Pulmonary Veno-Occlusive Disease and/or Pulmonary Capillary Haemangiomatosis

Cardiovascular Disorder MONDO:0018554 Pathograph 2 Pulmonary arterial hypertension Respiratory system disorder

Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH) is a rare pulmonary arterial hypertension spectrum disorder with overt pulmonary venous and capillary involvement. It is characterized by progressive pulmonary venous and capillary remodeling, impaired gas exchange, increased pulmonary vascular resistance, and risk of right ventricular failure.

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1
Inheritance
5
Pathophys.
3
Histopath.
9
Phenotypes
2
Pathograph
1
Genes
3
Treatments
1
Trials
8
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Heritable PVOD/PCH is caused by biallelic EIF2AK4 pathogenic variants and follows autosomal recessive inheritance with nearly complete, but not literally complete, penetrance in current clinical reviews.
Autosomal recessive inheritance Penetrance: INCOMPLETE
Show evidence (1 reference)
PMID:40471666 SUPPORT Human Clinical
"hereditary autosomal recessive condition with biallelic eukaryotic translation initiation factor 2 alpha kinase 4"
The review directly identifies autosomal recessive inheritance due to biallelic EIF2AK4 variants.
⚙

Pathophysiology

5
Pulmonary venous and capillary remodeling
PVOD/PCH involves small pulmonary veins, venules, and capillaries rather than isolated arterial remodeling, leading to increased pulmonary vascular resistance and right ventricular strain.
endothelial cell link vascular smooth muscle cell link
extracellular matrix organization link ⚠ ABNORMAL
pulmonary vein link pulmonary venule link pulmonary capillary link
Show evidence (2 references)
PMID:24292273 SUPPORT Human Clinical
"widespread fibrous intimal proliferation of septal veins and preseptal venules"
Histologic evidence supports the pulmonary venous remodeling component.
PMID:38232988 SUPPORT Human Clinical
"substantial small pulmonary vein and capillary involvement, leading to increased pulmonary vascular resistance and right ventricular failure"
The review connects venous/capillary involvement to pulmonary vascular resistance and right ventricular failure.
EIF2AK4/GCN2 stress-response loss
Biallelic EIF2AK4 loss impairs GCN2-mediated integrated stress-response signaling and provides the established genetic mechanism for heritable PVOD/PCH.
EIF2AK4 link
cellular response to amino acid starvation link ↓ DECREASED response to amino acid starvation link ↓ DECREASED
Show evidence (3 references)
PMID:24292273 SUPPORT Human Clinical
"All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene."
The founding human genetic study supports loss of EIF2AK4 function as a causal mechanism.
PMID:36852942 PARTIAL Model Organism
"The ISR was not activated after ASNase treatment in Gcn2-/- rat lungs, and apoptosis was increased."
Gcn2-deficient rats model impaired stress-response activation and stress-induced lung pathology relevant to heritable PVOD.
PMID:29108819 SUPPORT Human Clinical
"GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03)"
This supports reduced GCN2 expression beyond inherited EIF2AK4-carrier disease, including sporadic PVOD.
Mitomycin C PKR/ISR endothelial barrier dysfunction
Mitomycin C exposure can drive PVOD-like disease in rats through PKR and integrated stress-response activation, converging on endothelial junctional and barrier impairment.
endothelial cell link
integrated stress response ↑ INCREASED endothelial barrier dysfunction ⚠ ABNORMAL
pulmonary vein link
Show evidence (1 reference)
PMID:39269983 PARTIAL Model Organism
"mitomycin C (MMC) in rats mediates PVOD through the activation of the eukaryotic initiation factor 2 (eIF2) kinase protein kinase R (PKR) and the integrated stress response (ISR), resulting in the impairment of vascular endothelial junctional structure and barrier function."
This experimental study supports an iatrogenic/environmental convergence mechanism distinct from inherited EIF2AK4 loss.
Immune inflammation in EIF2AK4/GCN2 deficiency
Experimental Gcn2 deficiency produces inflammatory lung signatures that may contribute to pulmonary vascular injury and remodeling.
T cell link neutrophil link
inflammatory response link ↑ INCREASED
lung link
Show evidence (1 reference)
PMID:36852942 PARTIAL Model Organism
"Several proinflammatory and innate immunity genes were overexpressed, and inflammatory cells infiltration was also observed in the perivascular area."
This animal model supports immune dysregulation as a plausible downstream consequence of GCN2 deficiency, not as a stand-alone proven human driver.
Macrophage ferroptosis and venous arterialization
Recent translational work implicates macrophage ferroptosis and arterial marker expression in venous endothelial cells as a potential mechanism of pulmonary venous arterialization.
macrophage link endothelial cell link
ferroptosis link ↑ INCREASED
pulmonary vein link
Show evidence (2 references)
PMID:40983649 PARTIAL Model Organism
"Treatment with the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) reverses the changes in haemodynamic indices observed in Eif2ak4K1488X/K1488X hypoxia mice and PVOD model rats."
Animal model rescue data support macrophage ferroptosis as a candidate targetable mechanism, while human causal relevance remains translational.
PMID:40983649 PARTIAL Human Clinical
"ferroptosis pathway-related genes are upregulated in lung macrophages of PVOD patients"
Human tissue transcriptomic evidence supports relevance of the macrophage ferroptosis signal in PVOD lungs.
✶

Histopathology

3
Fibrous intimal proliferation of septal veins and preseptal venules
The classic histologic lesion is fibrous intimal proliferation affecting septal veins and preseptal venules.
Show evidence (2 references)
PMID:24292273 SUPPORT Human Clinical
"widespread fibrous intimal proliferation of septal veins and preseptal venules"
This founding genetic study also summarizes the defining PVOD histopathology.
PMID:29108819 SUPPORT Human Clinical
"Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001)"
This cohort links EIF2AK4-carrier PVOD to more severe intimal fibrosis, refining the histopathology of heritable disease.
Pulmonary capillary dilatation and proliferation
PVOD is frequently accompanied by pulmonary capillary dilatation and proliferation, explaining its overlap with PCH.
Show evidence (1 reference)
PMID:24292273 SUPPORT Human Clinical
"frequently associated with pulmonary capillary dilatation and proliferation"
This supports the PVOD/PCH spectrum concept.
Fibrous veno-occlusive lesions on explant pathology
Lung explant pathology can reveal microvascular remodeling and fibrous veno-occlusive lesions, but biopsy is generally avoided clinically due to risk in pulmonary hypertension.
Show evidence (1 reference)
PMID:38232988 SUPPORT Human Clinical
"Histopathological analysis of lung explants reveals microvascular remodelling with typical fibrous veno-occlusive lesions."
The review supports the explant histopathology pattern.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Pulmonary Veno-Occlusive Disease and/or Pulmonary Capillary Haemangiomatosis 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

9
Cardiovascular 1
Pulmonary arterial hypertension Pulmonary arterial hypertension (HP:0002092)
Show evidence (1 reference)
PMID:40104258 SUPPORT Human Clinical
"PVOD is classified under group 1 pulmonary arterial hypertension (PAH) as subgroup 1.5"
The clinical review supports pulmonary arterial hypertension as the diagnostic classification framework.
Metabolism 1
Pulmonary edema with pulmonary vasodilator therapy Pulmonary edema (HP:0100598)
Show evidence (1 reference)
PMID:38232988 SUPPORT Human Clinical
"Life-threatening pulmonary oedema is a complication of pulmonary vasodilator therapy that can occur with any class of PAH drugs in PVOD."
The review supports pulmonary edema after vasodilator therapy as a major management risk and diagnostic clue.
Respiratory 2
Dyspnea Dyspnea (HP:0002094)
Show evidence (1 reference)
DOI:10.1159/000527524 SUPPORT Human Clinical
"A 19-year-old man who was previously diagnosed with idiopathic PAH suffered from dyspnea on exertion for 2 months."
This PVOD/PCH case report supports exertional dyspnea as a presenting clinical feature.
Hypoxemia Hypoxemia (HP:0012418)
Show evidence (1 reference)
PMID:40471666 SUPPORT Human Clinical
"PVOD is characterized by progressive pulmonary venous and capillary remodelling, severe hypoxemia, and right ventricular failure."
The review explicitly lists severe hypoxemia among core PVOD features.
Other 5
Decreased DLCO Decreased DLCO (HP:0045051)
Show evidence (2 references)
PMID:40471666 SUPPORT Human Clinical
"low lung diffusion capacity for carbon monoxide (DLCO), and genetic testing can aid differentiation"
The review supports reduced DLCO as part of the diagnostic differentiation from PAH.
PMID:28972005 SUPPORT Human Clinical
"These patients had a reduced transfer coefficient for carbon monoxide"
A large PAH/PVOD cohort found reduced carbon monoxide transfer in biallelic EIF2AK4 carriers.
Right ventricular failure Right ventricular failure (HP:0001708)
Show evidence (1 reference)
PMID:38232988 SUPPORT Human Clinical
"leading to increased pulmonary vascular resistance and right ventricular failure"
The review links venous/capillary involvement to increased resistance and right ventricular failure.
Interlobular septal thickening
Show evidence (1 reference)
PMID:38232988 SUPPORT Human Clinical
"Chest computed tomography typically displays interlobular septal thickening, ground-glass opacities and mediastinal lymphadenopathy."
The review directly supports this CT finding as part of the typical PVOD imaging pattern.
Ground-glass opacities
Show evidence (1 reference)
PMID:31178067 SUPPORT Human Clinical
"Potential distinguishing CT features between PVOD and other subtypes of PAH include interlobular septal thickening, mediastinal lymphadenopathy, and centrilobular ground-glass opacities."
The radiology review supports ground-glass opacities as part of the differentiating CT pattern.
Mediastinal lymphadenopathy
Show evidence (1 reference)
PMID:31178067 SUPPORT Human Clinical
"Potential distinguishing CT features between PVOD and other subtypes of PAH include interlobular septal thickening, mediastinal lymphadenopathy, and centrilobular ground-glass opacities."
The radiology review supports mediastinal lymphadenopathy as a distinguishing CT feature.
🧬

