.00049; Jun 2024) (xiong2024keypointsfor pages 1-3). - Post‑SVR clinical management emphasizes ongoing HCC surveillance in patients with advanced fibrosis/cirrhosis due to residual risk, and monitoring/management of extrahepatic conditions (Viruses, 2024; URL above) (smirne2024chronichepatitisc pages 6-8).

Expert opinions and analysis - Immune evasion and autophagy: 2024 immunology reviews argue HCV’s success hinges on “imped[ing] signaling pathways initiated by PRRs” and harnessing autophagy/mitophagy to suppress IFN and inflammasome activation while facilitating replication (Frontiers in Immunology, 2024) (lee2024hcvinducedautophagyand pages 3-5). - Fibrosis reversibility: 2024 fibrosis overviews emphasize that removing the injurious trigger (e.g., HCV via DAAs) can inactivate HSCs, reduce inflammatory circuits, and enable fibrolysis, even in advanced disease, though approved antifibrotics remain an unmet need (IJMS, 2024) (lee2024hcvinducedautophagyand pages 3-5). - Oncogenesis: 2024–2025 oncology and inflammation reviews highlight persistent oxidative stress, cytokine signaling (NF‑κB/STAT3), and growth‑factor pathways as convergent drivers of HCV‑related HCC, with residual oncogenic risk post‑SVR necessitating risk stratification and surveillance (IJMS, 2024; Viruses, 2024) (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8, smirne2024chronichepatitisc pages 5-6).

Relevant statistics and data (recent) - Global burden: Contemporary reviews cite ≈50–71 million people living with chronic HCV (WHO 2023/2024 figures) (Microorganisms, 2024; URL: https://doi.org/10.3390/microorganisms12061035; May 2024; Pathogens, 2024; URL: https://doi.org/10.3390/pathogens13040339; Apr 2024) (sallam2024contemporaryinsightsinto pages 4-5, mendezsanchez2024chronichepatitisc pages 1-2). - Natural history and HCC risk: Progression to cirrhosis over ~20 years ranges ~2–24%; HCC incidence in cirrhotics ~1–4%/year; DAA‑induced SVR lowers HCC risk but does not abolish it, mandating surveillance in advanced fibrosis/cirrhosis (Exploration of Digestive Diseases, 2024; URL above; Viruses, 2024; URL above) (xiong2024keypointsfor pages 1-3, smirne2024chronichepatitisc pages 6-8).

Direct quotes (selected) - “HCV uses autophagic membranes to enhance its replication… [and] induces Rubicon to delay autophagosome maturation… autophagy mediates degradation of… IFNAR1… thus suppressing… type I IFN responses” (Frontiers in Immunology, 2024) (lee2024hcvinducedautophagyand pages 3-5). - “MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity,” and Cys508 is “a cleavage site of hepatitis C virus protease NS3/4A” (PNAS, 2024) (galasso2024inflammatoryresponsein pages 8-9). - “Activation of HSCs, triggered by TGFβ recognition, promotes liver fibrosis by inducing extracellular matrix (ECM) production” (IJMS, 2024) (galasso2024inflammatoryresponsein pages 8-9).

Ontology‑anchored annotations and structured artifact - Genes/proteins (HGNC), biological processes (GO), cell types (CL), anatomical locations (UBERON/GO cellular components), and chemicals/drugs (CHEBI) central to HCV pathophysiology are consolidated below.

