eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology

Arteriovenous Fistulae, Pulmonary

Author: Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St. Boniface General Hospital
Contributor Information and Disclosures

Updated: Apr 28, 2009

Introduction

Background

Pulmonary arteriovenous malformations (PAVMs) were first described in 1897. They consist of abnormal communications between the pulmonary arteries and the pulmonary veins and are usually congenital in origin. However, they may also occur in various acquired conditions, such as hepatic cirrhosis, schistosomiasis, mitral stenosis, trauma, actinomycosis, and metastatic thyroid carcinoma. In chronic inflammatory conditions (eg, bronchiectasis), communications between the bronchial arteries and the pulmonary arteries can also develop.

Hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder. The clinical manifestations are secondary to growth of vascular malformations in various organs, most commonly the skin, nasopharynx, GI tract, lungs, and brain. HHT is generally recognized as a triad of cutaneous telangiectasia, recurrent epistaxis, and a family history of this disorder.¹

Approximately 70% of pulmonary arteriovenous malformation cases are associated with HHT. Conversely, approximately 15-35% of persons with HHT have pulmonary arteriovenous malformations. Arteriovenous malformations (AVMs) and HHT are congenital but usually do not clinically manifest until adulthood.

Historical perspectives

In 1896, Henry Jules Rendu published a case describing a 52-year-old man with telangiectasia and epistaxis in the French literature. In the Johns Hopkins Hospital bulletin in 1901, Sir William Osler reported on a family known to have hereditary telangiectasia and hemorrhage. Frederick Weber published subsequent descriptions of this disorder in a 1907 issue of the Lancet. That is how this disease received the name Osler-Weber-Rendu syndrome.

Definition

Telangiectasia and arteriovenous malformations are the 2 abnormal vascular structures that occur in HHT. Telangiectasia is localized convoluted enlargement of the postcapillary venules. The walls of telangiectasia have smooth muscle proliferation, and perivascular lymphocytic infiltration is present. Arteriovenous malformations are much larger lesions than those of telangiectasia, consisting of direct connections of the pulmonary artery to the pulmonary vein. In arteriovenous malformations, dilatation of the feeding vessel, and localized aneurysmal enlargement are present. Proximally, the vein may be septate and its walls smooth.

Anatomy

Approximately 53-70% of pulmonary arteriovenous malformations are found in the lower lobes.

Approximately 70% of patients have unilateral disease, 36% have multiple lesions, and 50% of those with multiple lesions have bilateral disease. Pulmonary arteriovenous malformations may be microscopic (ie, telangiectasis), but they are typically 1-5 cm. Occasionally, pulmonary arteriovenous malformations as large as 10 cm are encountered. Approximately 10% of patients may have diffuse microvascular pulmonary arteriovenous malformations in combination with larger, radiographically visible pulmonary arteriovenous malformations.

The vascular channels are thin walled and lined with a layer of endothelium. The connective tissue stroma is scant and has no communication with the surrounding lung. Most pulmonary arteriovenous malformations drain into the left atrium, but anomalous drainage to the inferior vena cava or innominate veins has been reported. The malformations may appear as one of the following: a large single sac, a plexiform mass of dilated vascular channels, or a dilated tortuous direct communication between artery and vein.

Anatomy of subtypes

Pulmonary arteriovenous malformations can be classified as simple or complex types on the basis of their architecture. Simple pulmonary arteriovenous malformations have a single feeding segmental artery leading to single draining pulmonary vein. Approximately 79% of pulmonary arteriovenous malformations are of the simple type;² most of the associated aneurysms are nonseptate and occur in the lower lobes. Approximately 21% of pulmonary arteriovenous malformations are complex, having 2 or more feeding arteries or draining veins. They often occur in the lingula and right middle lobe distributions.

Pathophysiology

Advances in the genetics of HHT have led to the recognition of the possible etiology of pulmonary arteriovenous malformations.^3,4 Although primarily described in patients with HHT, these genetic abnormalities may also be present in patients without HHT. Genetic mapping in the last few years led to the discovery that HHT can be categorized into 2 linkage groups: HHT1 has been linked to band 9q33, and HHT2 has been linked to band 12q13. A third and rare variant of HHT not linked to chromosome 9 or 12 has been reported; its major manifestation is hepatic involvement.