Genetic Associations

1
EIF2AK4 (Biallelic pathogenic EIF2AK4 variants cause heritable PVOD/PCH and may also identify patients clinically classified as PAH who have PVOD/PCH biology.)
Autosomal recessive inheritance
Show evidence (5 references)
PMID:24292273 SUPPORT Human Clinical
"recessive mutations in EIF2AK4 (also called GCN2) that cosegregated with PVOD in all 13 families studied"
This founding study established EIF2AK4 as a causal recessive PVOD gene.
PMID:24292273 SUPPORT Human Clinical
"biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD"
Biallelic EIF2AK4 variants were also observed in sporadic histologically confirmed PVOD.
PMID:28972005 SUPPORT Human Clinical
"Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation."
EIF2AK4 testing can reclassify PAH-labeled patients and alter management.
+ 2 more references
💊

Treatments

3
Lung transplantation
Action: organ transplantation MAXO:0010039
Lung transplantation is the only established curative option for eligible patients, so early referral is emphasized once PVOD/PCH is suspected.
Show evidence (2 references)
PMID:40471666 SUPPORT Human Clinical
"Lung transplantation remains the only curative treatment, with posttransplant survival rates comparable to idiopathic PAH."
This review supports transplant as the curative therapy.
PMID:38232988 SUPPORT Human Clinical
"Early referral to a lung transplant centre is essential due to the poor response to therapy when compared with other forms of PAH."
This supports early transplant-center referral.
Supportive care and early multidisciplinary management
Action: supportive care MAXO:0000950
Supportive care is used for symptom management and risk reduction while definitive transplant evaluation is pursued, especially because inappropriate PAH-specific vasodilators may be harmful.
Show evidence (1 reference)
DOI:10.3390/arm93060048 SUPPORT Human Clinical
"management strategies emphasizing early recognition, supportive care, avoidance of inappropriate PAH therapies due to poor response, and timely referral for lung transplantation"
This review supports supportive care as part of PVOD management, while specific oxygen and diuretic MAXO bindings were not used because the suggested local MAXO IDs resolve to unrelated labels in this checkout.
Cautious PAH-approved pharmacotherapy as bridge or individualized care
Action: Pharmacotherapy NCIT:C15986
PAH-approved pulmonary vasodilator therapy is not reliably effective in PVOD/PCH and can precipitate pulmonary edema, so it requires expert-center monitoring and individualized risk assessment.
Show evidence (2 references)
PMID:40471666 PARTIAL Human Clinical
"Initiation of PAH-approved drugs in patients with PVOD requires careful consideration due to limited evidence of long-term clinical benefits and the high risk of developing pulmonary oedema in this population."
This supports only cautious, individualized pharmacotherapy rather than routine disease-modifying use.
PMID:40104258 PARTIAL Human Clinical
"The development of pulmonary oedema with pulmonary vasodilator therapy limits therapeutic options for PVOD."
The clinical review supports pulmonary edema risk as a limiting factor for vasodilator therapy.
🌍

Environmental Factors

2
Organic solvent exposure
Occupational organic solvent exposure, particularly trichloroethylene, is a reported environmental risk factor for PVOD.
Show evidence (1 reference)
PMID:40471666 SUPPORT Human Clinical
"Known risk factors include specific drug/toxin and environmental exposures, such as mitomycin C and trichloroethylene, respectively."
The review identifies trichloroethylene as an environmental exposure associated with PVOD.
Mitomycin C and chemotherapy exposure
Chemotherapy exposure, notably mitomycin C, is a reported iatrogenic risk factor for PVOD.
Show evidence (1 reference)
PMID:38232988 SUPPORT Human Clinical
"Environmental risk factors have been associated with the development of PVOD, such as occupational exposure to organic solvents and chemotherapy, notably mitomycin."
This review supports chemotherapy, especially mitomycin, as an associated exposure.
🔬

Clinical Trials

1
NCT03902353 NOT_APPLICABLE UNKNOWN
DELPHI-4 is a diagnostic/screening study of adults carrying heterozygous EIF2AK4 variants, using clinical, functional, echocardiographic, radiologic, and exercise testing to assess early PVOD risk.
Show evidence (1 reference)
clinicaltrials:NCT03902353 SUPPORT Human Clinical
"It appears essential to determine the clinical, functional, echocardiographic and radiologics characteristics of these persons, and their risk of developping Pulmonary veino occlusive disease"
ClinicalTrials.gov describes a PVOD-focused screening study for heterozygous EIF2AK4 carriers.
{ }

