Pulmonary Arteriovenous Malformations and Hereditary Hemorrhagic Telangiectasia

What every physician needs to know:

Pulmonary arteriovenous malformations (PAVMs)

PAVMs are abnormal lung vessels with direct communication between the pulmonary artery and the pulmonary vein and without an intervening capillary network. PAVMs are most commonly associated with a genetic disorder, hereditary hemorrhagic telangiectasia (HHT), and are less frequently idiopathic or acquired.

PAVMs are most commonly simple fistulas consisting of a feeding artery, an aneurysm, and a draining vein. Less frequently, PAVMs are complex and have multiple feeding arteries and/or draining veins or are even nidus-like with a septated aneurysm. The majority of PAVMs are found in the lower and subpleural lung zones. Among individuals with PAVM, 35-65 % have multiple lesions and about 25% have bilateral disease. The presence of multiple PAVMs should raise suspicion for underlying HHT.

A variety of serious complications can arise with PAVMs. Cerebrovascular accidents and brain abscesses are devastating complications that are thought to occur via the crossing of blood clot, bacteria, and air bubbles through a PAVM into the systemic circulation. The normal capillary bed, which is absent in a PAVM, would otherwise function as a filter for such material. Hemothorax and massive hemoptysis can occur with PAVMs given their fragile and abnormally structured walls and the turbulent blood flow through them. Hypoxemia can also be associated with PAVMs, given right-to-left shunting of deoxygenated blood.

Hereditary hemorrhagic telangectasia (HHT)

HHT, also known as Osler-Rendu-Weber syndrome, is an autosomal dominant disorder characterized by the presence of arteriovenous malformations (AVMs) involving the vasculature of potentially multiple organ systems, such as the lungs, brain, GI tract, liver, and skin. The clinical presentation of HHT can vary depending on which organ systems are involved in a particular patient. HHT is the most common cause of PAVMs, accounting for more than 80% of all PAVMs. PAVMs in HHT are usually multiple (mean of 3 per patient). Diffuse, innumerable PAVMs occur in about 5% of cases of HHT with PAVM disease.

In 2000, consensus clinical diagnostic criteria for HHT, known as the Curacao Criteria, were published to include:

• Spontaneous and recurrent epistaxis

• Multiple mucocutaneous telangiectasias at characteristic sites: lips, oral cavity, fingers, nose

• Visceral lesions: gastrointestinal telangiectasias, pulmonary, hepatic, cerebral, or spinal arteriovenous malformations

• A first-degree relative with HHT based on these criteria

Using these criteria, a diagnosis is considered “definite” if three or more criteria are met, “possible or suspected” if two criteria are met, and “unlikely” if one or no criterion is met.

Because it can sometimes be difficult to establish a definitive diagnosis of HHT in an individual, and because expertise and experience is required in the management of visceral disease involvement, it is recommended that individuals with suspected HHT be referred to an HHT Center of Excellence for diagnosis and management.

Classification:

The most common causes of PAVMs are inherited (with HHT accounting for at least 80% of all PAVMs) and idiopathic. Rarer causes of PAVMs include hepatic cirrhosis with hepatopulmonary syndrome, post-surgery for congenital heart disease (including the Glenn shunt and bidirectional cavopulmonary anastomosis), lung trauma, mitral stenosis, schistosomiasis, actinomycosis, Fanconi’s syndrome, and metastatic thyroid carcinoma.

HHT is a multisystem disorder, and it has many associated symptoms and complications from organ AVMs and telangiectasias, which are described in detail in the subsequent sections. In addition, HHT can be associated with pulmonary hypertension and juvenile polyposis.

Pulmonary hypertension is increasingly recognized to occur in association with HHT, although the exact prevalence is not known. Pulmonary hypertension in HHT most commonly manifests as venous hypertension in association with liver vascular malformations that are due to high cardiac output and resulting left-sided heart failure. These patients usually have elevated left atrial pressures and decreased pulmonary vascular resistance. However, a minority of HHT patients have pulmonary arterial hypertension with a normal left atrial pressure, normal or decreased cardiac output, and elevated pulmonary vascular resistance. Pulmonary hypertension in HHT of all types has been primarily reported in patients with the ACVRL1 mutation.

Juvenile polyposis is associated with the SMAD4 HHT mutation. Less than 1% of HHT patients have associated juvenile polyposis. These individuals are at increased risk for GI bleeding and GI malignancy.

Are you sure your patient has a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia? What should you expect to find?

Pulmonary arteriovenous malformations (PAVMs)

Symptoms of PAVM include dyspnea, chest pain, and hemoptysis. Signs include hypoxemia, orthodeoxia, cyanosis, clubbing, and pulmonary bruits.

