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2.
Biomolecules ; 12(12)2022 12 14.
Article in English | MEDLINE | ID: mdl-36551306

ABSTRACT

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast to PAH, PVOD is characterized by a particular remodeling of the pulmonary venous system and the obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation. The pathobiological knowledge of PVOD is poor, explaining the absence of medical therapy for PVOD. Lung transplantation remains the only therapy for eligible PVOD patients. As we recently demonstrated, respiratory diseases, chronic obstructive pulmonary disease, or cystic fibrosis exhibit lipointoxication signatures characterized by excessive levels of saturated phospholipids contributing to the pathological features of these diseases, including endoplasmic reticulum stress, pro-inflammatory cytokines production, and bronchoconstriction. In this study, we investigated and compared the clinical data and lung lipid signature of control (10 patients), idiopathic PAH (7 patients), heritable PAH (9 BMPR2 mutations carriers), hPVOD (10 EIF2AK4 mutation carriers), and sPVOD (6 non-carriers) subjects. Mass spectrometry analyses demonstrated lung lipointoxication only in hPVOD patients, characterized by an increased abundance of saturated phosphatidylcholine (PC) at the expense of the polyunsaturated species in the lungs of hPVOD patients. The present data suggest that lipointoxication could be a potential player in the etiology of PVOD.


Subject(s)
Pulmonary Arterial Hypertension , Pulmonary Veno-Occlusive Disease , Humans , Lipidomics , Lung/pathology , Protein Serine-Threonine Kinases/genetics , Pulmonary Arterial Hypertension/pathology , Pulmonary Veins , Pulmonary Veno-Occlusive Disease/genetics , Pulmonary Veno-Occlusive Disease/pathology
3.
Int J Mol Sci ; 23(18)2022 Sep 09.
Article in English | MEDLINE | ID: mdl-36142358

ABSTRACT

BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH is not well known and genetics could influence management and prognosis. OBJECTIVES: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. METHODS: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan-Meier curves. RESULTS: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease-PVOD-in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders-MSD-in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was "reclassified", with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. CONCLUSIONS: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.


Subject(s)
Pulmonary Arterial Hypertension , Pulmonary Veno-Occlusive Disease , Child , Familial Primary Pulmonary Hypertension/genetics , Genetic Background , Humans , Pulmonary Arterial Hypertension/genetics , Pulmonary Veno-Occlusive Disease/pathology , Registries
4.
Lung ; 200(2): 217-219, 2022 04.
Article in English | MEDLINE | ID: mdl-35253092

ABSTRACT

Pulmonary capillary hemangiomatosis (PCH) is an uncommon type of pulmonary vascular disease characterized by capillary proliferation and very poor prognosis owing to misdiagnosis and lack of effective therapeutic options. Mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have been reported in pulmonary veno-occlusive disease and PCH. In this report, we present a patient whose diagnosis of PCH was delayed by 2 ½ years despite prior surgical lung biopsy and clinical and laboratory findings suggestive of pulmonary hypertension. Genotyping revealed a novel likely pathogenic variant in the EIF2AK4 gene. Review of surgical lung biopsy performed 2 ½ years prior confirmed PCH histology along with constrictive bronchiolitis.


Subject(s)
Hemangioma, Capillary , Hypertension, Pulmonary , Lung Diseases , Pulmonary Veno-Occlusive Disease , Hemangioma, Capillary/diagnosis , Hemangioma, Capillary/genetics , Hemangioma, Capillary/pathology , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/genetics , Lung/diagnostic imaging , Lung/pathology , Lung/surgery , Protein Serine-Threonine Kinases , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/genetics , Pulmonary Veno-Occlusive Disease/pathology
5.
Acta Clin Belg ; 77(3): 697-702, 2022 Jun.
Article in English | MEDLINE | ID: mdl-34191691