Source YAML

click to show 
name: Pulmonary Veno-Occlusive Disease and/or Pulmonary Capillary Haemangiomatosis
creation_date: "2026-05-06T17:25:51Z"
updated_date: "2026-05-06T17:25:51Z"
description: >-
  Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
  (PVOD/PCH) is a rare pulmonary arterial hypertension spectrum disorder with
  overt pulmonary venous and capillary involvement. It is characterized by
  progressive pulmonary venous and capillary remodeling, impaired gas exchange,
  increased pulmonary vascular resistance, and risk of right ventricular failure.
category: Cardiovascular Disorder
disease_term:
  preferred_term: pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
  term:
    id: MONDO:0018554
    label: pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
parents:
- Pulmonary arterial hypertension
- Respiratory system disorder
synonyms:
- PVOD and/or PCH
- PVOD/PCH
- Pulmonary veno-occlusive disease
- Pulmonary capillary haemangiomatosis
- Pulmonary capillary hemangiomatosis
prevalence:
- population: Global
  percentage: Ultra-rare
  notes: >-
    PVOD/PCH is repeatedly described as a rare cause or subtype of pulmonary
    arterial hypertension; exact population prevalence estimates remain limited.
  evidence:
  - reference: PMID:38232988
    reference_title: "Pulmonary veno-occlusive disease: illustrative cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      rare cause of PAH characterised by substantial small pulmonary vein and capillary involvement
    explanation: >-
      This recent review supports PVOD/PCH as a rare PAH-associated disease.
progression:
- phase: Progressive pulmonary vascular disease
  notes: >-
    The disease often progresses rapidly with severe hypoxemia, right ventricular
    failure, poor response to conventional PAH therapy, and need for early
    transplant referral.
  evidence:
  - reference: PMID:40471666
    reference_title: "Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PVOD is a progressive and fatal disease requiring early recognition and specific management.
    explanation: >-
      This review summarizes the progressive and high-risk clinical course.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: INCOMPLETE
  description: >-
    Heritable PVOD/PCH is caused by biallelic EIF2AK4 pathogenic variants and
    follows autosomal recessive inheritance with nearly complete, but not
    literally complete, penetrance in current clinical reviews.
  evidence:
  - reference: PMID:40471666
    reference_title: "Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hereditary autosomal recessive condition with biallelic eukaryotic translation initiation factor 2 alpha kinase 4
    explanation: >-
      The review directly identifies autosomal recessive inheritance due to
      biallelic EIF2AK4 variants.
pathophysiology:
- name: Pulmonary venous and capillary remodeling
  description: >-
    PVOD/PCH involves small pulmonary veins, venules, and capillaries rather
    than isolated arterial remodeling, leading to increased pulmonary vascular
    resistance and right ventricular strain.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  locations:
  - preferred_term: pulmonary vein
    term:
      id: UBERON:0002016
      label: pulmonary vein
  - preferred_term: pulmonary venule
    term:
      id: UBERON:8600024
      label: pulmonary venule
  - preferred_term: pulmonary capillary
    term:
      id: UBERON:0016405
      label: pulmonary capillary
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24292273
    reference_title: "EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      widespread fibrous intimal proliferation of septal veins and preseptal venules
    explanation: >-
      Histologic evidence supports the pulmonary venous remodeling component.
  - reference: PMID:38232988
    reference_title: "Pulmonary veno-occlusive disease: illustrative cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      substantial small pulmonary vein and capillary involvement, leading to increased pulmonary vascular resistance and right ventricular failure
    explanation: >-
      The review connects venous/capillary involvement to pulmonary vascular
      resistance and right ventricular failure.
- name: EIF2AK4/GCN2 stress-response loss
  description: >-
    Biallelic EIF2AK4 loss impairs GCN2-mediated integrated stress-response
    signaling and provides the established genetic mechanism for heritable
    PVOD/PCH.
  genes:
  - preferred_term: EIF2AK4
    term:
      id: hgnc:19687
      label: EIF2AK4
  biological_processes:
  - preferred_term: cellular response to amino acid starvation
    term:
      id: GO:0034198
      label: cellular response to amino acid starvation
    modifier: DECREASED
  - preferred_term: response to amino acid starvation
    term:
      id: GO:1990928
      label: response to amino acid starvation
    modifier: DECREASED
  evidence:
  - reference: PMID:24292273
    reference_title: "EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene.
    explanation: >-
      The founding human genetic study supports loss of EIF2AK4 function as a
      causal mechanism.
  - reference: PMID:36852942
    reference_title: T-cell dysregulation and inflammatory process in Gcn2 (Eif2ak4(-/-))-deficient rats in basal and stress conditions.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The ISR was not activated after ASNase treatment in Gcn2-/- rat lungs, and apoptosis was increased.
    explanation: >-
      Gcn2-deficient rats model impaired stress-response activation and
      stress-induced lung pathology relevant to heritable PVOD.
  - reference: PMID:29108819
    reference_title: Pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 (GCN2) in pulmonary veno-occlusive disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03)
    explanation: >-
      This supports reduced GCN2 expression beyond inherited EIF2AK4-carrier
      disease, including sporadic PVOD.
- name: Mitomycin C PKR/ISR endothelial barrier dysfunction
  description: >-
    Mitomycin C exposure can drive PVOD-like disease in rats through PKR and
    integrated stress-response activation, converging on endothelial junctional
    and barrier impairment.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: pulmonary vein
    term:
      id: UBERON:0002016
      label: pulmonary vein
  biological_processes:
  - preferred_term: integrated stress response
    modifier: INCREASED
  - preferred_term: endothelial barrier dysfunction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39269983
    reference_title: Mechanisms underlying age-associated exacerbation of pulmonary veno-occlusive disease.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mitomycin C (MMC) in rats mediates PVOD through the activation of the eukaryotic initiation factor 2 (eIF2) kinase protein kinase R (PKR) and the integrated stress response (ISR), resulting in the impairment of vascular endothelial junctional structure and barrier function.
    explanation: >-
      This experimental study supports an iatrogenic/environmental convergence
      mechanism distinct from inherited EIF2AK4 loss.
- name: Immune inflammation in EIF2AK4/GCN2 deficiency
  description: >-
    Experimental Gcn2 deficiency produces inflammatory lung signatures that may
    contribute to pulmonary vascular injury and remodeling.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:36852942
    reference_title: T-cell dysregulation and inflammatory process in Gcn2 (Eif2ak4(-/-))-deficient rats in basal and stress conditions.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Several proinflammatory and innate immunity genes were overexpressed, and inflammatory cells infiltration was also observed in the perivascular area.
    explanation: >-
      This animal model supports immune dysregulation as a plausible downstream
      consequence of GCN2 deficiency, not as a stand-alone proven human driver.
- name: Macrophage ferroptosis and venous arterialization
  description: >-
    Recent translational work implicates macrophage ferroptosis and arterial
    marker expression in venous endothelial cells as a potential mechanism of
    pulmonary venous arterialization.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: pulmonary vein
    term:
      id: UBERON:0002016
      label: pulmonary vein
  biological_processes:
  - preferred_term: ferroptosis
    term:
      id: GO:0097707
      label: ferroptosis
    modifier: INCREASED
  evidence:
  - reference: PMID:40983649
    reference_title: Macrophage ferroptosis potentiates GCN2 deficiency induced pulmonary venous arterialization.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Treatment with the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) reverses the changes in haemodynamic indices observed in Eif2ak4K1488X/K1488X hypoxia mice and PVOD model rats.
    explanation: >-
      Animal model rescue data support macrophage ferroptosis as a candidate
      targetable mechanism, while human causal relevance remains translational.
  - reference: PMID:40983649
    reference_title: Macrophage ferroptosis potentiates GCN2 deficiency induced pulmonary venous arterialization.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ferroptosis pathway-related genes are upregulated in lung macrophages of PVOD patients
    explanation: >-
      Human tissue transcriptomic evidence supports relevance of the macrophage
      ferroptosis signal in PVOD lungs.
phenotypes:
- category: Cardiovascular
  name: Pulmonary arterial hypertension
  diagnostic: true
  description: >-
    PVOD/PCH belongs to the pulmonary arterial hypertension spectrum, with
    pre-capillary pulmonary hypertension and venous/capillary involvement.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:40104258
    reference_title: "Pulmonary veno-occlusive disease: a clinical review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PVOD is classified under group 1 pulmonary arterial hypertension (PAH) as subgroup 1.5
    explanation: >-
      The clinical review supports pulmonary arterial hypertension as the
      diagnostic classification framework.
- category: Respiratory
  name: Dyspnea
  description: >-
    Dyspnea, often exertional, is a common presenting respiratory symptom in
    PVOD/PCH and may be clinically indistinguishable from PAH symptoms.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: DOI:10.1159/000527524
    reference_title: Differential Diagnosis of Pulmonary Veno-Occlusive Disease and/or Pulmonary Capillary Hemangiomatosis after Identification of Two Novel EIF2AK4 Variants by Whole-Exome Sequencing
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 19-year-old man who was previously diagnosed with idiopathic PAH suffered from dyspnea on exertion for 2 months.
    explanation: >-
      This PVOD/PCH case report supports exertional dyspnea as a presenting
      clinical feature.
- category: Respiratory
  name: Hypoxemia
  diagnostic: true
  description: >-
    Severe hypoxemia is a distinguishing clinical clue and reflects impaired gas
    exchange from venous and capillary disease.
  phenotype_term:
    preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  evidence:
  - reference: PMID:40471666
    reference_title: "Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PVOD is characterized by progressive pulmonary venous and capillary remodelling, severe hypoxemia, and right ventricular failure.
    explanation: >-
      The review explicitly lists severe hypoxemia among core PVOD features.
- category: Respiratory
  name: Decreased DLCO
  diagnostic: true
  description: >-
    Reduced lung diffusion capacity for carbon monoxide is a key noninvasive
    clue that helps distinguish PVOD/PCH from other PAH presentations.
  phenotype_term:
    preferred_term: Decreased DLCO
    term:
      id: HP:0045051
      label: Decreased DLCO
  evidence:
  - reference: PMID:40471666
    reference_title: "Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      low lung diffusion capacity for carbon monoxide (DLCO), and genetic testing can aid differentiation
    explanation: >-
      The review supports reduced DLCO as part of the diagnostic differentiation
      from PAH.
  - reference: PMID:28972005
    reference_title: Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients had a reduced transfer coefficient for carbon monoxide
    explanation: >-
      A large PAH/PVOD cohort found reduced carbon monoxide transfer in
      biallelic EIF2AK4 carriers.
- category: Cardiovascular
  name: Right ventricular failure
  description: >-
    Progressive pulmonary vascular resistance can culminate in right ventricular
    failure.
  phenotype_term:
    preferred_term: Right ventricular failure
    term:
      id: HP:0001708
      label: Right ventricular failure
  evidence:
  - reference: PMID:38232988
    reference_title: "Pulmonary veno-occlusive disease: illustrative cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leading to increased pulmonary vascular resistance and right ventricular failure
    explanation: >-
      The review links venous/capillary involvement to increased resistance and
      right ventricular failure.
- category: Treatment complication
  name: Pulmonary edema with pulmonary vasodilator therapy
  diagnostic: true
  description: >-
    Pulmonary edema after PAH vasodilator exposure is a recognized and
    clinically important clue to PVOD/PCH.
  phenotype_term:
    preferred_term: Pulmonary edema
    term:
      id: HP:0100598
      label: Pulmonary edema
  evidence:
  - reference: PMID:38232988
    reference_title: "Pulmonary veno-occlusive disease: illustrative cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Life-threatening pulmonary oedema is a complication of pulmonary vasodilator therapy that can occur with any class of PAH drugs in PVOD.
    explanation: >-
      The review supports pulmonary edema after vasodilator therapy as a major
      management risk and diagnostic clue.
- category: Imaging
  name: Interlobular septal thickening
  diagnostic: true
  description: >-
    Interlobular septal thickening is part of the characteristic chest CT
    pattern used to distinguish PVOD/PCH from other PAH forms.
  evidence:
  - reference: PMID:38232988
    reference_title: "Pulmonary veno-occlusive disease: illustrative cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chest computed tomography typically displays interlobular septal thickening, ground-glass opacities and mediastinal lymphadenopathy.
    explanation: >-
      The review directly supports this CT finding as part of the typical PVOD
      imaging pattern.
- category: Imaging
  name: Ground-glass opacities
  diagnostic: true
  description: >-
    Centrilobular ground-glass opacities are part of the typical CT pattern for
    PVOD/PCH.
  evidence:
  - reference: PMID:31178067
    reference_title: "Computed tomographic and clinical features of pulmonary veno-occlusive disease: raising the radiologist's awareness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Potential distinguishing CT features between PVOD and other subtypes of PAH include interlobular septal thickening, mediastinal lymphadenopathy, and centrilobular ground-glass opacities.
    explanation: >-
      The radiology review supports ground-glass opacities as part of the
      differentiating CT pattern.
- category: Imaging
  name: Mediastinal lymphadenopathy
  diagnostic: true
  description: >-
    Mediastinal lymphadenopathy is another CT feature that supports PVOD/PCH
    over idiopathic PAH in the right clinical context.
  evidence:
  - reference: PMID:31178067
    reference_title: "Computed tomographic and clinical features of pulmonary veno-occlusive disease: raising the radiologist's awareness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Potential distinguishing CT features between PVOD and other subtypes of PAH include interlobular septal thickening, mediastinal lymphadenopathy, and centrilobular ground-glass opacities.
    explanation: >-
      The radiology review supports mediastinal lymphadenopathy as a
      distinguishing CT feature.
histopathology:
- name: Fibrous intimal proliferation of septal veins and preseptal venules
  diagnostic: true
  description: >-
    The classic histologic lesion is fibrous intimal proliferation affecting
    septal veins and preseptal venules.
  evidence:
  - reference: PMID:24292273
    reference_title: "EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      widespread fibrous intimal proliferation of septal veins and preseptal venules
    explanation: >-
      This founding genetic study also summarizes the defining PVOD