Only about half of the patients with PAVMs have dyspnea, and less than 10% have other symptoms and signs, such as hemoptysis, cyanosis, clubbing, or bruits. Platypnea (dyspnea experienced in the upright position that is improved in the supine position) and orthodeoxia (a drop of >5% in saturation when the patient moves from the supine to a standing position) may develop given the basilar lung predominance of PAVMs and the gravitational redistribution of blood flow within the lung on orthostasis.

Initial manifestations of PAVMs may not be respiratory-related but rather symptoms and signs of related complications, including stroke, transient ischemic attack, and cerebral abscess. This underscores the insufficiency of the clinical examination for identification of PAVMs and the importance of screening for PAVMs with investigations in order to help prevent life-threatening and debilitating complications.

Hereditary hemorrhagic telangectasia (HHT)

Symptoms of HHT include:

• Recurrent spontaneous epistaxis – This is the most common symptom of HHT. About half of HHT patients develop epistaxis by age twenty years, and about 80-100% develop epistaxis eventually. Epistaxis and mucocutaneous telangiectasias help confirm a diagnosis of HHT.

• Gastrointestinal bleeding – While 80% of HHT patients have gastric, small intestinal, and (less frequently) colonic telangiectasias or AVMs on endoscopy or capsule examination, only 25-30% develop GI bleeding, which generally presents as anemia. HHT-related GI bleeding generally presents later in life, in the fifth or sixth decade, and women are more frequently affected than men (2-3:1 ratio). GI bleeding in HHT is slow, chronic, and intermittent and is more often from upper GI telangiectasias rather than lower GI telangiectasias.

• Bleeding from other sites of telangiectasias, such as the lip, mouth, conjunctivae, and airway – these symptoms are infrequent.

• Symptoms from anemia, such as fatigue.

• Symptoms related to PAVMs (see above) – PAVMs are present in approximately 30% of patients with HHT.

• Symptoms related to cerebral vascular malformations – Cerebral vascular malformations, which occur in 10-23% of HHT patients, can cause headache, seizure, hemorrhagic stroke, or transient ischemic attack that is due to a steal effect on surrounding tissues. Complications arising from PAVMs are the source of neurologic symptoms in two-thirds of those who develop such symptoms, and cerebral vascular malformations are the cause in the remaining third.

• Symptoms of liver vascular malformations – Liver vascular malformations are present in 32-78% of HHT patients, although less than 10% will go on to develop symptoms from these malformations. Symptoms include right upper quadrant fullness or discomfort, symptoms of heart failure, or portal hypertension.

Signs of HHT include:

• Mucocutaneous telangiectasias – These occur in about 75% of individuals with HHT. They typically present later in life than epistaxis does, and typically increase in size and number with advancing age. Telangectasias are typically small, discrete, blanchable red or purple lesions. The telangiectasias can occur on the lips, tongue, palate, buccal mucosa, face, conjunctivae, hands, fingertips, nailbeds, and elsewhere.

• Signs of anemia.

• Signs related to PAVMs (see above).

• Signs of stroke related to cerebral vascular malformations or PAVMs.

• Signs related to liver vascular malformations, including hepatomegaly, liver bruit, high-output heart failure, signs of portal hypertension, and signs of biliary disease.

Beware: there are other diseases that can mimic a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia:

Clinical mimics of a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia are those that also have massive hemoptysis, hypoxemia and shunting, or dyspnea as symptoms.

Other causes of massive hemoptysis include acute bronchitis, chronic bronchitis, bronchiectasis, lung neoplastic disease, pulmonary infections (bacterial, mycobacterial, fungal, parasitic, lung abscess), interstitial lung disease, pulmonary vasculitis syndromes (e.g., granulomatosis with polyangiitis, Goodpasture’s disease), lung trauma, pulmonary embolus, cardiac causes (mitral stenosis, left ventricular failure), and spurious (epistaxis, hematemesis).

Other causes of hypoxemia and shunting include intrapulmonary vascular dilatations (IPVDs) and hepatopulmonary syndrome (HPS). IPVDs are abnormally dilated alveolar septal capillaries, but they are rarely visible on CT imaging. IPVDs are usually established by the presence of late shunting on agitated saline contrast echocardiography (i.e., bubbles appearing after three cardiac cycles) or shunting of radioisotope-labeled macroaggregated albumin. Like PAVMs, IPVDs can cause dyspnea, platypnea, clubbing, hypoxia, and orthodeoxia.

IPVDs, along with liver dysfunction and abnormal gas exchange, form the clinical triad that characterizes hepatopulmonary syndrome. The vast majority of HPS patients initially present with features of liver disease, while only a minority initially manifest with respiratory symptoms.

