Pulmonary Veno-Occlusive Disease

Updated: Oct 27, 2016
  • Author: Hakim Azfar Ali, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Overview

Background

Pulmonary veno-occlusive disease (PVOD) is one of the less commonly encountered causes of pulmonary hypertension. Some reports suggest that PVOD accounts for 5-20% of cases classified as idiopathic pulmonary arterial hypertension (PAH). [1, 2, 3] PAH remains an incurable disease that results in significant morbidity and mortality. (See Epidemiology, Treatment, and Medication.)

In the past, PVOD has been described by various terms, such as pulmonary venous sclerosis, obstructive disease of the pulmonary veins, or the venous form of primary pulmonary hypertension. As the name suggests, PVOD is a clinicopathologic entity characterized by occlusion or narrowing of the pulmonary veins and venules by sometimes loose, sometimes more dense and collagen-rich, fibrous tissue, [4] leading to clinical manifestations that are, in many ways, similar to PAH. (See Pathophysiology, Etiology, Presentation, and Workup.) However, owing to the differences in pathology and response to PAH-specific therapy, it was classified in a unique group 1 in the pulmonary hypertension classification in 2009.

Although the term pulmonary veno-occlusive disease was first used in the 1960s, the first case was described by Dr J. Hora in 1934 in a 48-year-old patient who died within one year of diagnosis with symptoms of right-sided heart failure. [5] Historically, the disease has been underdiagnosed, possibly because of lack of awareness by clinicians.

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Pathophysiology

Regardless of the mechanism of injury, the end result in pulmonary veno-occlusive disease (PVOD) is constriction and/or occlusion of the pulmonary veins and venules. In the early stage, the occlusion may be from loose, edematous tissue, which later transforms into dense and sclerotic fibrous tissue. Eccentric intimal thickening is seen in the lobular septal veins and venules and, rarely, in the larger veins. [6] In addition, dilatation of lymphatics occurs.

The plexiform arterial lesions seen in patients with primary pulmonary hypertension, or idiopathic pulmonary arterial hypertension (PAH), are absent, although some arterial medial thickening may occur. [7] The alveolar capillaries become dilated and engorged from back-pressure and sometimes causes capillary proliferation, which mimics another similar disease, pulmonary capillary hemangiomatosis. Recanalization of veins may occur over time. [8] (See the image below.)

Medium-power photomicrograph (original magnificati Medium-power photomicrograph (original magnification, X10; hematoxylin and eosin stain) demonstrates a fibrotic interlobular septum containing a vein with an occluded lumen (arrowhead). The occlusion is composed of dense, collagen-rich, fibrous tissue. Image courtesy of Thoracic Imaging Section, Department of Radiologic Pathology, Armed Forces Institute of Pathology.
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Etiology

The exact etiology of pulmonary veno-occlusive disease (PVOD) remains largely unknown. However, several indirect observations have led to many hypotheses regarding the etiology. One such hypothesis proposes that injury to the vessel walls leads to a cascade of humoral and mechanical events that eventually results in structural changes with the end result being widespread fibrotic venous constriction or occlusion. [9]

The following mechanisms for injury have been proposed:

  • Immune mediated
  • Infectious
  • Genetic
  • Toxic
  • Radiologic
  • Coagulopathic

Immune mediated

Either idiopathic autoimmune injury to venules or immune-mediated injury to venules related to viral or other environmental agents has been proposed as a mechanism for the development of PVOD. Cases have been reported in patients with other autoimmune clinical features. [10, 11]

Some cases of pulmonary hypertension in the setting of mixed connective disease and scleroderma, including the CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) variant, have been known to have a histopathology consistent with that of PVOD. [12, 13, 14]

Infectious

Various infections have been reported to be associated with PVOD. These include infections with viruses such as cytomegalovirus, Epstein-Barr virus, and measles virus. [15] One case has been reported with concomitant Toxoplasma infection. A few cases of PVOD in the setting of human immunodeficiency virus (HIV) infection have been reported. [16]

Genetic

Several cases of PVOD have been reported to occur in siblings, with a similar age of onset. [17, 18] These observations may indicate a genetic predisposition or common environmental exposures. A case of well-documented PVOD associated with a bone morphogenetic protein receptor protein type II (BMPR2) mutation has been reported suggesting a possible pathogenetic connection with idiopathic PAH or heritable PAH. [19]

Toxic

PVOD has been reported after the administration of various chemotherapeutic agents such as bleomycin, mitomycin, and carmustine (BCNU), similar to hepatic veno-occlusive disease. [20, 21] Other chemical exposures that have been linked to the development of PVOD include powdered cleaning products containing silica, soda ash, dodecyl benzyl sulfonate, and trichloro-s-triazinetrione. [22] PVOD seems to occur more commonly in bone marrow transplant recipients than in the general population. [23, 24]

Radiologic

Radiation exposure is a well-recognized cause of vascular injury. A case of PVOD that may be associated with previous mantle irradiation for Hodgkin lymphoma has been reported. [25] However, the presence of a prothrombotic state in malignancies, especially in adenocarcinomas, simultaneously with exposure to chemotherapeutic agents and radiotherapy precludes the establishment of a firm cause-and-effect relationship between malignancy and PVOD.

Coagulopathic

The association of some cases of PVOD with oral contraceptive use or pregnancy has lent some support to the theory that PVOD is related to coagulation disorders, but an absence of thrombosis in other organs may refute this notion.

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Epidemiology

In view of the underrecognition of pulmonary veno-occlusive disease (PVOD), the true incidence and prevalence of this condition is unknown. Many cases are treated as idiopathic pulmonary arterial hypertension (PAH). Estimates indicate, however, that 6% of patients clinically believed to have primary pulmonary hypertension may have evidence of PVOD at autopsy. [26] Depending on the cited series, the estimated prevalence of PVOD among patients clinically diagnosed with idiopathic PAH varies from 5-20%. [2]

An annual incidence of PVOD of 0.1-0.2 case per million persons in the general population has been suggested based on the incidence of primary pulmonary hypertension in the general population. [27] Note, however, that such indirect estimates of a rare disease’s incidence may be imprecise.

Age-related demographics

The age at diagnosis ranges from eight weeks [28] to the seventh decade of life with most reported cases occurring in young adults. PVOD in siblings tends to have an early onset usually within the first three decades of life.

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Prognosis

The prognosis in pulmonary veno-occlusive disease (PVOD) is grim. Most patients have a rapidly progressive course with most reported patients dying within two years of diagnosis without proper treatment. [29, 30] Currently available PAH therapies do not appear to have a profound effect on survival in patients with PVOD. (See Treatment and Medication.)

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