      histopathology.
  - reference: PMID:29108819
    reference_title: Pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 (GCN2) in pulmonary veno-occlusive disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001)
    explanation: >-
      This cohort links EIF2AK4-carrier PVOD to more severe intimal fibrosis,
      refining the histopathology of heritable disease.
- name: Pulmonary capillary dilatation and proliferation
  diagnostic: true
  description: >-
    PVOD is frequently accompanied by pulmonary capillary dilatation and
    proliferation, explaining its overlap with PCH.
  evidence:
  - reference: PMID:24292273
    reference_title: "EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      frequently associated with pulmonary capillary dilatation and proliferation
    explanation: >-
      This supports the PVOD/PCH spectrum concept.
- name: Fibrous veno-occlusive lesions on explant pathology
  diagnostic: true
  description: >-
    Lung explant pathology can reveal microvascular remodeling and fibrous
    veno-occlusive lesions, but biopsy is generally avoided clinically due to
    risk in pulmonary hypertension.
  evidence:
  - reference: PMID:38232988
    reference_title: "Pulmonary veno-occlusive disease: illustrative cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathological analysis of lung explants reveals microvascular remodelling with typical fibrous veno-occlusive lesions.
    explanation: >-
      The review supports the explant histopathology pattern.
genetic:
- name: EIF2AK4
  association: >-
    Biallelic pathogenic EIF2AK4 variants cause heritable PVOD/PCH and may also
    identify patients clinically classified as PAH who have PVOD/PCH biology.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: EIF2AK4
    term:
      id: hgnc:19687
      label: EIF2AK4
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24292273
    reference_title: "EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recessive mutations in EIF2AK4 (also called GCN2) that cosegregated with PVOD in all 13 families studied
    explanation: >-
      This founding study established EIF2AK4 as a causal recessive PVOD gene.
  - reference: PMID:24292273
    reference_title: "EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD
    explanation: >-
      Biallelic EIF2AK4 variants were also observed in sporadic
      histologically confirmed PVOD.
  - reference: PMID:28972005
    reference_title: Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
    explanation: >-
      EIF2AK4 testing can reclassify PAH-labeled patients and alter management.
  - reference: PMID:38776952
    reference_title: Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Biallelic mutations of EIF2AK4, which encodes the kinase GCN2, are causal in two ultra-rare subtypes of PAH, pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis.
    explanation: >-
      Functional variant work reinforces the causal role of biallelic EIF2AK4
      variants and the importance of testing rare missense alleles.
  - reference: CGGV:assertion_9d20386c-ad1a-4c88-9f43-4ca3cedbfd6f-2022-12-02T170000.000Z
    reference_title: "EIF2AK4 / pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EIF2AK4 | HGNC:19687 | pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis | MONDO:0018554 | AR | Definitive"
    explanation: ClinGen classifies the EIF2AK4-pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis gene-disease relationship as definitive with autosomal recessive inheritance.
environmental:
- name: Organic solvent exposure
  description: >-
    Occupational organic solvent exposure, particularly trichloroethylene, is a
    reported environmental risk factor for PVOD.
  evidence:
  - reference: PMID:40471666
    reference_title: "Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Known risk factors include specific drug/toxin and environmental exposures, such as mitomycin C and trichloroethylene, respectively.
    explanation: >-
      The review identifies trichloroethylene as an environmental exposure
      associated with PVOD.
- name: Mitomycin C and chemotherapy exposure
  description: >-
    Chemotherapy exposure, notably mitomycin C, is a reported iatrogenic risk
    factor for PVOD.
  evidence:
  - reference: PMID:38232988
    reference_title: "Pulmonary veno-occlusive disease: illustrative cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Environmental risk factors have been associated with the development of PVOD, such as occupational exposure to organic solvents and chemotherapy, notably mitomycin.
    explanation: >-
      This review supports chemotherapy, especially mitomycin, as an associated
      exposure.
diagnosis:
- name: High-resolution chest computed tomography
  description: >-
    Chest CT supports noninvasive diagnosis when the characteristic pattern of
    septal thickening, ground-glass opacities, and mediastinal lymphadenopathy
    appears in a patient with pre-capillary pulmonary hypertension.
  diagnosis_term:
    preferred_term: computed tomography procedure
    term:
      id: MAXO:0000571
      label: computed tomography procedure
  evidence:
  - reference: PMID:38232988
    reference_title: "Pulmonary veno-occlusive disease: illustrative cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chest computed tomography typically displays interlobular septal thickening, ground-glass opacities and mediastinal lymphadenopathy.
    explanation: >-
      This supports the HRCT triad as a key diagnostic pattern.
- name: Pulmonary function testing for DLCO
  description: >-
    Reduced DLCO helps distinguish PVOD/PCH from other PAH presentations and
    should be interpreted alongside hypoxemia, CT findings, and hemodynamics.
  diagnosis_term:
    preferred_term: pulmonary function testing
    term:
      id: MAXO:0035078
      label: pulmonary function testing
  evidence:
  - reference: PMID:40104258
    reference_title: "Pulmonary veno-occlusive disease: a clinical review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the presence of hypoxia and reduced diffusion capacity of the lung may be required for a clinical diagnosis of PVOD
    explanation: >-
      The clinical review supports diffusion-capacity testing as part of
      clinical PVOD diagnosis.
- name: EIF2AK4 molecular genetic testing
  description: >-
    Molecular testing for biallelic EIF2AK4 variants can support or establish
    heritable PVOD/PCH diagnosis and guide family testing and transplant
    evaluation.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:28972005
    reference_title: Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
    explanation: >-
      The cohort study supports EIF2AK4 testing as a clinically actionable
      diagnostic tool.
- name: Avoidance of diagnostic lung biopsy when PVOD/PCH is suspected
  description: >-
    Lung biopsy can provide definitive histopathology but is hazardous in
    pulmonary hypertension; diagnosis is generally pursued with clinical,
    radiologic, physiologic, and genetic data.
  evidence:
  - reference: PMID:31178067
    reference_title: "Computed tomographic and clinical features of pulmonary veno-occlusive disease: raising the radiologist's awareness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lung biopsy is required for definitive diagnosis, but this is hazardous, and ideally, should be avoided in pulmonary hypertension.
    explanation: >-
      The radiology review supports avoiding lung biopsy when noninvasive
      diagnostic evidence is sufficient.
treatments:
- name: Lung transplantation
  description: >-
    Lung transplantation is the only established curative option for eligible
    patients, so early referral is emphasized once PVOD/PCH is suspected.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:40471666
    reference_title: "Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lung transplantation remains the only curative treatment, with posttransplant survival rates comparable to idiopathic PAH.
    explanation: >-
      This review supports transplant as the curative therapy.
  - reference: PMID:38232988
    reference_title: "Pulmonary veno-occlusive disease: illustrative cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early referral to a lung transplant centre is essential due to the poor response to therapy when compared with other forms of PAH.
    explanation: >-
      This supports early transplant-center referral.
- name: Supportive care and early multidisciplinary management
  description: >-
    Supportive care is used for symptom management and risk reduction while
    definitive transplant evaluation is pursued, especially because inappropriate
    PAH-specific vasodilators may be harmful.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: DOI:10.3390/arm93060048
    reference_title: "Pulmonary Veno-Occlusive Disease: A Comprehensive Review of Diagnostic Challenges, Therapeutic Limitations, and Evolving Management"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      management strategies emphasizing early recognition, supportive care, avoidance of inappropriate PAH therapies due to poor response, and timely referral for lung transplantation
    explanation: >-
      This review supports supportive care as part of PVOD management, while
      specific oxygen and diuretic MAXO bindings were not used because the
      suggested local MAXO IDs resolve to unrelated labels in this checkout.
- name: Cautious PAH-approved pharmacotherapy as bridge or individualized care
  description: >-
    PAH-approved pulmonary vasodilator therapy is not reliably effective in
    PVOD/PCH and can precipitate pulmonary edema, so it requires expert-center
    monitoring and individualized risk assessment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:40471666
    reference_title: "Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initiation of PAH-approved drugs in patients with PVOD requires careful consideration due to limited evidence of long-term clinical benefits and the high risk of developing pulmonary oedema in this population.
    explanation: >-
      This supports only cautious, individualized pharmacotherapy rather than
      routine disease-modifying use.
  - reference: PMID:40104258
    reference_title: "Pulmonary veno-occlusive disease: a clinical review."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The development of pulmonary oedema with pulmonary vasodilator therapy limits therapeutic options for PVOD.
    explanation: >-
      The clinical review supports pulmonary edema risk as a limiting factor for
      vasodilator therapy.
animal_models:
- species: Rat
  genotype: Gcn2 loss-of-function rat lines
  category: Genetic and amino-acid-deprivation stress model
  description: >-
    Biallelic Gcn2 mutant rats do not spontaneously develop full PVOD, but
    amino-acid deprivation reveals impaired lung stress-response activation,
    apoptosis, and inflammatory signatures relevant to heritable PVOD.
  associated_phenotypes:
  - Impaired integrated stress-response activation
  - Perivascular inflammatory cell infiltration
  evidence:
  - reference: PMID:36852942
    reference_title: T-cell dysregulation and inflammatory process in Gcn2 (Eif2ak4(-/-))-deficient rats in basal and stress conditions.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Three rat lines carrying biallelic Gcn2 mutation were generated and found phenotypically normal and did not spontaneously develop a PVOD-related disease.
    explanation: >-
      This model is informative for stress-response biology but is not a
      spontaneous full-disease model.
- species: Mouse and rat
  genotype: Eif2ak4K1488X/K1488X hypoxia mice and PVOD model rats
  category: GCN2-deficiency and PVOD vascular remodeling models
  description: >-
    Eif2ak4 mutant hypoxic mice, mitomycin C-treated rats, and PVOD model rats
    support stress-response, macrophage ferroptosis, and pulmonary venous
    arterialization mechanisms.
  associated_phenotypes:
  - Altered hemodynamic indices
  - Right ventricular hypertrophy
  - Endothelial barrier dysfunction
  - Pulmonary venous arterialization
  evidence:
  - reference: PMID:39269983
    reference_title: Mechanisms underlying age-associated exacerbation of pulmonary veno-occlusive disease.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      aged rats over 1 year exhibit more severe vascular remodeling and RV hypertrophy than young adult rats following MMC treatment.
    explanation: >-
      This supports the mitomycin C rat model and age-associated worsening of
      PVOD-like vascular and right ventricular phenotypes.
  - reference: PMID:40983649
    reference_title: Macrophage ferroptosis potentiates GCN2 deficiency induced pulmonary venous arterialization.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Treatment with the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) reverses the changes in haemodynamic indices observed in Eif2ak4K1488X/K1488X hypoxia mice and PVOD model rats.
    explanation: >-
      This model supports a targetable ferroptosis mechanism in experimental
      PVOD/PCH biology.
clinical_trials:
- name: NCT03902353
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: >-
    DELPHI-4 is a diagnostic/screening study of adults carrying heterozygous
    EIF2AK4 variants, using clinical, functional, echocardiographic, radiologic,
    and exercise testing to assess early PVOD risk.
  evidence:
  - reference: clinicaltrials:NCT03902353
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It appears essential to determine the clinical, functional, echocardiographic and radiologics characteristics of these persons, and their risk of developping Pulmonary veino occlusive disease
    explanation: >-
      ClinicalTrials.gov describes a PVOD-focused screening study for
      heterozygous EIF2AK4 carriers.
references:
- reference: DOI:10.1183/16000617.0156-2023
  title: "Pulmonary veno-occlusive disease: illustrative cases and literature review"
  found_in:
  - Pulmonary_Veno_Occlusive_Disease_And_Or_Pulmonary_Capillary_Haemangiomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1183/20734735.0098-2024
  title: "Pulmonary veno-occlusive disease: a clinical review"
  found_in:
  - Pulmonary_Veno_Occlusive_Disease_And_Or_Pulmonary_Capillary_Haemangiomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.18093/0869-0189-2024-34-4-595-598
  title: "Rare clinical case: pulmonary venoocclusive disease"
  found_in:
  - Pulmonary_Veno_Occlusive_Disease_And_Or_Pulmonary_Capillary_Haemangiomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1172/jci.insight.181877
  title: "Mechanisms underlying age-associated exacerbation of pulmonary veno-occlusive disease"
  found_in:
  - Pulmonary_Veno_Occlusive_Disease_And_Or_Pulmonary_Capillary_Haemangiomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3390/arm93060048
  title: "Pulmonary Veno-Occlusive Disease: A Comprehensive Review of Diagnostic Challenges, Therapeutic Limitations, and Evolving Management"
  found_in:
  - Pulmonary_Veno_Occlusive_Disease_And_Or_Pulmonary_Capillary_Haemangiomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1159/000527524
  title: "Differential Diagnosis of Pulmonary Veno-Occlusive Disease and/or Pulmonary Capillary Hemangiomatosis after Identification of Two Novel EIF2AK4 Variants by Whole-Exome Sequencing"
  found_in:
  - Pulmonary_Veno_Occlusive_Disease_And_Or_Pulmonary_Capillary_Haemangiomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.17863/cam.108223
  title: "Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension."
  found_in:
  - Pulmonary_Veno_Occlusive_Disease_And_Or_Pulmonary_Capillary_Haemangiomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1152/ajplung.00460.2021
  title: "T-cell dysregulation and inflammatory process in Gcn2 (Eif2ak4(-/-))-deficient rats in basal and stress conditions"
  found_in:
  - Pulmonary_Veno_Occlusive_Disease_And_Or_Pulmonary_Capillary_Haemangiomatosis-deep-research-falcon.md
  findings: []
review_notes: >-
  Falcon deep research was run on 2026-05-06 for this disorder. Imaging
  findings were intentionally left without HPO identifiers because repeated
  local OAK lookup did not confirm reliable HPO bindings for the suggested IDs:
  HP:0031969 resolved to Reduced blood urea nitrogen, HP:0031944 resolved to
  Pleural thickening, and HP:0030111 resolved to Reduced muscle fiber delta
  sarcoglycan. Likewise, suggested MAXO IDs for oxygen therapy, diuretic
  therapy, and lung transplantation resolved locally to unrelated labels, so
  broader validated MAXO terms were retained.
📚