Other causes of dyspnea include obstructive airways disease, interstitial lung disease, pulmonary infections, lung neoplastic disease, pulmonary vascular disease (e.g., thromboembolic disease, pulmonary hypertension, IPVDs, HPS), pulmonary vasculitis syndromes, chest wall and neuromuscular disease, and cardiac causes (e.g., ischemia, pulmonary edema)

Capillary Malformation-AVM syndrome is an HHT-like syndrome. This is an autosomal dominant disorder associated with the RASA1 gene mutation. The capillary malformations associated with this syndrome are characterized by an erythematous-brownish colour, a non-discrete appearance, and a random and multifocal distribution. Affected individuals may have intracranial or spinal AVMs.

Imaging mimics for PAVMs include malignant lung nodule, benign lung nodule (e.g., hamartoma, fibroma), healed/non-specific granulomas, active granulomatous infection (mycobacterial, fungal), other local infection (bacterial abscess, parasitic), inflammatory nodules (e.g., granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis), congenital anomalies (e.g., bronchogenic cyst, bronchopulmonary sequestration), other pulmonary vascular abnormalities (e.g., pulmonary artery aneurysms, pulmonary varix), rounded atelectasis, healed pulmonary infarct, paraffinoma or lipoid pneumonia, loculated interlobular pleural effusion, mucoid impaction, and intrapulmonary lymphadenopathy.

How and/or why did the patient develop a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia?

The vast majority of PAVMs (80%) occur in individuals with HHT, which is inherited as an autosomal-dominant trait with varying penetrance and expression. Genes involved in HHT encode proteins that mediate signaling by the transforming growth factor-superfamily expressed on vascular endothelial cells. It is believed that HHT-related gene mutations results in a lack of sufficient gene products for normal vascular endothelial cell function.

At least five HHT gene mutations/and or loci have been identified:

• Endoglin (ENG) gene mutation on chromosome 9 (known as Type 1 HHT) – This gene mutation appears to be associated with increased PAVM, cerebral vascular malformation, and onset of epistaxis and telangiectasias at an earlier age than usual.

• Activin receptor-like kinase 1 (ACVRL1) gene mutation on chromosome 12 (known as Type 2 HHT) – This gene mutation is associated with increased risk of hepatic vascular malformations, and in some series, with GI bleeding. Although a rare manifestation, pulmonary arterial hypertension has mostly been reported with ACVRL1 gene mutations.

• Smad4 gene mutation on chromosome 18 – This gene mutation is also associated with juvenile polyposis and with the JP-HHT overlap syndrome.

• Unidentified gene mutation on chromosome 5 (known as Type 3 HHT).

• Unidentified gene mutation on chromosome 7 (known as Type 4 HHT).

More than six hundred mutations have been identified in the ENG and ACVRL1 genes in HHT patients. Neither gene displays a common mutation, and many mutations thus far identified have been reported only once. Deletions, insertions, missense and nonsense, and types of splice site mutations have all been identified in HHT. An estimated 85% of patients with HHT (with all four Curacao diagnostic criteria being present) have either ENG or ACVRL1 mutations, with ENG mutations more common in North American series and ACVRL1 mutations more common in European series. A Smad4 mutation is estimated in less than 2% of HHT patients.

More recently, two new mutations have been identified related to HHT. First, a missense mutation in the bone morphogenetic 9 (BMP9) gene (GDF2) on chromosome 10 has been identified that is estimated to account for <1% of HHT cases. Pulmonary arterial hypertension has been reported with the GDF2 mutation. Second, RASA1 gene mutations have been identified in small numbers of individuals with suspected HHT. However, individuals with RASA1 gene mutations have telangiectasias that are atypical in both appearance and location compared with HHT and are thought to have a distinct disorder (Capillary Malformation-AVM syndrome).

Which individuals are at greatest risk of developing a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia?

The vast majority of PAVMs (80%) occur in individuals with HHT. Other less common risk factors for PAVMs are listed above. Although PAVMs are seen with all known HHT gene mutations, the HHT gene mutation with which PAVMs are more commonly associated is the ENG gene mutation. PAVMs occur twice as frequently in women than in men. Significantly sized PAVMs are reported in children, although the risk of complications may be lower in children than in adults. Male sex, advancing age, and hypoxemia are associated with increased risk of cerebral abscess with PAVMs in the context of HHT. Multiplicity of PAVMs is also associated with increased risk of cerebrovascular accidents.

The epidemiology of HHT is poorly understood. The estimated prevalence is one in 5000-8000. HHT is thought to be present in all ethnic groups, although higher prevalence rates have been reported in certain ethnic groups, such as Afro-Caribbean residents of Curacao and Bonaire. Symptoms and complications of visceral organ involvement in HHT (lung, brain, GI tract) gradually increase with advancing age.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Pulmonary arteriovenous malformations (PAVMs)

Arterial blood gas, if hypoxemia suspected.

Hereditary hemorrhagic telangectasia (HHT)

• CBC, specifically to look for the presence of a microcytic anemia secondary to blood loss (epistaxis or occult GI bleeding)

• Ferritin, to assess for iron-deficiency secondary to blood loss (epistaxis or occult GI bleeding)

• Liver function tests (total bilirubin, INR, albumin) and liver enzymes (ALP, GGT, AST, ALT) as abnormalities may suggest the presence of liver vascular malformations

What imaging studies will be helpful in making or excluding the diagnosis of a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia?