ABSTRACT

Pulmonary veno-occlusive disease (PVOD) represents a rare and challenging form of pulmonary hypertension, characterized by preferential remodelling of the pulmonary venules. PVOD may be idiopathic as well as related to other conditions with environmental and genetic factors contributing to its development. Recently, bi-allelic mutations in the EIF2AK4-gene have been identified as a cause of heritable PVOD. PVOD shares an overlapping disease phenotype with pulmonary arterial hypertension (PAH) and is regularly misdiagnosed as such, although differentiation between these two conditions is important because of the different prognosis and therapeutic approach. The diagnosis of PVOD is frequently delayed because of the complex diagnostic process. The gold standard remains histology with widespread obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation as the pathological hallmark. At present, neither treatment guidelines nor curative medical therapies are available for PVOD. Because of the progressive nature of the disease, a quick referral for lung transplantation remains the only definitive therapy in subjects below the age of 65.


Subject(s)
Hematopoietic Stem Cell Transplantation , Hypertension, Pulmonary , Lung Transplantation , Pulmonary Veno-Occlusive Disease , Familial Primary Pulmonary Hypertension , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Hypertension, Pulmonary/genetics , Lung Transplantation/adverse effects , Protein Serine-Threonine Kinases , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/etiology , Pulmonary Veno-Occlusive Disease/pathology
6.
Int Heart J ; 62(5): 1186-1190, 2021.
Article in English | MEDLINE | ID: mdl-34588408

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease with obstructed airflow and frequently causes secondary mild-moderate pulmonary hypertension (PH). However, a low proportion (1%-5%) of COPD patients develop severe therapy-resistant PH, and it is crucial to determine whether the patient has another disease capable of causing severe PH, including pulmonary arterial hypertension.Here, we describe a case of a 71-year-old male with COPD complicated by severe PH and right heart failure. He had a history of heavy smoking and developed progressive hypoxemia on exertion. He had severe airflow limitation (forced expiratory volume % in one second, FEV 1.0% = 42.8%) with a markedly reduced diffusing capacity of the lung (predicted diffusion capacity of carbon monoxide, %DLCO = 29%), and high-resolution computed tomography (CT) demonstrated significant lung parenchymal abnormalities such as diffuse interlobular septal thickening, ground-glass opacities, and enlarged mediastinal lymph nodes. He was diagnosed with group 3 PH caused by COPD but resistant to the treatment of COPD, diuretics, and oxygen therapy. Pathohistological analysis of autopsy specimens revealed the coexistence of interstitial fibrosis and partial occlusion of the small intrapulmonary veins, which led to a conclusive diagnosis of pulmonary veno-occlusive disease (PVOD).Because of its rarity and similarity with idiopathic pulmonary arterial hypertension, PVOD is difficult to diagnose antemortem and has a poor prognosis. High-resolution CT findings (septal thickening, ground glass, and enlarged lymph nodes) and severely reduced DLCO should be carefully evaluated for the early detection and treatment of PVOD in COPD patients with severe PH.


Subject(s)
Hypertension, Pulmonary/complications , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Veno-Occlusive Disease/complications , Aged , Autopsy , Humans , Hypertension, Pulmonary/pathology , Male , Pulmonary Disease, Chronic Obstructive/pathology , Pulmonary Veno-Occlusive Disease/pathology , Severity of Illness Index
7.
Pathol Res Pract ; 216(9): 153100, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32825965

ABSTRACT

BACKGROUND: Pulmonary capillary hemangiomatosis (PCH) is a very rare and refractory pulmonary vascular disease that causes pulmonary hypertension. Differentiation of PCH from idiopathic pulmonary arterial hypertension (iPAH) is essential because treatment and prognosis can vary greatly between these two diseases. CASE PRESENTATION: A 20-year-old female and a 33-year-old male both presented with progressive exertional dyspnea and cough. High-resolution computed tomography (HRCT) showed bilateral, diffuse, ill-defined centrilobular nodules of ground-glass opacity, without subpleural thickened septal lines or mediastinal lymphadenopathy. Both cases showed clinical and imaging features characteristic of pulmonary veno-occlusive disease (PVOD) or PCH. The entire EIF2AK4 coding sequence was detected with Sanger sequencing, and no pathogenic EIF2AK4 mutations were identified in either case. Video-assisted thoracoscopic surgery (VATS) was safely performed in both cases, and histopathological examinations of biopsies showed that both patients had PCH. CONCLUSION: Two patients presented with clinical and imaging characteristics suspicious for PVOD/PCH. Despite having no pathogenic EIF2AK4 mutations, both were diagnosed with PCH by VATS lung biopsies. The diagnostic distinction of PCH is important to prompt timely evaluations of patients who may need lung transplantations.