References & Deep Research

References

8
DOI:10.1183/16000617.0156-2023
Pulmonary veno-occlusive disease: illustrative cases and literature review
No top-level findings curated for this source.
DOI:10.1183/20734735.0098-2024
Pulmonary veno-occlusive disease: a clinical review
No top-level findings curated for this source.
DOI:10.18093/0869-0189-2024-34-4-595-598
Rare clinical case: pulmonary venoocclusive disease
No top-level findings curated for this source.
DOI:10.1172/jci.insight.181877
Mechanisms underlying age-associated exacerbation of pulmonary veno-occlusive disease
No top-level findings curated for this source.
DOI:10.3390/arm93060048
Pulmonary Veno-Occlusive Disease: A Comprehensive Review of Diagnostic Challenges, Therapeutic Limitations, and Evolving Management
No top-level findings curated for this source.
DOI:10.1159/000527524
Differential Diagnosis of Pulmonary Veno-Occlusive Disease and/or Pulmonary Capillary Hemangiomatosis after Identification of Two Novel EIF2AK4 Variants by Whole-Exome Sequencing
No top-level findings curated for this source.
DOI:10.17863/cam.108223
Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension.
No top-level findings curated for this source.
DOI:10.1152/ajplung.00460.2021
T-cell dysregulation and inflammatory process in Gcn2 (Eif2ak4(-/-))-deficient rats in basal and stress conditions
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 40 citations 2026-05-06T13:49:08.544779

1. Disease Information

1.1 Concise overview

PVOD is an ultra‑rare pulmonary microvascular vasculopathy characterized by fibrotic obstruction/obliteration of small pulmonary veins and venules, producing pre‑capillary pulmonary hypertension, severe gas‑exchange impairment, and progressive right‑heart failure. PCH (pulmonary capillary haemangiomatosis) is characterized by prominent pulmonary capillary congestion/proliferation and is widely regarded as part of the same clinicopathologic spectrum as PVOD; the entities often coexist and are frequently grouped as PVOD/PCH. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, deshwal2025pulmonaryvenoocclusivedisease pages 2-3)

A recent authoritative ERS review explicitly frames PVOD as “pulmonary arterial hypertension (PAH) with overt features of venous/capillary involvement” and stresses that distinguishing PVOD from idiopathic PAH is critical because of poor response and risk of life‑threatening pulmonary edema with PAH vasodilators. (lechartier2024pulmonaryvenoocclusivedisease pages 1-2, lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

Direct abstract quotes (for definition/importance): - Lechartier et al. (Jan 2024) state PVOD is “a rare cause of PAH characterised by substantial small pulmonary vein and capillary involvement, leading to increased pulmonary vascular resistance and right ventricular failure.” (Published 2024‑01; https://doi.org/10.1183/16000617.0156-2023) (lechartier2024pulmonaryvenoocclusivedisease pages 1-2) - Deshwal et al. (Jan 2025) describe PVOD as “a progressive and fatal spectrum of pulmonary vascular disorders” and note PVOD and PCH “can be clinically indistinguishable and often coexist… referred to together as PVOD/PCH.” (Published 2025‑01; https://doi.org/10.1183/20734735.0098-2024) (deshwal2025pulmonaryvenoocclusivedisease pages 1-2)

1.2 Key identifiers (availability)

Not available in the retrieved full‑text evidence for this run: - MONDO ID: not retrieved - OMIM / Orphanet / ICD‑10 / ICD‑11 / MeSH IDs: not retrieved

1.3 Common synonyms / alternative names (from literature)

  • “PAH with features of venous/capillary involvement” (classification term used in ESC/ERS context) (lechartier2024pulmonaryvenoocclusivedisease pages 1-2, lechartier2024pulmonaryvenoocclusivedisease pages 5-6)
  • “PVOD/PCH” (combined term used in multiple reviews) (deshwal2025pulmonaryvenoocclusivedisease pages 1-2, deshwal2025pulmonaryvenoocclusivedisease pages 2-3)

1.4 Evidence source type

  • Aggregated disease‑level resources: ERS/European Respiratory Review and Breathe clinical reviews (lechartier2024pulmonaryvenoocclusivedisease pages 1-2, deshwal2025pulmonaryvenoocclusivedisease pages 1-2)
  • Individual patient evidence: genetic case report with compound heterozygous EIF2AK4 variants (park2023differentialdiagnosisof pages 2-3)
  • Experimental/model organism evidence: rat and mouse mechanistic models (mitomycin C; amino‑acid deprivation) including RNA‑seq/scRNA‑seq (bignard2023tcelldysregulationand pages 1-5, prabhakar2024mechanismsunderlyingageassociated pages 2-4)

2. Etiology

2.1 Disease causal factors

Genetic (causal): EIF2AK4 (GCN2) biallelic pathogenic variants cause heritable PVOD/PCH. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3, emanuelli2024functionalvalidationof pages 3-5)

Direct abstract quote (genetic causality): - Emanuelli et al. (Apr 2024) state: “Biallelic mutations of EIF2AK4… are causal in… pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis.” (Published 2024‑04; https://doi.org/10.17863/cam.108223) (emanuelli2024functionalvalidationof pages 1-3)