Category Entity Ontology Ontology ID Role/Notes Evidence
Gene/Protein DDX58 (RIG-I) HGNC Cytosolic RNA sensor initiating RIG-I–MAVS antiviral signaling and type I IFN induction. (brown2023exploringthemolecular pages 43-46, lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein IFIH1 (MDA5) HGNC Long dsRNA sensor cooperating with RIG-I to detect HCV replication intermediates. (brown2023exploringthemolecular pages 43-46, lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein MAVS HGNC/GO Mitochondrial antiviral-signaling adaptor cleaved by HCV NS3/4A to block RLR signaling and IFN responses. (lee2024hcvinducedautophagyand pages 3-5, brown2023exploringthemolecular pages 49-51)
Gene/Protein ZDHHC7 HGNC Palmitoyltransferase required for MAVS palmitoylation/aggregation and effective antiviral signaling. (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein IFNAR1 HGNC Type I IFN receptor subunit; targeted for degradation/downregulation by HCV-linked autophagy to blunt IFN signaling. (lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein ATG7 HGNC Core autophagy factor exploited by HCV for replication membranes; silencing increases IFN signaling and reduces HCV replication. (lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein SQSTM1 (p62) HGNC Selective autophagy adaptor linking oxidative stress (Keap1–Nrf2 axis), mitophagy and innate immune modulation in HCV infection. (lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein NFE2L2 (NRF2) HGNC Transcription factor activated via p62/Keap1 interactions; mediates antioxidant responses and is implicated in HCV-linked cell survival. (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9)
Gene/Protein TGFB1 HGNC Key profibrogenic cytokine that activates HSCs via SMAD signaling and drives ECM deposition in chronic HCV. (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Gene/Protein TGFBR1 HGNC Type I TGF-β receptor mediating SMAD2/3 phosphorylation during HSC activation and fibrogenesis. (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Gene/Protein SMAD2 HGNC Intracellular effector of canonical TGF-β signaling that promotes transcriptional programs for HSC activation and ECM production. (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Gene/Protein PDGFRB HGNC Receptor tyrosine kinase on HSCs that drives proliferation/migration in response to PDGF signals during liver injury. (smirne2024chronichepatitisc pages 6-8, smirne2024chronichepatitisc pages 5-6)
Gene/Protein EGFR HGNC Receptor involved in hepatocyte/HSC signaling, supports pro-survival, proliferative and EMT-like responses linked to fibrogenesis and oncogenesis. (smirne2024chronichepatitisc pages 5-6, smirne2024chronichepatitisc pages 6-8)
Gene/Protein STAT3 HGNC Transcription factor activated downstream of cytokines and growth factors (e.g., IL-6, EGFR) promoting inflammation, survival and HCC-related programs in HCV. (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Gene/Protein RELA (NF-κB p65) HGNC Central inflammatory transcription factor engaged by HCV-induced signaling and linked to cytokine production, fibrosis and carcinogenesis. (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Cell Type Hepatic stellate cell CL Primary fibrogenic cell in the liver that transdifferentiates to myofibroblasts (↑α-SMA, collagen) in response to TGF-β/PDGF signals in HCV. (moola2023restorationofsystemic pages 5-9, galasso2024inflammatoryresponsein pages 8-9)
Cell Type Kupffer cell (liver macrophage) CL Resident liver macrophage mediating inflammatory cytokine release and paracrine activation of HSCs during chronic HCV injury. (smirne2024chronichepatitisc pages 6-8, galasso2024inflammatoryresponsein pages 8-9)
Cell Type Hepatocyte CL Primary HCV host cell undergoing ER stress, oxidative stress, lipid remodeling, insulin resistance and viral replication-driven dysfunction. (lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5)
Cellular Component Mitochondrial outer membrane GO Site of MAVS localization/aggregation and HCV-modulated mitophagy; central to antiviral signaling and ROS generation in HCV infection. (lee2024hcvinducedautophagyand pages 3-5, brown2023exploringthemolecular pages 49-51)
Cellular Component Endoplasmic reticulum GO Membrane remodeling (NS4B, NS5A) creates the membranous web for HCV replication and triggers UPR/ER stress contributing to injury and oncogenesis. (lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5)
Cellular Component Lipid droplet GO Intracellular organelle co-opted by HCV (core/NS5A/NS4B) for assembly and linked to hepatic steatosis and metabolic dysregulation. (mendezsanchez2024chronichepatitisc pages 4-5, brown2023exploringthemolecular pages 43-46)
Chemical/Drug Reactive oxygen species (ROS) CHEBI Byproduct of HCV-induced mitochondrial/ER dysfunction that promotes DNA damage, inflammasome/oxidative signaling, and fibrogenic/oncogenic processes. (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9)
Chemical/Drug Sofosbuvir CHEBI/DrugBank NS5B nucleotide polymerase inhibitor (DAA) that achieves high SVR rates and is associated with improvements in extrahepatic/metabolic parameters post-clearance. (mendezsanchez2024chronichepatitisc pages 1-2, xiong2024keypointsfor pages 1-3)
Chemical/Drug Velpatasvir CHEBI/DrugBank Pan-genotypic NS5A inhibitor used in DAA combinations (e.g., sofosbuvir+velpatasvir) to achieve SVR and reduce HCV-driven inflammation/fibrosis progression. (xiong2024keypointsfor pages 1-3, mendezsanchez2024chronichepatitisc pages 1-2)

