Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults

INTRODUCTION — Pulmonary arteriovenous malformations (PAVMs), also known as pulmonary arteriovenous fistulae, are abnormal communications between pulmonary artery and pulmonary vein, lacking the normal intervening capillary bed and resulting in right-to-left shunt [1]. PAVMs are uncommon in the general population, but they are an important consideration in the differential diagnosis of common pulmonary problems, including hypoxemia, pulmonary nodules, and hemoptysis. They should also be considered in patients presenting with paradoxical embolization, including cryptogenic stroke or brain abscess. PAVMs are a common occurrence in patients with hereditary hemorrhagic telangiectasia (HHT, also called Osler-Weber-Rendu syndrome).

The epidemiology, etiology, pathology, clinical features, and natural course of PAVMs are reviewed here. The diagnosis and treatment of PAVMs are discussed separately. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults" and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".)

EPIDEMIOLOGY

General population — PAVMs are uncommon in the general population. This was illustrated by a study of 15,000 consecutive autopsies, in which only three cases of PAVMs were detected [2]. However, the prevalence may be higher than autopsy studies suggest. For example, in a study of over 21,000 screening computed tomography (CT) examinations, which allows detection of smaller PAVMs, the prevalence was approximately 1 per 2600 individuals [3].

PAVMs in the general population are 1.5 to 1.8 times as common among females, compared with males [4].

Among the general population, PAVMs are typically solitary (90 percent) and unilateral (97 percent) [5]. There is a lower lobe predilection, with at least two-thirds occurring in the lower lobes [6,7]. PAVMs tend to increase slowly in size over time and rarely regress spontaneously.

Hereditary hemorrhagic telangiectasia (HHT) — Most PAVMs (80 to 90 percent) are associated with hereditary hemorrhagic telangiectasia (HHT, also called Osler-Weber-Rendu syndrome), an autosomal dominant genetic disorder characterized by abnormal blood vessel formation. Conversely, approximately 30 to 50 percent of patients with HHT will have PAVMs [8]. In patients with HHT, PAVMs are more evenly distributed by sex (56 percent female), more frequently multiple, and more evenly distributed throughout the lungs [9].

PAVM screening is recommended for patients with HHT [10]. Screening for PAVMs and the clinical manifestations and treatment of HHT are discussed separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)" and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".)

ETIOLOGY — Most PAVMs are congenital and due to hereditary hemorrhagic telangiectasia (HHT). However PAVMs can occur in a variety of acquired medical conditions, the most common of which is hepatic cirrhosis (table 1) [11].

Less common associations include penetrating chest trauma, mitral stenosis, schistosomiasis, actinomycosis, Fanconi syndrome, and metastatic thyroid carcinoma [12,13]. PAVMs are also a well-established complication following surgery for congenital heart disease in children, including the classic Glenn shunt [14] and bidirectional cavopulmonary anastomosis [15]. The mechanism by which these various medical conditions become associated with PAVM is unknown. The remainder of PAVMs are believed to be idiopathic [16].

The genetics and pathogenesis of HHT, an autosomal dominant disorder of variable penetrance, may also provide insights into the etiology of PAVM, the details of which are discussed separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pathophysiology'.)

PATHOLOGY

Pathogenesis — The precise cause of pulmonary arteriovenous malformation (PAVM) is unknown. However, numerous causes of PAVM have been proposed, including the following: aberrant transforming growth factor-beta signaling during vascular development, possibly involving endoglin or activin receptor-like kinase 1; a defect in terminal arterial loops that allows dilation of thin-walled capillary sacs; incomplete resorption of the vascular septae that separate the arterial and venous plexuses during fetal development; failure of capillary development during fetal development, followed by the progressive dilation of favored limbs of smaller plexuses, formation of multiloculated sacs, and rupture of intervening vascular walls; and, development of many small PAVMs consisting of a single artery-to-vein connection without an intervening plexus [13].

Pathology — A PAVM is an abnormal connection between the pulmonary artery and pulmonary vein that lacks that normal capillary component that should exist between the pulmonary arterial and venous circulations of the lung.

A PAVM may appear macroscopically as a large, single or multi-lobulated sac, a plexiform mass of dilated vascular channels, or a dilated and tortuous direct anastomosis between an artery and vein [17].

Histologically, PAVMs are usually thin-walled, consisting of a single layer of endothelium and variable amounts of connective tissue stroma [2]. Calcification and mural thrombosis are occasionally seen.

PAVMs are classified as either simple or complex. Simple PAVMs are perfused by arteries arising from a single subsegmental artery, whereas complex PAVMs are perfused by more than one subsegmental artery. Eighty to 95 percent of PAVMs are simple [16,18]. Small microvascular PAVMs (ie, telangiectases) are most commonly of the complex type [19].

PAVMs are supplied by pulmonary arteries in about 95 percent of cases and are usually drained by pulmonary veins; however, they may occasionally be fed by systemic arteries (ie, the bronchial artery) and/or drain into the left atrium or inferior vena cava. When PAVMs are fed by systemic arteries, hereditary hemorrhagic telangiectasia (HHT) is usually not the cause of the PAVM.

SUMMARY

●Definition – Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between pulmonary arteries and veins, lacking the normal intervening capillary bed. PAVMs are an important consideration in the differential diagnosis of common pulmonary problems, including hypoxemia, pulmonary nodules, hemoptysis, and paradoxical embolization. (See 'Introduction' above.)

●Prevalence

•PAVMs are uncommon in the general population. They are more common among females, compared with males, and are typically solitary with a lower lobe distribution. (See 'General population' above.)

•Most PAVMs are associated with hereditary hemorrhagic telangiectasia (HHT, also called Osler-Weber-Rendu syndrome), with rates of underlying HHT exceeding 80 percent. In contrast, approximately 30 to 50 percent of patients with HHT have visible PAVMs on chest CT. (See 'Hereditary hemorrhagic telangiectasia (HHT)' above.)

●Etiology – Most PAVMs are congenital and secondary to HHT. PAVMs can also occur in a variety of acquired medical conditions (table 1), including hepatic cirrhosis, cardiothoracic surgery, penetrating chest trauma, mitral stenosis, schistosomiasis, actinomycosis, Fanconi syndrome, and metastatic thyroid carcinoma. (See 'Etiology' above.)

●Pathogenesis and pathology – The precise cause of PAVM is unknown. PAVMs macroscopically appear as a large single or multilobulated sac, a plexiform mass of dilated vascular channels, or a dilated and tortuous direct anastomosis between an artery and vein. Histologically, PAVMs are usually thin-walled, consisting of a single layer of endothelium and variable amounts of connective tissue stroma. (See 'Pathology' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James R Gossage, MD, who contributed to earlier versions of this topic review.