Also, a third locus for HHT has been reported at band 3p22, where transforming growth factor (TGF)– β2 receptor gene is located. The HHT1 gene is associated with higher incidence of pulmonary arteriovenous malformations, epistaxis, mucocutaneous telangiectasia, and cerebrovascular malformations.

The genetic mutations at the 2 major loci are recognized. Endoglin is identified as the gene product for HHT1 on band 9q33.⁵ The endoglin, a TGFβ, is a 180-kD glycoprotein that has been established to be a receptor for TGF-β1 and TGF-β2.

Approximately 16 mutations of the endoglin gene are reported. The mechanisms for gene mutation causing HHT1 include a dominant negative effect; a 2-hit model; and most likely, haploinsufficiency. The second locus for HHT has been mapped to chromosome arm 12q. The mutation in 12q may be in the β-glycan gene or in activin receptorlike kinase 1 (ALK-1). The ALK-1 protein has the properties of a type I serine-threonine kinase receptor. ALK-1 can bind either activin or TGFβ in the presence of their respective type II receptors.⁶ At least 12 mutations of the ALK-1 gene have been identified. The mechanisms of mutation appear to be similar to HHT1 mutations and include the dominant negative mechanism, the 2-hit model, and haploinsufficiency. The HHT2 gene is not predominantly associated with pulmonary arteriovenous malformations and cerebral arteriovenous malformations.

Endoglin and ALK-1 bind TGFβ, which is implicated in angiogenesis. Pulmonary arteriovenous malformations likely develops as a result of interplay of various factors among diverse cells and matrix during vascular insults. Changes in endoglin and ALK might cause endothelial cells to respond abnormally to TGFβ during the process of vascular remodeling, resulting in the formation of arteriovenous malformations.

Pathogenesis

The exact pathogeneses of pulmonary arteriovenous malformations is unknown. In the terminal arterial loops, a defect that allows dilatation of the thin-walled capillary sacs may occur. Alternatively, pulmonary arteriovenous malformations are the result of incomplete resorption of the vascular septa that separate the arterial and venous plexus, which normally anastomose during fetal development. Some have also suggested that multiple small pulmonary arteriovenous malformations develop as a result of capillary development failure during fetal growth. The large saccular pulmonary arteriovenous malformations develop by means of progressive dilation of the smaller plexus, leading to the formation of tortuous loops and multiloculated sacs. With time, the intervening vascular walls may rupture, resulting in the formation of a single large saccular pulmonary arteriovenous malformation.

Natural history

The natural history of pulmonary arteriovenous malformations has not been studied carefully. The initial manifestation of HHT is the appearance of cutaneous telangiectases or epistaxis. Fewer than 10% of patients who have visceral involvement by arteriovenous malformations have visceral signs and symptoms (eg, dyspnea or GI bleeding) as the initial manifestation of HHT. The visceral manifestations occur in adults, reflecting the additional time needed for the enlargement of arteriovenous malformations.

In one study of 16 patients, serial chest radiographs obtained over a median observation period of 18.9 years demonstrated enlargement in 4 patients and near total regression in 1 patient. The growth rate tended to be slow, with an increase of approximately 5-10 mm every 5-15 years.

Frequency

United States

In a 1953 study from The Johns Hopkins Hospital, 3 cases of pulmonary arteriovenous malformations were detected in 15,000 consecutive autopsies. The Mayo Clinic encountered 63 cases during the 20 years ending in 1972, and 38 cases were encountered during the subsequent 9 years ending in 1981. Approximately 70% of the cases of pulmonary arteriovenous malformations are associated with HHT, which is an autosomal dominant disorder. Conversely, approximately 15-35% of persons with HHT have pulmonary arteriovenous malformations.