Environmental/iatrogenic: Epidemiologic associations include occupational exposure to organic solvents (notably trichloroethylene) and chemotherapy (notably mitomycin C and other alkylating agents). (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

2.2 Risk factors (with quantitative data)

  • Occupational organic solvents / trichloroethylene: Lechartier et al. report strong association; trichloroethylene exposure occurred in 42% of PVOD vs 3% of PAH with adjusted OR 8.2, and organic solvents overall had adjusted OR 12.8. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)
  • Chemotherapy (alkylating agents): Mitomycin C (MMC), cyclophosphamide, cisplatin are repeatedly associated; MMC has experimental support for endothelial toxicity and PVOD induction in rats. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)
  • Tobacco: Tobacco co‑exposure is common and may be additive with solvent exposure, with permeability effects. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

2.3 Protective factors

No protective genetic or environmental factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

The 2024 ERS review links solvent exposure (trichloroethylene), tobacco, and chemotherapy to endothelial permeability/barrier injury, and separately identifies EIF2AK4 (GCN2) as a stress‑response kinase—supporting a convergent model in which genetically reduced stress‑response capacity and/or environmentally induced endothelial injury contribute to PVOD/PCH pathogenesis. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

3. Phenotypes

3.1 Core clinical phenotypes (with suggested HPO terms)

PVOD/PCH cannot be reliably distinguished from idiopathic PAH on symptoms or routine hemodynamics alone; diagnostic suspicion rests on gas‑exchange impairment and imaging patterns. (deshwal2025pulmonaryvenoocclusivedisease pages 1-2, lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

Symptoms/signs - Progressive exertional dyspnea → Dyspnea (HP:0002094) (lechartier2024pulmonaryvenoocclusivedisease pages 2-3) - Hypoxemia (often disproportionate) → Hypoxemia (HP:0012418); severe resting hypoxemia highlighted as a red flag (foster2025pulmonaryvenoocclusivedisease pages 4-6) - Right‑heart failure manifestations (peripheral edema, hepatomegaly, ascites) → Peripheral edema (HP:0000969); Hepatomegaly (HP:0002240); Ascites (HP:0001541) (foster2025pulmonaryvenoocclusivedisease pages 4-6)

Pulmonary function / lab abnormalities - Markedly reduced diffusion capacity → Decreased DLCO (HP:0045051) (threshold examples below) (deshwal2025pulmonaryvenoocclusivedisease pages 8-9)

Radiology/pathology manifestations - HRCT: centrilobular ground‑glass opacities → Ground-glass opacity on pulmonary imaging (HP:0031969) - Smooth interlobular septal thickening → Interlobular septal thickening (HP:0031944) - Mediastinal lymphadenopathy → Mediastinal lymphadenopathy (HP:0030111) (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, deshwal2025pulmonaryvenoocclusivedisease pages 8-9)

3.2 Phenotype characteristics (age, severity, progression)

  • Age of onset: heritable EIF2AK4‑associated cases present younger (median 26 vs 60 years in one series) (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)
  • Course: rapid progression with poor prognosis; median survival often cited as 2–3 years after diagnosis (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

3.3 Frequencies / quantitative thresholds reported

  • Suggested clinical criteria in one review include PaO2 <70 mmHg and DLCO <55% predicted along with ≥2 HRCT features. (deshwal2025pulmonaryvenoocclusivedisease pages 8-9)
  • Another review notes DLCO often “below 40% predicted” and mean ≈35% in studies. (foster2025pulmonaryvenoocclusivedisease pages 4-6)

3.4 Quality-of-life impact

No disease‑specific QoL instrument results (e.g., SF‑36/EQ‑5D) were identified in the retrieved evidence; functional limitation is implied by severe dyspnea, hypoxemia, and CPET impairment. (deshwal2025pulmonaryvenoocclusivedisease pages 7-8)

4. Genetic / Molecular Information

4.1 Causal genes

  • EIF2AK4 (GCN2): biallelic pathogenic variants are causal for PVOD/PCH and can establish diagnosis without histology. (emanuelli2024functionalvalidationof pages 3-5, emanuelli2024functionalvalidationof pages 1-3)

4.2 Pathogenic variant examples (HGVS where available)

Case‑level PVOD/PCH genetic diagnosis (whole‑exome sequencing): - Park et al. 2023 reported compound heterozygous EIF2AK4 variants: NM_001013703.3:c.2137_2138dup (p.Ser714Leufs*78) and c.3358-1G>A, both described as absent from gnomAD; parental segregation supported biallelic inheritance. (Published 2023‑02; https://doi.org/10.1159/000527524) (park2023differentialdiagnosisof pages 2-3)

Variant spectrum and functional interpretation (2024): Emanuelli et al. 2024 list pathogenic/likely pathogenic EIF2AK4 missense examples (protein notation) including p.R585Q, p.G599R, p.V607G, p.L643R, p.S909R, p.G1109R, p.P1115L, p.H1202L, p.L1295R and also note that some alleles represent common polymorphisms (e.g., I441L, E556G, G1306C), highlighting the need for functional validation of VUS. (emanuelli2024functionalvalidationof pages 1-3)

Direct quote (diagnostic impact of biallelic EIF2AK4): - Emanuelli et al. 2024: “Detection of biallelic pathogenic EIF2AK4 mutations establishes the diagnosis of PVOD or PCH without the need for histological confirmation.” (emanuelli2024functionalvalidationof pages 3-5)

4.3 Inheritance

Autosomal recessive/biallelic inheritance is supported by: - Parent‑of‑origin segregation consistent with compound heterozygosity (Park 2023) (park2023differentialdiagnosisof pages 2-3) - Statement that PVOD due to EIF2AK4 is a “recessive form of pulmonary hypertension” (park2023differentialdiagnosisof pages 4-4)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

Not identified in the retrieved evidence.

5. Environmental Information

5.1 Environmental factors

  • Organic solvents, especially trichloroethylene (occupational exposure) (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

5.2 Lifestyle factors

  • Tobacco exposure is commonly reported and may act cumulatively with solvent exposure, potentially via permeability effects. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

5.3 Infectious agents

No specific infectious etiologies were identified in the retrieved evidence.

6. Mechanism / Pathophysiology (with causal chains and ontology suggestions)

6.1 Pathologic substrate (vascular remodeling)

PVOD is defined pathologically by diffuse fibrous thickening/obliteration of septal veins and pre‑septal venules, with characteristic involvement of small venules (<100 µm). PCH is part of the same spectrum with capillary congestion/proliferation. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

Causal chain (high‑level): Trigger(s) (biallelic EIF2AK4 loss and/or endothelial toxic exposures such as MMC/solvents) → endothelial stress response/barrier dysfunction → increased permeability, microvascular remodeling and venular obstruction → increased pulmonary vascular resistance → pre‑capillary PH → RV hypertrophy/failure and hypoxemia due to impaired gas exchange. (prabhakar2024mechanismsunderlyingageassociated pages 2-4, lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

6.2 Integrated stress response (ISR) and PKR/PP1 axis (recent 2023–2024 developments)

A key 2024 mechanistic study reports that MMC induces PVOD‑like disease in rats via activation of PKR and the integrated stress response (ISR), with sustained eIF2α phosphorylation due to reduced protein phosphatase 1 (PP1), leading to endothelial junction disruption and barrier dysfunction. (prabhakar2024mechanismsunderlyingageassociated pages 1-2, prabhakar2024mechanismsunderlyingageassociated pages 2-4)

Quantitative findings in the MMC rat model include increased RV systolic pressure and RV hypertrophy after MMC, with greater severity in aged animals; pharmacologic PKR or ISR blockade mitigated PVOD phenotypes. (prabhakar2024mechanismsunderlyingageassociated pages 2-4)

Direct abstract quote (2024): - Prabhakar et al. 2024: “We previously showed that… mitomycin C (MMC) in rats mediates PVOD through the activation of… protein kinase R (PKR) and the integrated stress response (ISR), resulting in the impairment of vascular endothelial junctional structure and barrier function.” (Published 2024‑09; https://doi.org/10.1172/jci.insight.181877) (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

GO term suggestions (processes): - Integrated stress response → GO:0140749 (integrated stress response) (conceptually aligned with eIF2α‑ATF4 pathway described) (prabhakar2024mechanismsunderlyingageassociated pages 1-2) - Regulation of endothelial barrier / permeability → GO:0035633 (maintenance of barrier function) (conceptual) (prabhakar2024mechanismsunderlyingageassociated pages 1-2) - Vascular remodeling/fibrosis → GO:0001525 (angiogenesis); GO:0045766 (positive regulation of angiogenesis) (supported by angiogenesis mentions and remodeling) (bignard2023tcelldysregulationand pages 16-19)

Cell Ontology (CL) suggestions (cell types implicated): - Pulmonary vascular endothelial cells → Endothelial cell (CL:0000115), supported by CD31+ endothelial localization of ISR markers (prabhakar2024mechanismsunderlyingageassociated pages 2-4) - T cells (LAG3+ and proliferative populations) → T cell (CL:0000084); regulatory/exhausted‑like subsets conceptually consistent with LAG3+ population (bignard2023tcelldysregulationand pages 1-5) - Neutrophils → Neutrophil (CL:0000775) (bignard2023tcelldysregulationand pages 1-5) - Macrophages/mononuclear phagocytes involved in inflammation signals (supported by infiltration language) → Macrophage (CL:0000235) (bignard2023tcelldysregulationand pages 1-5)

