INTRODUCTION — Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between pulmonary arteries and veins [1]. Alternative names include pulmonary arteriovenous fistulae, pulmonary arteriovenous aneurysms, cavernous angiomas of the lung, and pulmonary telangiectases [2]. 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. In addition, they 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 — Pulmonary arteriovenous malformations (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]. Three additional case series from the Mayo Clinic suggested a similar low rate of PAVMs in the general population reporting 194 cases of PAVMs over 45 years (ie, 4.3 cases per year) [3-5].

PAVMs are 1.5 to 2 times as common among women, compared with men [6].

In patients that have PAVMs, they are commonly multiple, and vary in their number, distribution, and size. As an example, in one retrospective study of 350 patients with PAVMs, 36 percent of patients had multiple lesions and 25 percent had bilateral disease [7]. More than half of the lesions were in the lower lung fields and almost 80 percent involved the pleura. In another study of 112 patients who underwent embolization of PAVM, 67 percent had multiple PAVMs and 92 percent were in the lower lobes [8]. Other retrospective series indicate that PAVMs are typically 1 to 5 cm in size (but occasionally exceed 10 cm) and that 7 to 11 percent of patients have diffuse microvascular PAVMs that may occur in combination with radiographically visible PAVMs [5,9,10]. PAVMs tend to increase slowly in size over time and rarely regress spontaneously.

Hereditary hemorrhagic telangiectasia (HHT) — Reports suggest that in patients with PAVMs, the rate of hereditary hemorrhagic telangiectasia (HHT, also called Osler-Weber-Rendu syndrome) ranges from 25 to 98 percent. While it was previously estimated that 70 percent of cases of PAVM were associated with HHT [11], reports from HHT treatment centers report higher rates of at least 94 to 96 percent [8,12,13]. In our experience with over 200 patients with PAVM as of 2018, HHT was either confirmed or strongly suspected in at least 97 percent of the patients with macroscopic PAVM. In contrast, a study from Japan performed low dose CT to screen for lung cancer in 21,235 patients and found eight cases of PAVM, only two of which were due to HHT [14]. This latter study suggests that only 25 percent of PAVMs seen outside of HHT referral centers are associated with HHT. Although all PAVM were confirmed with CT angiography or catheter angiography, the number of patients that had each test was not reported. Eight of nine PAVM were smaller than 1 cm. In our experience, CT angiography can misdiagnose PAVM smaller than 1 cm, raising the possibility that the incidence of PAVM may have been overestimated in this study. We await additional studies for true estimates on the incidence of HHT in patients with PAVM.

Approximately 11 to 40 percent of patients with HHT have visible PAVMs on chest CT [11,15-17], although this appears to be substantially higher among patients with HHT1 due to an ENG mutation [18]. Although HHT-associated PAVMs are uncommon during infancy, they may still be seen, and then gradually increase in incidence through the fifth and sixth decades of life [19]. The largest study of screening for PAVM in 175 children with definite HHT found an incidence of 22 percent [20]. Another study found that 13 percent of children with definite HHT had symptomatic PAVM and several of these presented before age 7, usually with hypoxia or cyanosis [21].

Many specialized centers screen HHT patients for PAVMs to identify those who may benefit from therapy. For those too small for therapy on the initial screen, one retrospective study reported that five years later 18 percent of patients demonstrated lesions that had grown to a size that warranted embolization [22]. 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 pulmonary arteriovenous malformations (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) [23].  

Less common associations include penetrating chest trauma, mitral stenosis, schistosomiasis, actinomycosis, Fanconi's syndrome, and metastatic thyroid carcinoma [24,25]. PAVMs are also a well-established complication following surgery for congenital heart disease in children, including the classic Glenn shunt [26] and bidirectional cavopulmonary anastomosis [27]. The mechanism by which these various medical conditions become associated with PAVM is unknown.

The remainder of PAVMs are believed to be idiopathic [28]. One study suggested that idiopathic PAVM may be more common than HHT [14], but this has not been confirmed by other studies and does not reflect the experience at HHT centers in North America.

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 [25].

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 [7].

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 [28,29]. Small microvascular PAVMs (ie, telangiectases) are most commonly of the complex type [30].

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

●Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between pulmonary arteries and veins. PAVMs are an important consideration in the differential diagnosis of common pulmonary problems, including hypoxemia, pulmonary nodules, and hemoptysis. (See 'Introduction' above.)

●PAVMs are uncommon in the general population. They are more common among women compared with men. They are often multiple and vary in their number, distribution, and size. (See 'General population' above.)

●Most PAVMs are associated with hereditary hemorrhagic telangiectasia (HHT, also called Osler-Weber-Rendu syndrome) with rates of underlying HHT ranging from 25 to 98 percent, with higher rates reported at HHT referral centers. In contrast, approximately 11 to 40 percent of patients with HHT have visible PAVMs on chest CT. (See 'Hereditary hemorrhagic telangiectasia (HHT)' above.)

●Most PAVMs are congenital and due to HHT, PAVMs can occur in a variety of acquired medical conditions, the most common of which is hepatic cirrhosis (table 1). Less common associations include penetrating chest trauma, mitral stenosis, schistosomiasis, actinomycosis, Fanconi's syndrome, and metastatic thyroid carcinoma. (See 'Etiology' above.)

●The precise cause of PAVM is unknown. PAVMs macroscopically appear 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. Histologically, PAVMs are usually thin-walled, consisting of a single layer of endothelium and variable amounts of connective tissue stroma. Calcification and mural thrombosis are occasionally seen. (See 'Pathology' above.)