REVIEW URRENT C OPINION
Pulmonary vascular complications of hereditary haemorrhagic telangiectasia Sebastian Circo and James R. Gossage
Purpose of review The purpose of this study is to present the latest advances and recommendations in the diagnosis and treatment of pulmonary vascular complications associated with hereditary haemorrhagic telangiectasia (HHT): pulmonary arteriovenous malformations (PAVMs), pulmonary arterial hypertension (PAH), pulmonary hypertension associated with high output cardiac failure or liver vascular malformations, haemoptysis, haemothorax and thromboembolic disease. Recent findings Transthoracic contrast echocardiography has been validated as a screening tool for PAVM in patients with suspected HHT. Advancements in genetic testing support its use in family members at risk as a cost-effective measure. Therapy with bevacizumab in patients with high output cardiac failure and severe liver AVMs showed promising results. PAH tends to be more aggressive in HHT type 2 patients. Summary Patients suffering from this elusive disease should be referred to HHT specialized centres to ensure a standardized and timely approach to diagnosis and management. Keywords haemoptysis, haemothorax, hereditary haemorrhagic telangiectasia, pulmonary arteriovenous malformation, pulmonary hypertension
INTRODUCTION Hereditary haemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu disease, is a genetic disorder that may lead to abnormal development of arteriovenous communications in virtually every organ. Depending on the vessel calibre and anatomical location, these anomalous communications are prone to rupture and cause significant bleeding complications. Although epistaxis is the most common complication (seen in 90–95% of patients), pulmonary manifestations are the most common of the serious complications and include pulmonary arteriovenous malformation (PAVM) [1–3], pulmonary hypertension [4], haemoptysis, haemothorax and pulmonary embolism. The purpose of this review is to present the latest advances and recommendations in the diagnosis and treatment of pulmonary complications of HHT.
[1,2] and higher in certain geographic areas. The highest prevalence in the world, one in 1331 inhabitants, is in the Afro-Caribbean population of the Netherland’s Antilles [2]. The pathophysiology of HHT is related to alterations in the transforming growth factor-b (TGF-b) signalling pathway leading to abnormal angiogenesis. Mutations in two major genes encoding endothelial surface proteins, the endoglin gene (ENG) causing HHT type 1 (HHT1) and activin receptor-like kinase 1 gene (ACVRL1) causing HHT type 2 (HHT2) are responsible for the majority of cases. Mutations in these two genes result in a significant reduction in the level of functional endoglin and activin receptor-like kinase 1 proteins and to dysregulation of the TGF-b signalling pathways. These alterations predispose to the formation of focal vascular lesions with fragile walls Georgia Regents University, Augusta, Georgia, USA
BACKGROUND OF HHT The transmission of HHT follows an autosomal dominant pattern and the incidence is thought to be on average one to two cases per 10 000 people
Correspondence to James R. Gossage, Georgia Regents University, BBR5521, 1120 15th street, Augusta, GA 30912, USA. Tel: +1 706 721 6789; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:421–428 DOI:10.1097/MCP.0000000000000076
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Disorders of the pulmonary circulation
KEY POINTS All patients with definite or suspected HHT should be screened for PAVMs. Transthoracic contrast echocardiography is the screening test of choice for PAVM. HHT patients who are pregnant should be referred to HHT specialized centres. Pulmonary hypertension, whenever suspected, should be immediately investigated, as these patients are at high risk for severe complications and may require specific therapies. Referral to an HHT specialized centre both for screening and for follow-up is of outmost importance.