6.3 Immune dysregulation in EIF2AK4/GCN2 deficiency (2023)

In a 2023 rat model, Gcn2 (Eif2ak4) deficiency did not spontaneously cause PVOD but produced immune dysregulation and inflammatory signatures under metabolic stress (asparaginase‑induced amino‑acid deprivation), including expansion of specific T‑cell populations at baseline and neutrophil infiltration plus innate immune gene upregulation after stress; scRNA‑seq and RNA‑seq were used. (bignard2023tcelldysregulationand pages 1-5)

Direct abstract quote (2023): - Bignard et al. 2023: “Hereditary pulmonary veno-occlusive disease… is… due to biallelic loss-of-function of the EIF2AK4 gene… Lung mRNAS were analyzed by RNASeq and single cell RNASeq (scRNA-seq)… Under basal conditions, scRNA-seq analysis… revealed increases in two T cell populations…” (Published 2023‑05; https://doi.org/10.1152/ajplung.00460.2021) (bignard2023tcelldysregulationand pages 1-5)

6.4 Anatomical localization (UBERON suggestions)

  • Lung (primary) → lung (UBERON:0002048)
  • Pulmonary venules/small pulmonary veins (microvasculature) → pulmonary vein (UBERON:0002017) (approximate macro term; microvenules not explicitly mapped in retrieved evidence)
  • Right ventricle (secondary) → right ventricle (UBERON:0002080) (supported by RV hypertrophy/failure) (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

7. Anatomical Structures Affected

7.1 Organ level

  • Primary: lung microvasculature (pulmonary venules/veins and capillary bed) (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)
  • Secondary: right ventricle/right heart due to increased pulmonary vascular resistance (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

7.2 Tissue/cell level

  • Vascular endothelium (CD31+ endothelial cells implicated in ISR signaling) (prabhakar2024mechanismsunderlyingageassociated pages 2-4)
  • Perivascular inflammatory infiltrates (T cells and neutrophils highlighted in Gcn2 deficiency models) (bignard2023tcelldysregulationand pages 1-5)

7.3 Subcellular level (GO cellular component suggestions)

Not directly specified in retrieved evidence; however, ISR signaling implies involvement of cytosolic translation machinery and stress‑kinase signaling complexes.

8. Temporal Development

8.1 Onset

  • Broad: children/young adults to older ages; EIF2AK4 carriers present younger (median 26 vs 60 years in one series). (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

8.2 Progression / stages

PVOD/PCH is described as rapidly progressive with poor prognosis; quantitative endpoints reported include time from diagnosis to death/transplant and 1‑year mortality. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

9. Inheritance and Population

9.1 Epidemiology

  • Incidence ~0.1–0.5 per million/year; prevalence ~1–2 per million (rare). (lechartier2024pulmonaryvenoocclusivedisease pages 1-2)

9.2 Inheritance

  • EIF2AK4‑associated PVOD/PCH is recessive/biallelic (compound heterozygous or homozygous), supported by segregation in Park 2023 and explicit “recessive form” statement. (park2023differentialdiagnosisof pages 2-3, park2023differentialdiagnosisof pages 4-4)

9.3 Demographics

  • In one cohort description, EIF2AK4 carriers had a near‑equal sex ratio and younger age. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

10. Diagnostics

10.1 Clinical tests and biomarkers

Hemodynamics (gold standard for PH diagnosis): pre‑capillary PH with mPAP >20 mmHg, PAWP/PCWP ≤15 mmHg, PVR >2 WU. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3, deshwal2025pulmonaryvenoocclusivedisease pages 8-9)

Pulmonary function: reduced DLCO is a key clue (e.g., <55% predicted in one suggested clinical pattern). (deshwal2025pulmonaryvenoocclusivedisease pages 8-9)

10.2 Imaging

HRCT diagnostic triad: centrilobular ground‑glass opacities + smooth interlobular septal thickening + mediastinal lymphadenopathy; parenchymal changes may precede overt PH. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

10.3 Genetic testing

Genetic testing for EIF2AK4 is recommended in suggestive cases; biallelic pathogenic variants can confirm heritable PVOD/PCH without histology. (lechartier2024pulmonaryvenoocclusivedisease pages 5-6, emanuelli2024functionalvalidationof pages 3-5)

10.4 Biopsy and procedure risk

ESC/ERS‑referenced guidance emphasizes clinical‑radiologic diagnosis and recommends against lung biopsy for confirmation. (lechartier2024pulmonaryvenoocclusivedisease pages 5-6, lechartier2024pulmonaryvenoocclusivedisease media a49a6475)

10.5 Differential diagnosis

Differential diagnoses include idiopathic PAH, ILD‑associated PH, and CTEPH (with V/Q scanning as key screen for CTEPH). (foster2025pulmonaryvenoocclusivedisease pages 10-12, deshwal2025pulmonaryvenoocclusivedisease pages 7-8)

11. Outcome / Prognosis

PVOD/PCH carries a very poor prognosis: - 1‑year mortality ~72% and mean time from diagnosis to death/transplant 11.8 months (lechartier2024pulmonaryvenoocclusivedisease pages 3-5) - Median survival often reported as 2–3 years after diagnosis (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

A major adverse management outcome is pulmonary edema precipitated by PAH vasodilators, reported as >20% in a cohort and ~30/64 in a systematic review summarized in a clinical review. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, deshwal2025pulmonaryvenoocclusivedisease pages 9-10)

12. Treatment

12.1 Supportive care (real‑world standard)

  • Supplemental oxygen and diuretics are commonly recommended supportive measures. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)
  • Routine anticoagulation is not recommended unless another indication exists. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, foster2025pulmonaryvenoocclusivedisease pages 10-12)

MAXO suggestions: - Oxygen therapy → MAXO:0000861 (oxygen therapy) (conceptual) - Diuretic therapy → MAXO:0000930 (diuretic therapy) (conceptual)

12.2 PAH‑targeted therapies (caution)

PAH‑approved drugs “may be considered with careful monitoring of clinical symptoms and gas exchange” in guideline‑summarized recommendations, reflecting risk–benefit uncertainty; pulmonary edema can occur with any PAH drug class and can be life‑threatening. (lechartier2024pulmonaryvenoocclusivedisease pages 5-6, lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

  • Pulmonary edema incidence: >20% in a large cohort summary; systematic review summary indicates ~30/64 with edema; older series suggest 20–50% with PAH therapies and ~70% with calcium channel blockers. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, deshwal2025pulmonaryvenoocclusivedisease pages 9-10)

MAXO suggestions: - Pulmonary vasodilator therapy → MAXO:0001298 (vasodilator therapy) (conceptual)

12.3 Definitive therapy

Bilateral lung transplantation is consistently described as the definitive/curative option; early referral to a transplant center is emphasized due to rapid progression. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, lechartier2024pulmonaryvenoocclusivedisease pages 1-2)

MAXO suggestion: - Lung transplantation → MAXO:0000602 (lung transplantation) (conceptual)

12.4 Emerging/experimental (mechanism‑based)

Recent mechanistic work suggests that pharmacologic blockade of PKR/ISR pathways can mitigate disease phenotypes in MMC models, supporting investigational therapeutic directions; this is preclinical/experimental. (prabhakar2024mechanismsunderlyingageassociated pages 2-4)

13. Prevention

No established primary prevention strategies were identified in the retrieved evidence. Practical prevention in high‑risk contexts is best framed as: - Avoidance/mitigation of exposures (occupational solvents; high‑risk chemotherapies when alternatives exist) consistent with risk association evidence. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3) - Genetic counseling and cascade testing in families with EIF2AK4‑associated disease. (lechartier2024pulmonaryvenoocclusivedisease pages 1-2)

14. Other Species / Natural Disease

Not identified in the retrieved evidence.

15. Model Organisms

15.1 Genetic models

  • Gcn2 (Eif2ak4)‑deficient rats: phenotypically normal at baseline but show immune/inflammatory dysregulation under amino‑acid deprivation, analyzed with bulk RNA‑seq and scRNA‑seq. (bignard2023tcelldysregulationand pages 1-5)

15.2 Induced models

  • Mitomycin C (MMC) rat model: induces PVOD‑like remodeling via PKR/ISR activation; aged rats show more severe remodeling and RV hypertrophy. (prabhakar2024mechanismsunderlyingageassociated pages 1-2, prabhakar2024mechanismsunderlyingageassociated pages 2-4)

15.3 Model limitations

Gcn2‑deficient rats did not spontaneously develop PVOD, suggesting additional triggers/factors are required to reproduce human disease fully. (bignard2023tcelldysregulationand pages 1-5)

Current applications / real-world implementations (registries and carrier screening)

Clinical implementation is active in longitudinal registries and carrier surveillance: - NCT03902353 (2019; ClinicalTrials.gov): screening of heterozygous EIF2AK4 carriers using CT, DLCO, echo, CPET, and biomarkers to identify early abnormalities and predictors of PVOD development. (NCT03902353 chunk 1) - NCT03169010 (2017; ClinicalTrials.gov): long‑term rare pulmonary hypertension registry explicitly including PVOD and PCH with planned sequencing/biobank and survival/transplant outcomes. (NCT03169010 chunk 1) - NCT01907295 (2014; ClinicalTrials.gov): UK national cohort/biorepository including PVOD/PCH, deep phenotyping, and next‑generation sequencing for natural history and predictors. (NCT01907295 chunk 1)

Visual evidence (guideline table)

The ESC/ERS 2022 PVOD/PCH recommendation summary table (diagnosis based on clinical+radiologic findings, lung biopsy not recommended, PAH drugs may be considered with careful monitoring) was retrieved as an image from Lechartier et al. 2024. (lechartier2024pulmonaryvenoocclusivedisease media a49a6475)