Pulmonary arteriovenous malformations (PAVMs)

Agitated saline contrast echocardiography

This test demonstrates the presence of intrapulmonary shunting. In this procedure, saline microbubbles are injected intravenously during transthoracic echocardiography. In the normal pulmonary capillary bed, these microbubbles become trapped in the pulmonary capillaries and are eventually absorbed. However, with PAVMs, these microbubbles travel directly from the pulmonary arteries to the pulmonary veins and then appear in the left sided-heart chambers.

The degree of microbubbles seen in the left heart are graded on a five-point scale. Although this is a subjective and qualitative grading system, grade has been shown to be associated with positive predictive value for PAVMs in HHT patients. Since an intracardiac shunt (e.g., patent foramen ovale, atrial septal defect) can result in microbubbles appearing in the left heart, the timing of the appearance of the bubbles in the left heart is also used to distinguish between intracardiac and intrapulmonary shunt. By convention, if the bubbles appear within three cardiac beats, the shunt is classified as “early” and likely intracardiac, whereas if the bubbles appear after three cardiac beats, the shunt is classified as “delayed” and likely intrapulmonary.

However, the studies of bubble timing have not confirmed timing to be a reliable indicator of the location of the shunt, probably because the timing depends not just on the location but also on the severity of the shunt (e.g., large intrapulmonary shunts have early bubbles). Therefore the timing should be interpreted in the context of the shunt grading and the presence /absence of other echocardiographic findings of intracardiac shunt.

Agitated saline contrast echocardiography has been demonstrated to have the highest sensitivity (93%-97%) and lowest risk among screening tests for PAVMs in patients with HHT, compared to CT scan and pulmonary angiography. When chest radiography is combined with agitated saline contrast echocardiography, the sensitivity increases to 100%, which is why this combination of testing is recommended for initial screening of PAVMs.

The specificity of agitated saline contrast echocardiography is only 52%, perhaps because of the relatively high prevalence of patent foramen ovale in the general population (~30%). However, mild (grade 1) intrapulmonary shunting has also been demonstrated to occur in at least 10% of normal subjects. In HHT patients in whom the pre-test probability of PAVMs is high, a mild intrapulmonary shunt on contrast echocardiography, combined with a negative CT scan for PAVMs, is considered to represent possible microscopic PAVMs.

Computed tomography (CT) chest scanning

This is the current accepted diagnostic gold standard for confirming the presence and size of PAVMs suspected on chest radiography and/or contrast echocardiography (Figure 1). CT chest scans do carry a small radiation burden. Contrast enhancement is not required as non-contrast three-dimensional thin-cut CT scans can detect even small PAVMs (feeding artery diameter of 1mm)

Figure 1.

Chest radiography

On chest radiography, a discrete PAVM will typically present as a solitary, well-circumscribed, round or oval nodule/mass located in the lower and peripheral lung zones, with associated serpiginous structures representing associated vessels (Figure 2) (Figure 3). Anteroposterior chest radiography has excellent specificity (98%) but poor sensitivity (50-70%) in detecting PAVMs compared to CT scan and/or pulmonary angiography. However, when chest radiography is combined with agitated saline contrast echocardiography, the sensitivity increases to 100%. Therefore, agitated saline contrast echocardiography coupled with chest radiography are recommended as the initial screening tests for patients with suspected PAVMs. If both of these tests are negative, the presence of PAVM is very unlikely, but if either or both of these tests are positive, a CT chest scan should be obtained.

Figure 2.

Figure 3.

Pulmonary angiography

Although it is routinely performed during treatment with transcatheter embolotherapy, pulmonary angiography is used diagnostically only in circumstances in which there is uncertainty about the nature of the imaging abnormalities after CT scan. This test has more radiation burden and complications with lower resolution than CT scans, so it is not recommended for initial diagnosis. Digital subtraction angiography requires less radiation exposure than conventional angiography does, and both techniques appear to be of equal efficacy.

Hereditary hemorrhagic telangectasia (HHT)

Magnetic resonance imaging (MRI) of the head

The finding of cerebral vascular malformations can support the diagnosis of HHT since visceral organ involvement is one of the diagnostic criteria. Given that cerebral vascular malformations occur in approximately 10-23% of HHT patients, often with no warning symptoms, and given that catastrophic complications like intracranial bleeding can occur as a result, screening for cerebral vascular malformations for cases of possible or definite HHT is recommended. MRI is considered a safe, non-invasive method for screening for cerebral vascular malformations, but there are no screening studies that have assessed its utility in HHT.