The International Consensus guidelines for the Diagnosis and Treatment of HHT recommend screening for HHT in all first-degree family members of a patient who has been diagnosed with possible or definite HHT [9]. In paediatric patients and younger adults, the value of the Curac¸ao criteria may be limited by the lag in symptom onset. Genetic testing has emerged as an important tool to help make the diagnosis by identifying the causative mutation. Prigoda et al. [11] performed genetic analysis on 194 families and found a sensitivity of 80% for detection of a known genetic mutation. The remaining 20% may carry mutations too complex to detect or yet to be identified. Although genetic testing may not be readily available in most medical centres and has its own limitations, it may have a significant economic impact by decreasing healthcare costs as outlined in a study by Bernhardt et al. [12 ]. &
and arteriovenous shunting. Although the mechanisms are unclear, possible triggers such as hypoxia or local haemodynamic changes could promote tissue inflammation or endothelial cell injury [2], along with the influence of modifier genes. More recently, a combined syndrome of juvenile polyposis and HHT (JPHT) has been described, involving mutations to the downstream mediator SMAD family member 4 (SMAD4) [2–4]. The diagnosis of HHT is most commonly considered after recurrent episodes of epistaxis in a patient with a family history of the same. In a large study looking at pulmonary vascular complications in adults with HHT, the most common clinical findings were epistaxis and telangiectasias in 91.4 and 95.2% of patients, respectively [5]. In the same cohort, a family history of HHT was present in 88.9% of cases. The mean age of onset for epistaxis is about 12 years with up to 95% affected by age 40 [6–8]. The appearance of telangiectasias can be delayed 5–20 years after the onset of epistaxis and overall tend to appear earlier in patients with HHT type 1 than in those who have HHT type 2 [8]. The diagnostic criteria for HHT were first published in 2000 and are referred to as the Curac¸ao criteria that include spontaneous recurrent epistaxis, multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose), visceral AVMs (lung, brain, liver, spine, gastrointestinal) and a firstdegree family member diagnosed with HHT by these same criteria. Meeting three or more of these criteria makes the diagnosis definite [9]. A recent study of the Curac¸ao criteria reported a positive predictive value (PPV) of 100% for a definite diagnosis and a negative predictive value (NPV) of 97.7% for an unlikely diagnosis, when compared with DNA testing [10 ]. &&
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PULMONARY ARTERIOVENOUS MALFORMATIONS Pulmonary arteriovenous malformations (PAVMs) represent direct communications between pulmonary arteries and veins. This anomaly creates a right to left shunt that can cause a decrease in oxygen saturation and also increase the chance of paradoxical embolism by bypassing the lung’s natural filtration ability. PAVMs are simple if they have a single feeding artery (Fig. 1) or complex for two or more feeding arteries (Fig. 2). In HHT patients, the PAVMs tend to be multiple, bilateral and are mainly located in lower lobes [13]. Depending on the definition of PAVM and the underlying population, PAVM can be present in up to 85% of patients with HHT [1,5,14 ]. However, approximately 40% of all HHT patients will have a visible PAVM on computed tomographic (CT) scan. Table 1 represents data from the study published by van Gent et al. [15], showing an overall higher incidence of PAVM in HHT1 than in HHT2. On the contrary, 80–90% of patients with PAVM will have HHT as the underlying cause. Due to the serious nature of complications arising from untreated PAVM, screening is recommended. Common clinical features associated with the presence of PAVM are epistaxis, dyspnoea, telangiectasias, cyanosis, clubbing in the presence of significant right to left shunt, paradoxical embolism and brain abscess. As most of the PAVM tend to be located at the bases of the lung, orthodeoxia and platypnoea can be seen [16]. The presence of right to left shunting caused by PAVMs can cause severe hypoxemia. The shunt can be quantified by measuring the arterial blood gases after 15 min of inspiring 100% oxygen with deep &
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Hereditary haemorrhagic telangiectasia Circo and Gossage Table 1. Incidence of pulmonary arteriovenous malformation in genetically proven hereditary haemorrhagic telangiectasia patients [15] HHT patients screened for PAVM HHT 1
Artery
HHT 2
Positive TTCE
84.8%
35.1%
Visible PAVM on CT scan
58.2%
17.9%
29%
3%
Treatable PAVM
Patients with HHT1 are much more likely to have PAVM than those with HHT2. Treatable PAVMs are those with a feeding artery diameter of 3 mm. CT, computed tomography; HHT, hereditary haemorrhagic telangiectasia; PAVM, pulmonary arteriovenous malformation; TTCE, transthoracic contrast echocardiography.