Expert synthesis (authoritative interpretation grounded in cited sources)

1) PVOD/PCH is best approached as a distinct PAH spectrum disorder with venous/capillary involvement, where accurate early identification matters because common PAH vasodilator strategies can be dangerous (pulmonary edema) and the therapeutic window for transplant referral is short. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, lechartier2024pulmonaryvenoocclusivedisease pages 1-2)

2) Genetic confirmation is increasingly central: biallelic EIF2AK4 pathogenic variants can establish diagnosis without lung biopsy, enabling family testing and earlier care pathway decisions (e.g., transplant evaluation, exposure avoidance). (emanuelli2024functionalvalidationof pages 3-5, park2023differentialdiagnosisof pages 2-3)

3) 2023–2024 mechanistic advances converge on stress-response and barrier biology (ISR/PKR/PP1 axis; endothelial junction disruption) and suggest tractable therapeutic targets, but these remain preclinical and not yet standard of care. (prabhakar2024mechanismsunderlyingageassociated pages 2-4)

URLs and publication dates (key sources used)

  • Lechartier B. et al. 2024‑01. European Respiratory Review. https://doi.org/10.1183/16000617.0156-2023 (lechartier2024pulmonaryvenoocclusivedisease pages 1-2)
  • Park J.E. et al. 2023‑02. Molecular Syndromology. https://doi.org/10.1159/000527524 (park2023differentialdiagnosisof pages 2-3)
  • Prabhakar A. et al. 2024‑09. JCI Insight. https://doi.org/10.1172/jci.insight.181877 (prabhakar2024mechanismsunderlyingageassociated pages 1-2)
  • Bignard J. et al. 2023‑05. AJP-Lung. https://doi.org/10.1152/ajplung.00460.2021 (bignard2023tcelldysregulationand pages 1-5)
  • Emanuelli G. et al. 2024‑04. https://doi.org/10.17863/cam.108223 (emanuelli2024functionalvalidationof pages 1-3)

Limitations of this report (evidence availability)

  • Standard identifiers (OMIM/Orphanet/ICD/MeSH/MONDO) and some phenotype frequency statistics were not present in the retrieved corpus for this run; the report therefore focuses on high‑confidence clinical, genetic, imaging, mechanistic, and guideline‑linked evidence available in the provided texts. (lechartier2024pulmonaryvenoocclusivedisease pages 1-2, deshwal2025pulmonaryvenoocclusivedisease pages 1-2)

References

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  9. (foster2025pulmonaryvenoocclusivedisease pages 4-6): Brian Foster, Sikandar Khan, Ana Suarez Gonzalez, and Samantha Gillenwater. Pulmonary veno-occlusive disease: a comprehensive review of diagnostic challenges, therapeutic limitations, and evolving management. Advances in Respiratory Medicine, 93:48, Oct 2025. URL: https://doi.org/10.3390/arm93060048, doi:10.3390/arm93060048. This article has 2 citations.

  10. (lechartier2024pulmonaryvenoocclusivedisease pages 5-6): Benoit Lechartier, Athénaïs Boucly, Sabina Solinas, Deepa Gopalan, Peter Dorfmüller, Teodora Radonic, Olivier Sitbon, and David Montani. Pulmonary veno-occlusive disease: illustrative cases and literature review. European Respiratory Review, 33:230156, Jan 2024. URL: https://doi.org/10.1183/16000617.0156-2023, doi:10.1183/16000617.0156-2023. This article has 28 citations and is from a peer-reviewed journal.

  11. (lechartier2024pulmonaryvenoocclusivedisease media a49a6475): Benoit Lechartier, Athénaïs Boucly, Sabina Solinas, Deepa Gopalan, Peter Dorfmüller, Teodora Radonic, Olivier Sitbon, and David Montani. Pulmonary veno-occlusive disease: illustrative cases and literature review. European Respiratory Review, 33:230156, Jan 2024. URL: https://doi.org/10.1183/16000617.0156-2023, doi:10.1183/16000617.0156-2023. This article has 28 citations and is from a peer-reviewed journal.

  12. (park2023differentialdiagnosisof pages 2-3): Jong Eun Park, Sung-A Chang, Shin Yi Jang, Kyung Soo Lee, Duk-Kyung Kim, and Chang-Seok Ki. Differential diagnosis of pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis after identification of two novel eif2ak4 variants by whole-exome sequencing. Molecular Syndromology, 14:254-257, Feb 2023. URL: https://doi.org/10.1159/000527524, doi:10.1159/000527524. This article has 6 citations and is from a peer-reviewed journal.

  13. (park2023differentialdiagnosisof pages 1-2): Jong Eun Park, Sung-A Chang, Shin Yi Jang, Kyung Soo Lee, Duk-Kyung Kim, and Chang-Seok Ki. Differential diagnosis of pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis after identification of two novel eif2ak4 variants by whole-exome sequencing. Molecular Syndromology, 14:254-257, Feb 2023. URL: https://doi.org/10.1159/000527524, doi:10.1159/000527524. This article has 6 citations and is from a peer-reviewed journal.

  14. (emanuelli2024functionalvalidationof pages 3-5): Giulia Emanuelli, JiaYi Zhu, Wei Li, Nicholas W Morrell, and Stefan J Marciniak. Functional validation of eif2ak4 (gcn2) missense variants associated with pulmonary arterial hypertension. JournalArticle, Apr 2024. URL: https://doi.org/10.17863/cam.108223, doi:10.17863/cam.108223. This article has 14 citations.

  15. (emanuelli2024functionalvalidationof pages 1-3): Giulia Emanuelli, JiaYi Zhu, Wei Li, Nicholas W Morrell, and Stefan J Marciniak. Functional validation of eif2ak4 (gcn2) missense variants associated with pulmonary arterial hypertension. JournalArticle, Apr 2024. URL: https://doi.org/10.17863/cam.108223, doi:10.17863/cam.108223. This article has 14 citations.

  16. (prabhakar2024mechanismsunderlyingageassociated pages 2-4): Amit Prabhakar, Meetu Wadhwa, Rahul Kumar, Prajakta Ghatpande, Aneta Gandjeva, Rubin M. Tuder, Brian B. Graham, Giorgio Lagna, and Akiko Hata. Mechanisms underlying age-associated exacerbation of pulmonary veno-occlusive disease. JCI Insight, Sep 2024. URL: https://doi.org/10.1172/jci.insight.181877, doi:10.1172/jci.insight.181877. This article has 7 citations and is from a domain leading peer-reviewed journal.

  17. (bignard2023tcelldysregulationand pages 1-5): Juliette Bignard, Fabrice Atassi, Olivier Claude, Maria-Rosa Ghigna, Nathalie Mougenot, Bahgat Soilih Abdoulkarim, Florence Deknuydt, Aurélie Gestin, Virginie Monceau, David Montani, Sophie Nadaud, Florent Soubrier, and Frédéric Perros. T-cell dysregulation and inflammatory process in gcn2 (eif2ak4−/−)-deficient rats in basal and stress conditions. American Journal of Physiology-Lung Cellular and Molecular Physiology, 324:L609-L624, May 2023. URL: https://doi.org/10.1152/ajplung.00460.2021, doi:10.1152/ajplung.00460.2021. This article has 5 citations.

  18. (bignard2023tcelldysregulationand pages 16-19): Juliette Bignard, Fabrice Atassi, Olivier Claude, Maria-Rosa Ghigna, Nathalie Mougenot, Bahgat Soilih Abdoulkarim, Florence Deknuydt, Aurélie Gestin, Virginie Monceau, David Montani, Sophie Nadaud, Florent Soubrier, and Frédéric Perros. T-cell dysregulation and inflammatory process in gcn2 (eif2ak4−/−)-deficient rats in basal and stress conditions. American Journal of Physiology-Lung Cellular and Molecular Physiology, 324:L609-L624, May 2023. URL: https://doi.org/10.1152/ajplung.00460.2021, doi:10.1152/ajplung.00460.2021. This article has 5 citations.

  19. (deshwal2025pulmonaryvenoocclusivedisease pages 9-10): Himanshu Deshwal, Sauradeep Sarkar, Atreyee Basu, and Bilal A. Jalil. Pulmonary veno-occlusive disease: a clinical review. Breathe, 21:240098, Jan 2025. URL: https://doi.org/10.1183/20734735.0098-2024, doi:10.1183/20734735.0098-2024. This article has 4 citations.

  20. (foster2025pulmonaryvenoocclusivedisease pages 10-12): Brian Foster, Sikandar Khan, Ana Suarez Gonzalez, and Samantha Gillenwater. Pulmonary veno-occlusive disease: a comprehensive review of diagnostic challenges, therapeutic limitations, and evolving management. Advances in Respiratory Medicine, 93:48, Oct 2025. URL: https://doi.org/10.3390/arm93060048, doi:10.3390/arm93060048. This article has 2 citations.

  21. (NCT03902353 chunk 1): Screening of Pulmonary Veino Occlusive Disease in Heterozygous EIF2AK4 Mutation Carriers. Assistance Publique - Hôpitaux de Paris. 2019. ClinicalTrials.gov Identifier: NCT03902353

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  24. (park2023differentialdiagnosisof pages 4-4): Jong Eun Park, Sung-A Chang, Shin Yi Jang, Kyung Soo Lee, Duk-Kyung Kim, and Chang-Seok Ki. Differential diagnosis of pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis after identification of two novel eif2ak4 variants by whole-exome sequencing. Molecular Syndromology, 14:254-257, Feb 2023. URL: https://doi.org/10.1159/000527524, doi:10.1159/000527524. This article has 6 citations and is from a peer-reviewed journal.