Subject(s)
Hemangioma, Capillary/genetics , Hemangioma, Capillary/pathology , Lung Neoplasms/pathology , Protein Serine-Threonine Kinases/genetics , Asian People , Diagnosis, Differential , Female , Hemangioma, Capillary/diagnosis , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/physiopathology , Lung/pathology , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/genetics , Pulmonary Veno-Occlusive Disease/pathology , Young Adult
8.
Eur Respir Rev ; 29(156)2020 Jun 30.
Article in English | MEDLINE | ID: mdl-32461209

ABSTRACT

Pulmonary capillary haemangiomatosis (PCH) is a rare and incompletely understood histopathological finding characterised by abnormal capillary proliferation within the alveolar interstitium, which has long been noted to share many overlapping features with pulmonary veno-occlusive disease (PVOD). But are PCH and PVOD distinct entities that occur in isolation, or are they closely intertwined manifestations along a spectrum of the same disease? The classic clinical features of both PCH and PVOD include signs and symptoms related to pulmonary hypertension, hypoxaemia, markedly impaired diffusion capacity of the lung and abnormal chest imaging with ground glass opacities, septal lines and lymphadenopathy. In recent years, increasing evidence suggests that the clinical presentation, histopathological features, genetic substrate and pathobiological mechanisms of PCH and PVOD are overlapping and usually indistinguishable. The discovery of biallelic mutations in the eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) gene in heritable PCH and PVOD greatly advanced our understanding of the overlapping nature of these conditions. Furthermore, recognition of PCH and PVOD-like changes in other pulmonary vascular diseases and in conditions that cause chronic pulmonary venous hyper-perfusion or hypertension suggests that PCH/PVOD may develop as a reactive process to various insults or injuries to the pulmonary vasculature, rather than being primary angiogenic disorders.


Subject(s)
Capillaries/pathology , Hemangioma, Capillary/pathology , Lung Neoplasms/pathology , Pulmonary Alveoli/blood supply , Pulmonary Arterial Hypertension/pathology , Pulmonary Veins/pathology , Pulmonary Veno-Occlusive Disease/pathology , Genetic Predisposition to Disease , Hemangioma, Capillary/genetics , Hemangioma, Capillary/therapy , Humans , Lung Neoplasms/classification , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Mutation , Phenotype , Prognosis , Pulmonary Arterial Hypertension/classification , Pulmonary Arterial Hypertension/genetics , Pulmonary Arterial Hypertension/therapy , Pulmonary Veno-Occlusive Disease/classification , Pulmonary Veno-Occlusive Disease/genetics , Pulmonary Veno-Occlusive Disease/therapy , Risk Assessment , Risk Factors , Terminology as Topic
9.
Bull Exp Biol Med ; 168(5): 699-703, 2020 Mar.
Article in English | MEDLINE | ID: mdl-32248453

ABSTRACT

The histological and immunohistochemical methods were employed to examine the peculiarities of histological structure of pulmonary veins and left atrium of the heart in norm and in various types of total anomalous drainage of pulmonary veins. In contrast to normal pulmonary vein covered with external multiple muscle layers (myocardial sleeve), such sleeve is absent in veins that have no connection with the left atrium irrespective of the type of the defect. In patients with total anomalous pulmonary venous drainage, the structure of left atrium was heterogeneous featuring either the presence or absence of inner angiomural lining in this atrium. The structural peculiarities are important for insight into etiology of the development of postoperative pulmonary venous obstruction in patients with total anomalous pulmonary venous drainage.