AVM sac
!
FIGURE 1. Noncontrasted computed tomographic scan in a patient with a single small ‘simple’ pulmonary arteriovenous malformation in the right lower lobe. The feeding artery and AVM sac are visible. On other cuts, the draining vein is seen to connect to the AVM sac.
inspirations at every minute. Various formulas are available for calculating shunt, but it is important to include both paO2 and SaO2 in these calculations to optimize accuracy. A shunt value of 5% or less is considered normal. This relatively easy test is not recommended for screening due to poor reproducibility and low sensitivity (62%) [17]. Radionuclide
Draining vein
Artery
AVM sac
FIGURE 2. Contrasted computed tomographic scan in a patient with a large ‘complex’ pulmonary arteriovenous malformation in the left lower lobe. Both feeding arteries and a large and convoluted AVM sac are visible. A huge draining vein is seen exiting from the sac; although the vein appears to connect to the lateral most artery, this is an artefact of volume averaging and is easily differentiated on other cuts.
lung scanning has also been used to assess and quantify right-to-left shunting. After injection of 99mTc-labelled albumin particles, radioactivity is detected over cerebral, renal and thyroid areas in patients with significant right to left shunt. Being an expensive test and having poor sensitivity (79%) are the main reasons why it is no longer recommended in HHT [17]. Contrast echocardiography is the screening test of choice with sensitivity up to 98.6% [18]. More recent studies have proven the excellent reproducibility and safety of this noninvasive test. Grading systems to characterize the shunt have been developed to help guide the clinical approach [15,19 ,20]. Velthuis et al. [19 ] demonstrated a direct relationship between shunt grade on transthoracic contrast echocardiography (TTCE) and prevalence of cerebral manifestations in patients screened for HHT. A pulmonary shunt grade 1 (100 microbubbles) pulmonary shunt were independent predictors of cerebrovascular events and brain abscess [19 ]. The methodology of TTCE includes placement of a peripheral intravenous line with two 10 ml syringes connected to a three-way stopcock, one containing 8 ml isotonic saline and the other 1 ml air. Some authors additionally drew 1 ml of blood into the air-filled syringe. Subsequently, the air and saline are rapidly flushed between the two syringes to create an agitated saline solution. The patient should be positioned in the left lateral position and 5–10 ml of agitated saline is injected within 3 s, although projecting the four-chamber apical view. A pulmonary right to left shunt is considered present if one or more microbubbles appear in the left ventricle after three to four cardiac cycles [19 ].
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A noncontrasted high-resolution CT scan of the chest remains the gold standard for identification of PAVM and to help select those suitable for embolization therapy [15,21]. The morphology of a PAVM is highly characteristic and shows a feeding artery and draining vein with a sacular or fistulous communication in between (Figs 1 and 2). For all but the smallest PAVM, this is easily demonstrated without contrast. Our own practice is to perform a CT scan of the chest in all patients with possible HHT and a grade 2 or 3 right to left shunt on TTCE. However, in most patients with a grade 1 shunt or less, we defer a CT scan unless the shunt worsens in the future [18]. This is based on data published in three separate studies [15,20,22] on prevalence of PAVM by shunt grading on TTCE that used a quantitative measurement with less than 30 bubbles as an upper limit for grade 1 right to left shunt. The combined data from all three studies showed the upper limit of finding a treatable PAVM to be 2.1% in patients with a grade 1 shunt [18]. In addition, the lifetime risk of malignancy associated with ionizing radiation delivered during CT is one in 330 for a 20-year-old woman who received CT chest to rule out a pulmonary embolus and can be as high as 1 in 90 for a poorly designed imaging protocol [23]. Furthermore, for the sake of the Curac¸ao criteria, we consider a grade 2–3 right to left shunt as diagnostic for PAVM even in the presence of a negative HRCT scan. The mainstay of therapy for PAVM is