MRI studies for cerebral vascular malformations in non-HHT populations suggest sensitivity of 80-95% for medium-sized to large lesions. The addition of contrast enhancement and the use of sequences to detect blood products may increase the sensitivity of testing, especially for micro-cerebral vascular malformations.

Esophagogastroduodenoscopy (EGD)

The finding of GI telangiectasias can support the diagnosis of HHT since visceral organ involvement is one of the diagnostic criteria. Although the majority of HHT patients have GI telangiectasias, the utility of endoscopic assessment is primarily in the anemic or iron-deficient patient. EGD is considered the initial study of choice for evaluating GI bleeding in HHT patients.

Liver imaging

The finding of liver vascular malformations can support the diagnosis of HHT since visceral organ involvement is one of the diagnostic criteria for HHT. Liver AVMs are detected in 32-78% of HHT patients, depending on the imaging modality used. It is recommended that patients with possible or definite HHT and abnormal liver enzymes and/or a clinical picture suggestive of complications from liver AVMs (i.e., high output heart failure, portal hypertension, biliary obstruction, encephalopathy, intestinal ischemia) be screened for liver AVMs with some form of imaging.

Several different liver imaging modalities are possible, including (from the least to the most invasive) Doppler ultrasonography, enhanced MRI, triphasic spiral CT, and mesenteric angiography. Doppler ultrasound is non-invasive, requires no contrast, and is not associated with procedural complications. MRI does require contrast enhancement, but it involves no radiation exposure. The triphasic CT protocol involves considerable radiation exposure and also the risks of contrast.

Mesenteric angiography has historically been considered the gold standard, but it is invasive and rarely used. It has been largely replaced by MRI or CT imaging. There are no comparative proper screening studies that have assessed the performance of these various imaging modalities, although the positive predictive value of Doppler ultrasonography has been reported to be near 100%.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia?

Oximetry – Hypoxemia can be present in cases of severe right-to-left shunting through a PAVM. Orthodeoxia may be present when the patient transitions from the supine to the upright position, given the basilar lung predominance of PAVMs and the gravitational redistribution of blood flow in the lung on orthostasis. However, these are not sensitive screening tests, as they are often normal in patients with significant PAVMs.

100% oxygen shunt test -This test can be used to assess for the presence of and estimate the degree of intrapulmonary shunting that is due to PAVMs. In this test, the arterial partial pressure of oxygen (PaO2) and the arterial partial pressure of carbon dioxide (PaCO2) are measured before and after 100% oxygen is breathed for fifteen to twenty minutes. The shunt fraction is then calculated using standard equations that include the measured PaO₂ and the alveolar partial pressure of oxygen estimated by the alveolar gas equation using measured arterial PaCO₂.

In normal subjects, about 5% of the cardiac output is shunted because of blood draining into the left atrium from the bronchial and coronary circulations and because of some degree of accepted alveolar ventilation-perfusion mismatch. A shunt fraction greater than 5% is considered abnormal. Many pulmonary disease states, such as atelectasis, pulmonary edema, and pneumonia, can cause right-to-left shunting through alveolar capillaries being in contact with non-functioning or partially functioning alveoli. Increasing the inspired fraction of oxygen (FiO₂) will partially or completely correct hypoxemia that is due to shunting from these conditions.

However, with PAVMs, since venous blood passes directly into the pulmonary venous system without coming into contact with alveoli, increasing the FiO₂ will not completely correct the shunt. Therefore, shunting that persists after application of 100% oxygen indicates the presence of an “absolute” shunt with an abnormal capillary network, such as a PAVM.

The 100% oxygen shunt test has excellent specificity (98%) but a relatively poorer sensitivity (68%). Because high arterial pO₂ is unstable and difficult to measure accurately, performing the 100% shunt test relies on a careful collection technique and rapid measurement using specially calibrated arterial blood gas equipment. Local ROC curves should be performed in every institution that performs this test.

Cardiopulmonary exercise stress testing – This is not commonly used in the evaluation of patients with PAVMs and HHT. Depending on the degree of shunting, arterial oxygen saturation and exercise capacity may fall when the patient moves from rest to exercise.

Pulmonary function tests – These are not helpful in diagnosing PAVMs or HHT. However, pulmonary function tests are helpful in determining whether other causes of dyspnea and hypoxemia are present.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia?

Pulmonary arteriovenous malformations (PAVMs)

As discussed above, agitated saline contrast echocardiography coupled with chest radiography are recommended as the initial screening tests for patients with suspected PAVMs. If both these tests are negative, the presence of a PAVM is highly unlikely. If either or both of these tests are positive, a CT chest should be obtained to confirm the presence of a PAVM. If the diagnosis is uncertain after CT, pulmonary angiography can be considered to clarify the diagnosis.

Hereditary hemorrhagic telangectasia (HHT)

It is difficult clinically to exclude the diagnosis of HHT since the “expression” of typical symptoms and signs (recurrent spontaneous epistaxis and multiple muco-cutaneous telangiectasias) are age-related and often do not appear until mid-life.