Subject(s)
Postoperative Complications/pathology , Pulmonary Veins/pathology , Pulmonary Veno-Occlusive Disease/pathology , Scimitar Syndrome/pathology , Scimitar Syndrome/surgery , Autopsy , Cardiac Surgical Procedures/adverse effects , Case-Control Studies , Heart Atria/pathology , Heart Atria/surgery , Humans , Infant, Newborn , Postoperative Complications/etiology , Postoperative Complications/physiopathology , Postoperative Period , Pulmonary Circulation/physiology , Pulmonary Veins/abnormalities , Pulmonary Veno-Occlusive Disease/etiology , Pulmonary Veno-Occlusive Disease/physiopathology , Scimitar Syndrome/physiopathology
10.
Am J Respir Cell Mol Biol ; 63(1): 118-131, 2020 07.
Article in English | MEDLINE | ID: mdl-32209028

ABSTRACT

Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular, and molecular levels to unravel common altered pathomechanisms. MMC exposure in rats was associated primarily with arterial and microvessel remodeling, and secondarily by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there was convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of HO-1 (heme oxygenase 1) and CHOP (CCAAT-enhancer-binding protein [C/EBP] homologous protein), two downstream effectors of GCN2 signaling and endoplasmic reticulum stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4-/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells using pharmacological and siRNA approaches demonstrated that GCN2 loss of function negatively regulates BMP (bone morphogenetic protein)-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced proliferation of pulmonary artery endothelial cells. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9, as potential therapeutic options for PVOD.


Subject(s)
Pulmonary Veno-Occlusive Disease/metabolism , Pulmonary Veno-Occlusive Disease/pathology , Animals , Disease Models, Animal , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Lung/metabolism , Lung/pathology , Mutation/genetics , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Rats , Signal Transduction/physiology , Transcription Factor CHOP/metabolism
11.
Clin Rheumatol ; 39(5): 1687-1691, 2020 May.
Article in English | MEDLINE | ID: mdl-31965379

ABSTRACT

Pulmonary hypertension is a serious complication of systemic sclerosis and remains one of the leading causes of mortality. Pulmonary veno-occlusive disease (PVOD), recently reclassified as pulmonary arterial hypertension (PAH) with overt features of venous/capillaries involvement, is a subgroup of group 1 pulmonary hypertension, which has been rarely reported in systemic sclerosis patients. It is symptomatically indistinguishable from idiopathic pulmonary arterial hypertension and should be suspected in those with manifestations of pulmonary arterial hypertension who have evidence of pulmonary venous congestion in the absence of left-sided heart disease. Thoracic high-resolution computed tomography can give important hints for the diagnosis, such as ground-glass opacities/nodules, mediastinal lymph node enlargement and interlobular septal thickening. Patients with PVOD usually have a poor prognosis and might experience acute pulmonary oedema after introduction of pulmonary vasodilators. Due to clinical similarities between scleroderma-related PAH and PVOD, some patients are misdiagnosed and this could explain, in part, the worse prognosis associated with this clinical condition, when compared with idiopathic PAH. We report the case of a 72-year-old woman with limited systemic sclerosis, who was initially diagnosed with systemic sclerosis-related pulmonary arterial hypertension. However, after introduction of sildenafil and bosentan, the patient developed acute pulmonary oedema, and findings from complementary exams were suggestive of PVOD.


Subject(s)
Lung/pathology , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/etiology , Scleroderma, Systemic/complications , Aged , Diagnosis, Differential , Female , Humans , Hypertension, Pulmonary/diagnosis , Lung/diagnostic imaging , Pulmonary Veno-Occlusive Disease/pathology , Radiography, Thoracic , Tomography, X-Ray Computed
12.
J Pediatr Hematol Oncol ; 42(7): e677-e679, 2020 10.
Article in English | MEDLINE | ID: mdl-31335821