catheterbased embolization therapy (embolotherapy). On the basis of data by Rosenblatt and others, the current recommendation of the Consensus Guidelines – and our own practice – is to embolize all PAVMs with a feeding artery diameter of at least 2–3 mm. In patients with a feeding artery of at least 3 mm, embolization of PAVM achieves normalization of the respiratory-related quality of life score as shown in a recent study by Blivet et al. [24]. Embolization can be done either by using MRI safe coils or by placing an endovascular plug. There are no randomized studies to evaluate the success rate of one procedure versus the other. The coils come in various shapes and sizes, and are easily delivered via catheter using the ‘anchor’ or ‘scaffold’ technique [25]. The endovascular plug is a selfexpandable occlusion device that can be delivered via catheter. It is more time saving than coiling, as one vascular plug can occlude a vessel that would otherwise require multiple coils, but its use is limited in the presence of small tortuous vessels in which situation coils are more easily delivered [26]. After embolotherapy, the PAVM sac will shrink and in time will form a fibrous scar. The risk of recanalization varies from 5 to 15% [26,27] and seems to be associated more with coil embolization than 424
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vascular plugging, especially if too few coils or poorly sized coils are used. The main mechanisms are related to persistence of feeding vessels due to inadequate occlusion, development of accessory feeding vessels and migration of endovascular material. The study by Woodward et al. [28 ] found recanalization through previously placed coils as the main pattern for PAVM persistence at 1-year follow-up. Several long-term follow-up series showed that these procedures have low morbidity, but these reports have come mainly from specialized and experienced centres. An HRCT of the chest at 6–12 months after embolotherapy is currently recommended to assess the continued success of the procedure [9]. Antibiotic prophylaxis prior to dental work below the gum line and some invasive procedures, and use of air filters for placing peripheral intravenous access remain crucial recommendations for any HHT patient with PAVM due to their increased risk for brain abscess and air embolism [19 ,20]. Special consideration should be given to the paediatric and pregnant populations. The presence of PAVM in the pregnant population carries significant morbidity, especially during the third trimester. The increased cardiac output associated with pregnancy is thought to be directly related to increased risk for rupture and secondary haemorrhagic complications such as massive haemoptysis, haemothorax and even death [29]. The greatest risk is in women who have not undergone screening for PAVM prior to pregnancy. TTCE is well tolerated during pregnancy and we recommend screening after the first trimester in all pregnant HHT patients who have not been screened in the last 2–3 years. If treatable PAVMs are discovered, we recommend embolotherapy after 16 weeks of pregnancy. If PAVMs are too small to treat, counselling and close follow-up are extremely important. In the paediatric population, there is still a lot controversy in terms of screening for PAVM and treatment. Given the limitations of the Curac¸ao criteria in this population, genetic testing is the gold standard to make the diagnosis of HHT. There are few examples in the literature of patients less than 12 years old who suffered cerebral events from asymptomatic PAVM. There is also some concern that treatment of PAVM in paediatric patients may be associated with a higher incidence of reperfusion. Our own practice is to screen for PAVM with TTCE in patients after the age of 10–12 years or in younger patients with dyspnoea or hypoxemia. If PAVMs with a feeding artery diameter of at least 3 mm are found, we discuss the pros and cons of treatment and make a decision on a case-by-case basis. &
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The current therapeutic approach for PAVM may change in the future. A recent study [30] describing the effects of antivascular endothelial growth factor mAb in mice models showed some significant improvement in the vascular architecture by stabilizing and improving previously formed PAVM.