Table: Concise ontology-mapped overview of high-yield genes/proteins, cells, compartments and drugs implicated in Hepatitis C pathophysiology. The table links each entity to its role in HCV biology and cites supporting evidence from the gathered references (sallam2024contemporaryinsightsinto pages 25-26, galasso2024inflammatoryresponsein pages 7-8).

Phenotype associations (examples; HP terms) - Chronic hepatitis (HP:0012115): persistent hepatocellular injury linked to ER/oxidative stress and immune dysregulation (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9). - Hepatic steatosis (HP:0001397): linked to HCV core/NS proteins and insulin resistance (mendezsanchez2024chronichepatitisc pages 4-5). - Liver fibrosis (HP:0001394) and cirrhosis (HP:0001396): HSC activation via TGF‑β/SMAD, PDGF/EGFR; potential regression after SVR (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Hepatocellular carcinoma (HP:0002897): oncogenic pathways (TERT, p53–Rb, Wnt/β‑catenin, EGFR/PI3K–AKT–mTOR), ROS/STAT3/NF‑κB signaling; residual risk post‑SVR (smirne2024chronichepatitisc pages 5-6, smirne2024chronichepatitisc pages 6-8, galasso2024inflammatoryresponsein pages 8-9). - Mixed cryoglobulinemia (HP:0031886) and cryoglobulinemic glomerulonephritis (HP:0033540): immune complex–mediated vasculitis and renal injury; improvement after SVR (mendezsanchez2024chronichepatitisc pages 4-5, mendezsanchez2024chronichepatitisc pages 1-2). - Type 2 diabetes mellitus (HP:0005978) and insulin resistance (HP:0000855): inflammation‑ and virus‑mediated metabolic derangements; partial normalization post‑SVR (mendezsanchez2024chronichepatitisc pages 4-5, sallam2024contemporaryinsightsinto pages 25-26).

Evidence items (PMIDs/DOIs/URLs and dates) - Lee & Ou, 2024. HCV‑induced autophagy and innate immunity. Frontiers in Immunology. DOI: 10.3389/fimmu.2024.1305157; Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1305157 (lee2024hcvinducedautophagyand pages 3-5). - Liu et al., 2024. MAVS Cys508 palmitoylation… PNAS. DOI: 10.1073/pnas.2403392121; Aug 2024. URL: https://doi.org/10.1073/pnas.2403392121 (galasso2024inflammatoryresponsein pages 8-9). - Xie & Zhu, 2024. Regulation of cGAS–STING by RNA virus components. Virology Journal. DOI: 10.1186/s12985-024-02359-1; May 2024. URL: https://doi.org/10.1186/s12985-024-02359-1 (galasso2024inflammatoryresponsein pages 8-9). - Galasso et al., 2024. Inflammatory response in HCC pathogenesis. IJMS. DOI: 10.3390/ijms25137191; Jun 2024. URL: https://doi.org/10.3390/ijms25137191 (galasso2024inflammatoryresponsein pages 8-9). - Akkız et al., 2024. Liver fibrosis… role of HSCs. IJMS. DOI: 10.3390/ijms25147873; Jul 2024. URL: https://doi.org/10.3390/ijms25147873 (lee2024hcvinducedautophagyand pages 3-5). - Méndez‑Sánchez et al., 2024. Chronic HCV, extrahepatic disease, and impact of DAAs. Pathogens. DOI: 10.3390/pathogens13040339; Apr 2024. URL: https://doi.org/10.3390/pathogens13040339 (mendezsanchez2024chronichepatitisc pages 4-5). - Pascual‑Oliver et al., 2024. Lipid profile and CV risk after HCV eradication. Pathogens. DOI: 10.3390/pathogens13040278; Mar 2024. URL: https://doi.org/10.3390/pathogens13040278 (sallam2024contemporaryinsightsinto pages 25-26). - Xiong & Guo, 2024. Management in the era of pan‑genotypic DAAs. Exploration of Digestive Diseases. DOI: 10.37349/edd.2024.00049; Jun 2024. URL: https://doi.org/10.37349/edd.2024.00049 (xiong2024keypointsfor pages 1-3). - Smirne et al., 2024. DAAs and HCC occurrence/recurrence after SVR. Viruses. DOI: 10.3390/v16121899; Dec 2024. URL: https://doi.org/10.3390/v16121899 (smirne2024chronichepatitisc pages 5-6, smirne2024chronichepatitisc pages 6-8).