ABSTRACT

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension that is usually difficult to diagnose and is refractory to conservative treatment. PVOD can occur in connection with high-dose chemotherapy or hematopoietic stem cell transplantation, similar to hepatic veno-occlusive disease (HVOD). Here, we present a case of neuroblastoma with PVOD following HVOD after high-dose chemotherapy that was resolved with conservative treatment. Respiratory symptoms or edema after HVOD may suggest PVOD, and prompt diagnosis on high-resolution computed tomography will result in a favorable prognosis.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , Hepatic Veno-Occlusive Disease/pathology , Neuroblastoma/therapy , Pulmonary Veno-Occlusive Disease/pathology , Child, Preschool , Combined Modality Therapy , Female , Hepatic Veno-Occlusive Disease/etiology , Humans , Neuroblastoma/pathology , Prognosis , Pulmonary Veno-Occlusive Disease/etiology , Transplantation, Autologous
13.
J Formos Med Assoc ; 119(1 Pt 2): 300-309, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31202500

ABSTRACT

BACKGROUND/PURPOSE: Pulmonary veno-occlusive disease (PVOD) is a rare but fatal cause of pulmonary hypertension reported to be linked to mutations of eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4), also known as general control nonderepressible 2 kinase (GCN2). PVOD is difficult to diagnose and often initially misdiagnosed as other types of idiopathic pulmonary arterial hypertension (IPAH). To rapidly and correctly identify PVOD patients and explore the possible pathogenesis, we thoroughly investigated histopathological features and GCN2 protein levels in non-PAH, PVOD and PAH patients. METHODS: Lung specimens were examined for histopathological changes, including those of pulmonary arteries and veins, by Masson's trichrome, modified Verhoeff's and α-SMA staining in the PVOD, IPAH, and non-PAH groups. GCN2 and α-SMA expression in lung tissue was examined by immunohistochemistry and western blotting. RESULTS: PVOD and IPAH patients showed significant intimal and medial thickening of muscular pulmonary arteries compared with non-PAH patients. PVOD patients had more prominent intimal and medial thickening of muscular pulmonary veins than the other two groups. Interestingly, specialized muscle bundles surrounding the tunica adventitia of the pulmonary artery and vein were observed in PVOD patients. A significant decrease in GCN2 expression in the PVOD group was confirmed by immunohistochemistry and western blotting. CONCLUSION: Our study is the first to show remarkable histological structures, including the wreath-like arrangement of a hyperplastic muscle bundle in the adventitia of pulmonary arteries, in PVOD patients as a diagnostic clue and to disclose the biological difference between PAH and PVOD in a Taiwanese population.


Subject(s)
Lung/pathology , Muscle, Smooth/pathology , Pulmonary Arterial Hypertension/pathology , Pulmonary Veno-Occlusive Disease/pathology , Actins/genetics , Actins/physiology , Adult , Aged , Cell Proliferation , Female , Humans , Immunohistochemistry , Male , Middle Aged , Mutation , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/physiology , Pulmonary Arterial Hypertension/genetics , Pulmonary Artery/pathology , Pulmonary Veins/pathology , Pulmonary Veno-Occlusive Disease/genetics , Vascular Remodeling
14.
Am J Pathol ; 189(6): 1159-1175, 2019 06.
Article in English | MEDLINE | ID: mdl-30926335

ABSTRACT

Hepatic veno-occlusive disease (HVOD), alias sinusoidal obstruction syndrome, may develop as a complication of chemotherapy in the setting of hematopoietic stem cell transplantation. HVOD is less frequently described after exposure to chemotherapy in the nontransplant setting and can also be a complication after ingestion of toxins, such as pyrrolizidine alkaloids. Veno-occlusive disease may also affect the lungs, and it is therefore termed pulmonary veno-occlusive disease (PVOD). Similarly, PVOD can develop after exposure to chemotherapeutic agents in the treatment of solid and hematological malignancies. In addition, PVOD has also been linked to autoimmune disorders and occupational solvent exposure. Finally, the heritable form of PVOD is due to biallelic mutations of the EIF2AK4 gene. Both HVOD and PVOD share common histopathological features and pathophysiologic mechanisms. Both clinical disorders are rare complications that can appear after exposure to the common inciting trigger of chemotherapeutic agents. The present review aims to summarize the current knowledge of HVOD and PVOD and to describe both similarities as well as differences regarding both conditions.