As discussed above, results of imaging investigations showing evidence of visceral organ involvement are one of the Curacao Criteria used to establish a diagnosis of HHT. Although genetic testing is not one of the four Curacao Criteria to establish a diagnosis of HHT in a potential index case, a positive test for one of the known HHT gene mutations can help support the diagnosis of HHT in such an individual.

However, the converse is not true. Negative genetic testing does not rule out the diagnosis of HHT in a potential index case since only a few of the genes that cause HHT have thus far been identified. If a gene mutation is discovered in an individual with definite HHT, genetic testing can be applied to other family members to confirm or rule out the presence of HHT in the family. If the relatives of the index case do not carry the family-specific gene mutation, a diagnosis of HHT can be effectively ruled out in these individuals. Further discussion around genetic testing for HHT follows in subsequent sections.

There are no other diagnostic tests or procedures that rule out HHT.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia?

Genetic testing in HHT is more complex than in many other genetic conditions because a mutation in one of several genes can cause HHT, HHT has variable penetrance and expression, not all genes that cause HHT have been discovered, and there are no common mutations. More than six hundred mutations have been identified so far, many of which have been reported only once.

While positive genetic testing in a possible case of HHT may help support the diagnosis of HHT in that individual, the primary goal of genetic testing in HHT is to identify the specific HHT gene mutation in a particular family in order to identify other individuals in that family who require further screening tests for HHT. Genetic testing is recommended on the index case of HHT in a family. Genetic testing usually involves DNA sequencing and deletion/duplication analysis of the coding exons for the two genes that account for the majority of cases of HHT: the ENG and ACVRL1 genes. If mutations in the ENG and ACVRL1 genes cannot be identified, SMAD4 gene mutation testing should be requested. If there is suspicion for a telangiectasia syndrome, but not classic HHT, GDF2 and RASA1 mutations should also be tested.

If you decide the patient has a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia, how should the patient be managed?

Pulmonary arteriovenous malformations (PAVMs)

Transcatheter embolotherapy or embolization is the recommended therapy for PAVMs. This technique involves conventional pulmonary angiography and the direct placement of embolic material (e.g., coils, plugs, or detachable balloons) into the feeding artery of the PAVM, with occlusion of blood flow. The selection of PAVMs for embolization is primarily based on a feeding artery diameter larger than 3mm since most complications of untreated PAVMs have been reported with lesions with a feeding artery diameter larger than 3mm. However, treating PAVMs with a feeding diameter of as low as 2mm may be appropriate, especially if there is evidence of paradoxical embolization or other complications. Embolotherapy should be performed by individuals with expertise, preferably in an HHT Center of Excellence.

Non-controlled studies of embolotherapy in centers with expertise in the procedure have shown high rates of immediate procedural success (close to 100%), improvements in dyspnea, improvements in oxygenation, and involution of PAVMs. There are no reports of procedural mortality. The most common post-procedural complication is self-limited pleuritic chest pain in 10-30% of cases. Other serious but rare post-procedural complications include TIA (0.5%), transient air embolus (5%), radiographic pulmonary infarction (3%), deep vein thrombosis (1.5%), migration of embolic material (1%), and arterial wall damage and perforation.

Reperfusion of PAVMs post-embolotherapy occurs in a minority of cases long-term (10-17%), so long-term follow-up of treated PAVMs is required with CT imaging. Non-contrast thin-slice CT chest scanning should be performed at approximately one year post-embolization to detect PAVM non-involution and interval growth of other small PAVMs, and every three to five years thereafter. Agitated saline contrast echocardiography is not usually useful post-embolization, as it remains positive in 90% of patients post-procedure.

Approximately half of HHT patients have small (i.e., with a feeding artery diameter <3 mm) but radiographically detectable PAVMs that are not routinely treated with embolotherapy. Such patients should be followed long-term with serial low-dose thin-slice CT chest scans about every three years, although some patients may require more frequent radiographic follow-up based on the size of their PAVMs and the development of new symptoms. Any lesions should be embolized when they become of significant size.

For patients with possible micro-PAVMs not detectable on initial CT chest scan but suggested by the presence of intrapulmonary shunting on echocardiography, reassessment with low-dose thin-slice CT chest scan should also be considered, although the interval for long-term reassessment remains uncertain in this low risk group. Consideration should always be given to limiting radiation exposure to patients.

Diffuse PAVM disease (~5% of HHT cases) poses special management challenges. Any discrete PAVMs with feeding arteries 3mm or larger in size should be embolized as described above. Often, 2-3mm PAVMs may be embolized as well, if feasible, although doing so often has only minimal impact on the severe hypoxemia that is typically present in these cases. Lobar and segmental artery embolization, lobectomy/pneumonectomy, and lung transplantation can be considered in cases of diffuse PAVM disease, although the evidence is limited for such cases, and these patients should ideally be managed in centers with expertise.