To screen for occult brain, lung, and liver arteriovenous malformations in pediatric patients with confirmed HHT, a study undertook molecular analysis and clinical assessment.⁷ The molecular analysis demonstrated the mutation-carrier status in 22 of 35 children. Nasal telangiectases were found in 68%, mucocutaneous telangiectases (fingers, lips, oral cavity) in 79%, pulmonary arteriovenous malformations in 53%, hepatic arteriovenous malformations (HAVMs) in 47%, and cerebral arteriovenous malformations and/or cerebral ischemic changes secondary to pulmonary arteriovenous malformations in 12%.

Mortality/Morbidity

The mortality rate of pulmonary arteriovenous malformations has been 0-55%. Investigators in more recent studies have reported a mortality rate 0-15%; however, the duration of follow-up in these studies is short. The morbidity rate of untreated pulmonary arteriovenous malformations is also significant. The incidence of stroke is 11.4%, and the incidence of brain abscess is 6.8%. The total morbidity and mortality rate is 23%.

Sex

Pulmonary arteriovenous malformations occur twice as often in women than in men, but a male predominance is observed among newborns.

Age

Approximately 10% of the cases of pulmonary arteriovenous malformations are identified in infancy or childhood; however, the incidence gradually increases through the fifth and sixth decades of life.

Clinical

History

Symptoms in early life may vary from being totally absent to being severe. Common signs and symptoms are cyanosis, congestive heart failure, and fulminant respiratory failure. Symptoms related to pulmonary arteriovenous malformations (PAVMs) often develop between the fourth and fifth decades of life. Symptoms are more common in persons with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia (HHT) than in those with pulmonary arteriovenous malformations but not HHT.

• The most common complaint in symptomatic patients with pulmonary arteriovenous malformations is epistaxis caused by mucosal telangiectases.
• Dyspnea is the second most common complaint in patients with pulmonary arteriovenous malformations. Dyspnea is common in persons with large or multiple pulmonary arteriovenous malformations and is observed in all patients who have clubbing. Some patients also have platypnea, which indicates an improvement in dyspnea upon reclining.
• Hemoptysis is the third most common symptom; massive hemoptysis may also occur. Bleeding from telangiectasis on the skin and in the GI tract is observed in patients with pulmonary arteriovenous malformations and HHT. The incidence is 15-30%.
• The incidence of gastrointestinal hemorrhage in patients with HHT is 15-30%; specific incidences in patients with pulmonary arteriovenous malformations have not been reported.
• Less common complaints include chest pain, cough, migraine headaches, tinnitus, dizziness, dysarthria, syncope, vertigo, and diplopia. The cause of these symptoms is not entirely clear, but it may be related to hypoxemia, polycythemia, or cerebral vascular complications.

Physical

Superficial telangiectases attributable to HHT are the most common physical findings in patients with pulmonary arteriovenous malformations. These lesions are papular, slightly rounded, and sharply demarcated from surrounding skin. They have a few dendritic projections that are ruby colored and partially blanche with pressure. The lesions are present on the face, mouth, chest, and upper extremities (see Media file 1).

• Murmurs or bruits over the location of the pulmonary arteriovenous malformations are heard in one half of patients. These murmurs are most audible during inspiration and are called machinery murmurs.
• Digital clubbing and cyanosis is also observed.
• The murmurs are loud during inspiration and increase when the patient assumes positions in which pulmonary arteriovenous malformations are gravitationally dependent.
• Digital clubbing and cyanosis are observed in 60-80% of patients.
• The triad of dyspnea, cyanosis, and clubbing is uncommon and observed in a minority of patients.