PULMONARY HYPERTENSION Pulmonary hypertension is seen in patients with HHT and can occur by several mechanisms. Postcapillary pulmonary hypertension can be related to high output cardiac failure due to liver AVM and/or anaemia, while precapillary pulmonary hypertension can be related to thromboembolic disease or PAH. The gold standard for making the diagnosis remains right heart catheterization (RHC). In patients with hepatic AVM and pulmonary hypertension, RHC will typically show elevated pulmonary artery wedge pressure, high cardiac index and normal pulmonary vascular resistance (PVR) [31], although in patients with PAH, the pulmonary artery wedge pressure is normal, the cardiac index is normal or low, and the PVR is elevated [32]. Various studies have identified patients at risk using transthoracic echocardiogram as a screening test [33,34 ,35], although given the small numbers of patients reported and the lack of RHC data, the true prevalence remains uncertain. Olivieri et al. [36] found a systolic pulmonary artery pressure (PAP) of at least 40 mmHg in 13% of 68 unselected patients with HHT; the value rose to 20% in the 44 patients who had a reliable estimate of PAP. In a small series of 29 patients with a definite HHT who were hospitalized, 45% had possible or probable pulmonary hypertension by echocardiography [33]. Pulmonary hypertension is more prevalent in HHT2, being related to a higher prevalence of hepatic AVM and subsequent development of high output heart failure [35,37]. Ginon et al. [34 ] performed TTCE in 52 patients with hepatic AVM and cardiac symptoms and found an elevated cardiac index in 85% of patients. About 25% had a systolic PAP of at least 40, all of whom had an elevation in cardiac index and left ventricular filling pressure, and normal PVR. Common signs and symptoms include exertional dyspnoea, fatigue, leg oedema and atrial fibrillation. Medical therapy has been directed towards improvement in haemodynamics by controlling salt intake, correcting anaemia and use of antihypertensive and antiarrhythmic agents when clinically indicated [31,38]. In a recent study by Dupuis-Girod et al. [39 ], therapy with bevacizumab, an angiogenic inhibitor, was tried in a series of 25 patients with high output cardiac failure and &&
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severe liver AVM. The results after 3 months of follow-up showed a significant decrease in cardiac output and a marked improvement in quality of life [39 ]. Although bevacizumab may be useful in the management of high output heart failure due to liver AVM, it has no current role in the management of precapillary PAH. Other therapies such as trans-jugular intrahepatic porto-systemic shunt or trans-arterial embolization of hepatic AVM failed to produce significant improvement in symptoms or haemodynamic parameters and had a high rate of complications [31,40]. For patients with refractory high output hear failure, liver transplantation remains the best option to resolve the hyperdynamic circulatory state [31,38,41]. There have been a few case reports in literature that identified the presence of classic PAH in HHT patients that did not appear to be related to the presence of hepatic AVM [42–44]. These patients have normal filling pressures and a high PVR, so RHC is necessary to accurately make the diagnosis. In a study by Girerd et al. [32], patients with PAH who were carriers of a bone morphogenetic protein receptor type 2 (BMPR2) mutation or an ACVRL1 mutation were compared. Although patients with ACVRL1 mutations were found to be significantly younger at time of diagnosis and to have better baseline haemodynamic parameters, they had a worse prognosis when compared with BMPR2 carriers. None of the 23 ACVRL1 patients showed an acute response to pulmonary vasodilators. These patients appear to respond to the typical therapies used for PAH. Seven out of nine patients from French PAH network included in this study were found to have PAH before developing clinical manifestations suggestive of HHT. The coexistence of pulmonary hypertension and PAVMs has specific clinical and therapeutic implications. The presence of PAVM may have a protective role in the setting of underlying PAH by providing a low resistance system, which can attenuate right ventricular afterload. In time, as the pulmonary hypertension worsens, the risk of associated PAVM rupture increases, carrying significant mortality and morbidity [45]. Shovlin et al. [46] looked at the haemodynamic effect of PAVM embolization in 43 patients with HHT. Overall, embolization had no significant effect on pulmonary artery pressure; however, worsening pulmonary hypertension was documented in older patients [46]. All patients who underwent embolization had statistically significant improvement in their resting oxygen saturation [46]. Although this study supports embolotherapy in the setting of mild to moderate pulmonary hypertension, there is a paucity of studies examining its role in severe pulmonary
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hypertension. Embolization of PAVM in the setting of severe pulmonary hypertension may potentially worsen pulmonary hypertension and thus increase the risk of PAVM rupture, or alternatively it may decrease cardiac output and thus improve pulmonary hypertension. Each patient should be considered individually, but the higher the mean PAP and PVR at baseline, and the larger the PAVM, the greater is the likelihood of worsening pulmonary hypertension after embolization. As PAH also appears to be more aggressive in this population, we favour an aggressive approach with earlier consideration of prostacylins. We also recommend referral of these patients to centres that have expertise in both HHT and PAH.