All patients with PAVMs, regardless of size, should take the following precautions to limit the risk of related complications:

• Antibiotic prophylaxis prior to any procedures with risk of bacteremia to prevent cerebral abscess – choice and duration of antibiotic therapy should follow the American Heart Association Guidelines for prevention of bacterial endocarditis.

• Use of an air-eliminating filter on all intravenous lines to prevent paradoxical air embolism.

• Avoidance of SCUBA diving to prevent decompression-related complications.

Hereditary hemorrhagic telangiectasia (HHT)

Comprehensive diagnosis and management of all aspects of HHT that are detailed in the International HHT Guidelines are summarized below.

Screening for visceral organ involvement – All patients with possible or definite HHT should be screened for PAVMs at initial clinical assessment with chest radiography and agitated saline contrast echocardiography. Positive screening should be confirmed with non-contrast three-dimensional thin-cut CT chest scan. In patients with negative initial screening, repeat screening should be considered after puberty, within five years preceding a planned pregnancy, and otherwise every five to ten years.

All patients with possible or definite HHT should be screened for cerebral vascular malformations at initial clinical assessment with head MRI with or without contrast administration and using sequences that detect blood products. If a head MRI is negative during adulthood, no further screening is recommended. Although there is international controversy regarding the role of routine screening for cerebral vascular malformations in HHT, there is excellent consensus across North America. Such screening is routinely performed in HHT Centers in North America.

When patients with HHT have abnormal liver enzymes and/or a clinical picture suggestive of complications of vascular malformations in the liver (i.e., high output heart failure, portal hypertension, biliary ischemia, encephalopathy, intestinal ischemia), they should be screened for liver AVMs with some form of imaging.

Anemia and iron-deficiency in HHT is often due to epistaxis, but when the anemia and/or iron deficiency is disproportionate to the severity of epistaxis, a GI source should be considered and EGD undertaken.

Management of epistaxis: Agents that help humidify the nasal mucosa, such as topical antibiotic ointment and saline, are recommended as first-line therapy. Systemic antioxidant therapy (N-acetylcysteine 600 mg t.i.d) is low-risk and has been shown in one non-controlled study to improve epistaxis, so it is given early in management. Topical estrogen (0.1% estriol applied twice daily) or antifibrinolytic ointments (e.g., tranexamic acid) can be used as the next-line therapy. The aforementioned topical therapies, plus topical bevacizumab (which is an angiogenesis inhibitor), have been recently evaluated in randomized controlled trials among HHT patients. A multi-center, multi-arm, randomized controlled trial showed no significant difference in epistaxis frequency between topical bevacizumab 1%, topical estriol 0.1%, topical tranexamic acid 10% and placebo. Another multi-center randomized controlled trial showed no difference in mean monthly epistaxis duration with topical bevacizumab 1% versus placebo.

Systemic estrogens (> 625 mcg/day ethinylestradiol equivalent), antifibrinolytic agents (high-dose tranexamic acid 1g q.i.d.) and antiestrogens (tamoxifen 20 mg/day for six months), have been shown in controlled trials to reduce epistaxis and can be used in cases not responsive to topical therapies. The potential benefits of hormone and antifribrinolytic agents should be weighed against these agents’ potential for being prothrombotic and the increased risk for HHT patients, particularly patients with PAVMs, for complications such as thromboembolic strokes.

Procedural therapies for epistaxis non-responsive to pharmacologic therapies include endonasal laser, electrical or chemical coagulation, replacement of endonasal mucosa with skin or buccal mucosa (septal dermoplasty), nasal artery embolization, and closure of the nasal cavity (Young’s procedure). Such procedures can be considered in refractory cases but should be performed by otolaryngologists with HHT expertise.

Management of cerebral vascular malformations – Given the relatively low prevalence of cerebral vascular malformations in HHT and given the associated risks of treatment, decisions about invasive testing and therapy should be made on a case-by-case basis at centers with expertise in the various treatment modalities. Treatment modalities include embolization, surgical resection, stereotactic radiation, or a combination of these.

Management of GI telangiectasias – Aggressive iron replacement to correct iron deficiency should be the initial approach. Beyond iron replacement, medical management options for GI bleeding in HHT include hormonal therapy (estrogen/progesterone preparations) and antifibrinolytics (tranexamic acid). Endoscopic management of GI telangiectasias using argon plasma coagulation or ND-YAG laser can be used to help treat significant ongoing GI bleeding refractory to medical management. However, endoscopic therapy is often not definitive, and repeated endoscopic procedures are often risky and not useful. Argon plasma coagulation is considered superior to ND-YAG laser. There is no role for surgery, embolotherapy, or cauterization of GI telangiectasias.