Subject(s)
Hepatic Veno-Occlusive Disease/pathology , Pulmonary Veno-Occlusive Disease/pathology , Animals , Diagnosis, Differential , Disease Models, Animal , Genetic Predisposition to Disease , Hepatic Veno-Occlusive Disease/diagnosis , Hepatic Veno-Occlusive Disease/etiology , Hepatic Veno-Occlusive Disease/therapy , Humans , Prognosis , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/etiology , Pulmonary Veno-Occlusive Disease/therapy , Rats , Risk Factors
15.
J Pathol Clin Res ; 5(2): 108-114, 2019 04.
Article in English | MEDLINE | ID: mdl-30697960

ABSTRACT

Pulmonary veno-occlusive disease (PVOD) is a rare lung disease characterized by fibrotic narrowing of pulmonary veins leading to pulmonary hypertension (PH) and finally to death by right heart failure. PVOD is often accompanied by pulmonary capillary hemangiomatosis (PCH), a marked abnormal proliferation of pulmonary capillaries. Both morphological patterns often occur together and are thought to be distinct manifestations of the same disease process and accordingly are classified together in group 1' of the Nice classification of PH. The underlying mechanisms of these aberrant remodeling processes remain poorly understood. In this study, we investigated the three-dimensional structure of these vascular lesions in the lung explant of a patient diagnosed with PVOD by µ-computed tomography, microvascular corrosion casting, electron microscopy, immunohistochemistry, correlative light microscopy and gene expression analysis. We were able to describe multifocal intussusceptive neoangiogenesis and vascular sprouting as the three-dimensional correlate of progressive PCH, a process dividing pre-existing vessels by intravascular pillar formation previously only known from embryogenesis and tumor neoangiogenesis. Our findings suggest that venous occlusions in PVOD increase shear and stretching forces in the pulmonary capillary bloodstream and thereby induce intussusceptive neoangiogenesis. These findings can serve as a basis for novel approaches to the analysis of PVOD.


Subject(s)
Hemangioma, Capillary/pathology , Hypertension, Pulmonary/pathology , Pulmonary Veins/pathology , Pulmonary Veno-Occlusive Disease/pathology , Humans , Lung Neoplasms/pathology , Neovascularization, Pathologic/pathology
17.
J Vet Intern Med ; 33(1): 114-123, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30499214

ABSTRACT

BACKGROUND: Histologic features of pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) have been described in dogs but without a thorough clinical description. OBJECTIVES: To report the clinical features, diagnostics, treatment, and outcome of dogs with histologic evidence of PVOD and PCH. ANIMALS: Fifteen pet dogs meeting histopathologic criteria of PVOD (occlusive remodeling of small-sized to medium-sized pulmonary veins) or PCH (alveolar capillary proliferation and congestion), or both. METHODS: Medical records of dogs with PVOD and PCH identified based on histopathologic features between 2003 and 2017 were retrospectively reviewed. RESULTS: Fifteen dogs met inclusion criteria of a histologic diagnosis of PVOD or PCH or both. Dogs were older (median 11 years) with no apparent breed or sex predisposition. Dogs presented with acute clinical signs (median 3 days), usually respiratory distress. Thoracic radiography (available in 10 dogs) revealed right cardiomegaly and patchy or diffuse interstitial to alveolar patterns, with 9 dogs having a normal left cardiac silhouette. In 5 dogs tested, pulmonary arterial hypertension (PAH) was documented. In all 3 dogs, thoracic computed tomography scans showed pulmonary arterial enlargement and perivascular diffuse nodular ground-glass opacities. Ten of 15 dogs died within 1 day; median survival was 3 days. CONCLUSIONS AND CLINICAL IMPORTANCE: In dogs with PAH, the inability to document left-sided congestive heart failure and failure to identify another cause of signs of respiratory disease should increase suspicion for PVOD and PCH. With increased awareness of PVOD and PCH by clinicians and pathologists, dogs with compatible clinicopathologic features should be evaluated for these pulmonary vascular disorders.