Causes

• Epidemiology: Great heterogeneity of symptoms is noted among different families and within single large families with HHT. Some families with HHT predominantly have the pulmonary arteriovenous malformations and cerebral arteriovenous malformations; whereas other affected families predominantly have GI mucosal telangiectasis, which lead to GI bleeding and iron-deficiency anemia.
• Inheritance: HHT is an autosomal dominant disorder; however, 20% of cases involve no family history of telangiectasia or recurrent bleeding. Penetrance is age related and nearly complete by age 40 years. Although the arteriovenous malformations in HHT are inherited and should be present at birth, they commonly manifest clinically during adult life, after the vessels have been subjected to pressure for several decades.
• Associated syndromes: Communication between pulmonary arteries and pulmonary veins has been reported in cases of trauma and in hepatic cirrhosis, schistosomiasis, mitral stenosis, actinomycosis, Fanconi syndrome, and metastatic thyroid carcinoma. Communications between bronchial arteries and pulmonary arteries that cause a left-to-right shunt develop in chronic inflammatory conditions such as bronchiectasis. Most individuals with pulmonary arteriovenous malformations have HHT. The diagnostic criteria for a definite diagnosis of HHT include at least 3 of the following:
  • Recurrent and spontaneous epistaxis
  • Multiple mucocutaneous telangiectases
  • Visceral lesions (eg, GI arteriovenous malformations, pulmonary arteriovenous malformations)
  • First-degree relative with HHT by these criteria
• Associated noncardiac conditions: The most frequently reported associated noncardiac conditions are CNS complications, which occur in 30% of patients. Strokes occur in 18% of patients with CNS complications, transient ischemic attacks occur in 37%, brain abscesses occur in 9%, migraine headaches occur in 43%, and seizures occur in 8%. Paradoxic embolism across pulmonary arteriovenous malformations is the most likely mechanism for major noninfectious strokes. Embolism of infected material accounts for solitary or recurrent brain abscesses. These complications most commonly occur when the feeding arteries are larger than 3 mm in diameter. Hemoptysis and hemothorax are other potentially life-threatening complications. Hemoptysis occurs from ruptured pulmonary arteriovenous malformations or endobronchial telangiectasia.
• Other causes of pulmonary arteriovenous malformations
  • Idiopathic congenital pulmonary arteriovenous malformations: Idiopathic congenital pulmonary arteriovenous malformations are likely to be single. They are less likely to become enlarged, and the are associated with fewer physical findings than other pulmonary arteriovenous malformations. Idiopathic pulmonary arteriovenous malformations are diagnosed by using the same criteria as for other pulmonary arteriovenous malformations. Idiopathic congenital pulmonary arteriovenous malformations are successfully treated with embolotherapy.
  • Acquired arteriovenous malformations in hepatopulmonary syndrome
    • Hepatopulmonary syndrome (HPS), increased alveolar-arterial oxygen gradient, and intrapulmonary right-to-left shunting (defined as the triad of liver disease) may occur in as many as 47% of patients with end-stage liver disease. All types of chronic liver disease may give rise to this syndrome. Approximately 80% of affected patients have signs and symptoms of end-stage liver disease before symptoms from pulmonary arteriovenous malformations develop. These patients have dyspnea, platypnea, clubbing, cyanosis, hypoxia, and orthodeoxia. Pulmonary function results indicate normal lung volumes and expiratory flow rates with low diffusing capacity.
    • In contrasts to patients with HHT, patients with HPS rarely have discrete arteriovenous malformations on chest radiographs. The calculation of the shunt fraction with the use of 100% oxygen, contrast echocardiography, and radionuclide scanning are diagnostic tests for HPS.
    • Results of HPS management have been disappointing. Liver transplantation may result in the resolution of HPS, and HPS is not a contraindication to liver transplantation. An improvement in HPS-related pulmonary shunting after therapeutic transjugular intrahepatic portosystemic shunting has been described.
  • Acquired arteriovenous malformations after surgery for congenital cyanotic heart disease: Pulmonary arteriovenous malformations may develop after Glenn or modified Fontan procedures for congenital cyanotic heart disease. Pulmonary arteriovenous malformations are a known late complication of Glenn anastomosis (ie, superior vena cava [SVC] to right pulmonary artery [RPA]), which occur in as many as 25% of cases. The Fontan operation (ie, SVC to right atrium and proximal RPA; hepatic veins to left pulmonary artery) was designed as a surgical repair for congenital tricuspid atresia. Contrast echocardiography and radionuclide shunt studies have been used to diagnose pulmonary arteriovenous malformations, and embolotherapy has been used successfully to occlude the pulmonary arteriovenous malformations in these cases.

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