Management of liver vascular malformations – Most patients with liver vascular malformations are asymptomatic and do not require treatment. The initial treatment of high output cardiac failure associated with liver malformations should focus on aggressive diuresis, beta blockers, correction of anemia, and management of atrial fibrillation if present. Beta blockers should also be the initial medical management in complications of biliary ischemia.

Liver transplantation can be considered in patients with liver malformations who develop complications of ischemic biliary necrosis, intractable heart failure, and intractable portal hypertension. HHT-related liver transplantation is associated with symptom improvement in many and with good survival rates (five-year survival of 83%). Case reports of angiogenesis inhibitors like the VEGF antagonist bevacizumab have been positive–even temporarily obviating the need for liver transplantation in a case. Hepatic artery embolization is discouraged because its effects are often transient and because complications, such as death and the need for liver transplantation, are high (30%).

Management of iron-deficiency anemia – Treating the underlying cause(s) of bleeding (e.g., epistaxis, GI bleeding), as well as aggressive iron replacement, should be the initial approach. In severe cases, intravenous iron therapy and even regular blood transfusions are necessary.

What is the prognosis for patients managed in the recommended ways?

Pulmonary arteriovenous malformations (PAVMs)

PAVMs generally slowly increase in size over time, and they rarely spontaneously regress. PAVMs also increase in size during pregnancy, which highlights the need for their prompt identification and management in patients who are pregnant or plan to become pregnant. Untreated PAVMs are associated with a risk of cerebral abscess in about 10-20%, stroke/TIA in 10-40%, massive hemoptysis or spontaneous hemothorax in 4-20%, and mortality in upwards of about 20% of cases. Embolotherapy has high rates of PAVM involution, with reperfusion occurring in a minority of cases (10-17%).

Hereditary hemorrhagic telangiectasia (HHT)

The natural history of HHT is not well understood. Disease manifestations are usually not present at birth but appear with advancing age. Epistaxis is usually the first symptom to appear, often in childhood, followed by PAVMs often after puberty, followed by mucocutaneous telangiectasias and gastrointestinal involvement later in life. Rupture and hemorrhage of cerebral vascular abnormalities is estimated at 0.5-4.0% per year. Symptomatic GI bleeding occurs in about 25-30% of HHT patients.

The natural history of liver vascular abnormalities in HHT is poorly understood, but symptoms and complications appear to occur in under 10% of cases. The efficacy of the various treatment options available for cerebral vascular abnormalities, HHT-related GI bleeding, and liver vascular abnormalities is poorly understood.

What other considerations exist for patients with a pulmonary arteriovenous malformation or hereditary hemorrhagic telangiectasia?

Family genetic counseling

Once a clinical diagnosis of HHT has been established and an HHT gene mutation has been identified, the patient/index case should be encouraged to speak to other family members about screening for HHT. Genetic testing should be recommended for first-degree relatives who are asymptomatic or do not clearly meet clinical diagnostic criteria, while those with a clinical diagnosis of HHT do not require confirmation by genetic testing. If the relatives of the index case do not carry the familial HHT mutation, a diagnosis of HHT can be effectively ruled out.

However, if the relatives of the index case are found to carry the familial HHT mutation, basic clinical examination supplemented by screening for PAVMs (i.e., with agitated saline contrast echocardiography and chest radiography) and screening for cerebral vascular malformations (i.e., with head MRI) should be performed, with additional screening for other possible visceral organ involvement depending on symptoms and the results of the initial assessment. If no mutation is identified in the index case, genetic testing cannot be offered to other family members. In these situations, at-risk family members should consider screening for PAVMs and cerebral vascular malformations since the diagnosis of HHT is difficult to rule out on clinical grounds, especially in children and young adults.

Because HHT symptoms may not manifest until later in life, the diagnosis of HHT cannot be ruled out in a young child of a parent with HHT unless the child has undergone genetic testing and the results are negative. Prenatal genetic testing is feasible but rarely pursued because most children with HHT are asymptomatic and because fetal diagnosis does not alter pregnancy or delivery management.

Pregnancy

Pregnancy is not contraindicated in HHT; the vast majority of pregnant patients with HHT have a normal pregnancy and delivery. Because PAVMs can enlarge during pregnancy, identification and treatment of PAVMs should occur before pregnancy, although treatment can be undertaken safely in pregnancy if required. Cerebral vascular malformations should also be managed before pregnancy.

If a patient is already pregnant, it is recommended that definitive treatment of any cerebral vascular malformations be deferred until after delivery. In the vast majority of patients, epidural anesthesia can be safely given prior to delivery, given that the prevalence of spinal AVMs in HHT is very low (<1%) with no known cases of hemorrhage related to epidural anesthesia in HHT in the literature. An MRI of the spine can also be undertaken to exclude the possibility of spinal AVMs. In cases of known or suspected PAVMs, antibiotic prophylaxis should be provided for delivery, and air filters should be applied on any intravenous lines.

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