Subject(s)
Dog Diseases/pathology , Hemangioma/veterinary , Lung Neoplasms/veterinary , Pulmonary Veno-Occlusive Disease/veterinary , Animals , Capillaries/pathology , Dog Diseases/diagnosis , Dog Diseases/diagnostic imaging , Dogs , Female , Hemangioma/diagnosis , Hemangioma/diagnostic imaging , Hemangioma/pathology , Lung/blood supply , Lung/diagnostic imaging , Lung/pathology , Lung Neoplasms/diagnosis , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Male , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/diagnostic imaging , Pulmonary Veno-Occlusive Disease/pathology , Radiography, Thoracic/veterinary , Retrospective Studies , Tomography, X-Ray Computed/veterinary
18.
Intern Med ; 58(7): 955-964, 2019 Apr 01.
Article in English | MEDLINE | ID: mdl-30568112

ABSTRACT

Pulmonary veno-occlusive disease (PVOD) is a rare disease in the subgroup of conditions known as pulmonary arterial hypertension. Although a histological examination is needed for a definitive diagnosis, a non-invasive diagnosis is required for patients with pulmonary hypertension because a lung biopsy is deemed risky. We herein report a 32-year-old woman diagnosed with PVOD via a surgical lung biopsy and autopsy whose disease showed radiological findings mimicking those of hypersensitivity pneumonitis (pneumonia) at the time of the transbronchial lung biopsy, without obvious pulmonary hypertension on admission. When clinicians encounter patients with interstitial lung disease, they should not forget the possibility of PVOD and should be alert for emerging pulmonary hypertension.


Subject(s)
Alveolitis, Extrinsic Allergic/diagnosis , Pulmonary Veno-Occlusive Disease/diagnosis , Adult , Autopsy , Biopsy , Diagnosis, Differential , Fatal Outcome , Female , Humans , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/pathology , Lung/pathology , Pulmonary Veno-Occlusive Disease/complications , Pulmonary Veno-Occlusive Disease/pathology , Radiography, Thoracic , Tomography, X-Ray Computed
19.
BMC Pulm Med ; 18(1): 112, 2018 Jul 11.
Article in English | MEDLINE | ID: mdl-29996818

ABSTRACT

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of pulmonary hypertension that is associated with malignancies and is marked by the presence of non-occlusive tumor emboli and fibrocellular intimal proliferation of small pulmonary arteries leading to increased pulmonary vascular resistance and right heart failure. The diagnosis of PTTM is challenging to make pre-mortem and guidelines on treatment are lacking. CASE PRESENTATION: A 45-year-old woman with advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and evidence of right heart failure during a phase I clinical trial with cediranib and durvalumab. After an extensive evaluation, pre-capillary pulmonary hypertension was confirmed by right heart catheterization. Vasodilator therapy was initiated but resulted in the development of symptomatic hypoxemia and was discontinued. Despite continued supportive care, she continued to decline and was transitioned to hospice care. At autopsy, the cause of her right heart failure was found to be due to PTTM with features of pulmonary veno-occlusive disease (PVOD). CONCLUSION: PTTM and PVOD are important diagnoses to consider in patients with a malignancy and the development of right heart failure and may be manifestations of a spectrum of similar disease processes.


Subject(s)
Carcinoma, Squamous Cell/pathology , Lung Neoplasms/secondary , Pulmonary Veno-Occlusive Disease/pathology , Thrombotic Microangiopathies/pathology , Uterine Cervical Neoplasms/pathology , Antibodies, Monoclonal/therapeutic use , Autopsy , Carcinoma, Squamous Cell/drug therapy , Fatal Outcome , Female , Humans , Lung/blood supply , Lung/pathology , Lung/physiopathology , Lung Neoplasms/complications , Middle Aged , Neoplastic Cells, Circulating/pathology , Pulmonary Veno-Occlusive Disease/etiology , Quinazolines/therapeutic use , Thrombotic Microangiopathies/etiology , Uterine Cervical Neoplasms/drug therapy
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