Notes on evidence quality and gaps Where mechanistic claims rely on review syntheses, we quoted the authors’ language and provided URLs/dates. Several cited items are reviews (some in MDPI journals); key mechanistic anchors (Frontiers in Immunology, PNAS) provide higher‑confidence mechanistic detail for innate evasion and autophagy/mitophagy. Quantitative post‑SVR HCC risks vary by cohort and fibrosis stage; surveillance remains standard for advanced fibrosis/cirrhosis.

Gene/protein annotations with ontology terms (examples) - DDX58 (HGNC:19102) – GO: RIG‑I signaling; antiviral defense (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9). - MAVS (HGNC:30930) – GO: mitochondrial outer membrane; RLR signaling adaptor (galasso2024inflammatoryresponsein pages 8-9). - IFNAR1 (HGNC:5432) – GO: type I IFN receptor complex; negative regulation by autophagy in HCV (lee2024hcvinducedautophagyand pages 3-5). - TGFB1 (HGNC:11766), TGFBR1 (HGNC:11772), SMAD2/3 (HGNC:6767/6769) – GO: TGF‑β receptor signaling; fibrogenesis (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - PDGFRB (HGNC:8803), EGFR (HGNC:3236) – GO: RTK signaling; HSC proliferation/migration, hepatocyte EMT/injury (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 5-6). - STAT3 (HGNC:11364), RELA/NF‑κB p65 (HGNC:9955) – GO: inflammatory/oncogenic transcriptional programs (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 5-6).

Cell type involvement (CL terms; examples) - Hepatocyte (CL:0000182) – HCV replication, ER/oxidative stress (lee2024hcvinducedautophagyand pages 3-5). - Hepatic stellate cell (CL:0000632) – fibrogenic effector (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9). - Kupffer cell (CL:0000091) – inflammatory cytokines/macrophage crosstalk (smirne2024chronichepatitisc pages 6-8).

Anatomical locations (UBERON; examples) - Liver (UBERON:0002107); hepatic sinusoid (UBERON:0001983); mitochondrial outer membrane (GO:0005741); endoplasmic reticulum (GO:0005783); lipid droplet (GO:0005811) (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, mendezsanchez2024chronichepatitisc pages 4-5).

Chemical entities (CHEBI; examples) - Reactive oxygen species (CHEBI:26523); cholesterol (CHEBI:16113); sofosbuvir (DrugBank DB08934); velpatasvir (DrugBank DB11613) (lee2024hcvinducedautophagyand pages 3-5, xiong2024keypointsfor pages 1-3, mendezsanchez2024chronichepatitisc pages 1-2).

Citations - Innate immune evasion and autophagy/mitophagy: (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5) - Hepatocyte ER/oxidative stress; lipid/insulin signaling: (lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5, galasso2024inflammatoryresponsein pages 8-9) - Fibrosis mechanisms and reversibility: (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5) - Oncogenesis mechanisms and residual HCC risk: (smirne2024chronichepatitisc pages 5-6, galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8) - Extrahepatic disease and modification after SVR: (mendezsanchez2024chronichepatitisc pages 4-5, mendezsanchez2024chronichepatitisc pages 1-2, sallam2024contemporaryinsightsinto pages 25-26) - Burden and management statistics: (sallam2024contemporaryinsightsinto pages 4-5, xiong2024keypointsfor pages 1-3, smirne2024chronichepatitisc pages 6-8)

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