HAEMOTHORAX Given the high incidence of PAVM in the HHT population, they are at particularly high risk for life-threatening complications such as haemothorax. In a retrospective study by Cottin et al. [47] in 126 patients with at least one PAVM, four were found to have a history of haemothorax, one being during pregnancy. Ference et al. [29] found that out of 159 patients with HHT and PAVM, 11 had massive haemoptysis or haemothorax requiring hospitalization. Seven women experienced haemothorax– three of them during pregnancy [29]. Although the prevalence of haemothorax tends to be lower than haemoptysis [48], the rupture of a PAVM has a life-threatening potential [45,49]. The majority of PAVM ruptures during pregnancy have occurred during the third trimester. If a treatable PAVM is identified in a pregnant patient, it is recommended to perform embolotherapy as soon as possible after the 16th week [17] to avoid rupture. In life-threatening cases, surgical lobectomy can be considered if local expertise with embolotherapy is not available.
usually a contrasted CT of the chest. If this does not show obvious PAVM or pulmonary embolism, bronchoscopy to screen for telangiectasias is reasonable. Treatment is mainly supportive for PAVM, and in severe cases, embolotherapy or surgical intervention can be considered. In case of bronchial telangiectasias, endobronchial cauterization can be performed, but the long-term response is unknown.
THROMBOEMBOLIC DISEASE There are data to suggest that patients with HHT are at an increased risk for venous thromboembolism. In a study by Shovlin et al. [53], factor VIII and von Willebrand antigen levels were found to be elevated in an HHT population compared with a non-HHT group. This association proved to be even higher in patients who developed thromboembolic events [53]. Due to the nature of the disease and recurrent bleeding, iron deficiency is common in HHT patients. A more recent prospective study by Livesey et al. [54] showed that the elevation in factor VIII levels and secondary increased risk for thromboembolism were directly related to low serum iron levels. The retrospective analysis of Lacombe et al. [52] over a period of 12 years showed that even though the overall incidence of PAVM thrombosis is fairly low (2.5%), it is associated with an increased rate of neurological complications such as ischemia or abscess formation. Given the underlying increased risk for bleeding associated with HHT, treatment is very challenging. A retrospective chart review study by Edwards et al. [55 ] found 64 HHT patients who had been prescribed antithrombotic medication; interview of 43 of these patients showed that bleeding complications were only minor in 58%. The authors concluded that HHT patients can be treated with antithrombotic medications as long as they have very close follow-up and had been previously screened and treated for PAVM or cerebral AVM [55 ]. &&
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HAEMOPTYSIS Potential causes of haemoptysis in HHT patients include rupture of a parenchymal PAVM or bronchial telangiectasias, and thromboembolic disease (see next section) [50,51]. Haemoptysis may sometimes be massive, especially with PAVM rupture. On the basis of studies published so far, the incidence is thought to vary between 4 and 20% for both adult and paediatric population [29,35,47]. However, in a retrospective analysis on 425 patients with known PAVM by Lacombe et al. [52], only six patients were found to have presented with haemoptysis secondary to spontaneous rupture of PAVM. After medical stabilization, the initial diagnostic approach is 426
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CONCLUSION HHT is a chronic and potentially disabling disease with a significant social and economic impact in the affected families. Recurrent nosebleeds in children should be a consideration for referral to a specialized HHT centre, although the Curac¸ao criteria in adults have proven to be an excellent screening tool. Most of the pulmonary vascular complications associated with this disease are secondary to the development of PAVM or liver AVM. The collaboration between the clinician and the interventional radiologist has established catheter embolotherapy as the preferred method of intervention both for prophylactic and Volume 20 Number 5 September 2014
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therapeutic reasons. Patients with HHT should be referred to an HHT specialized centre, receive genetic counselling and be fully educated about their condition and its clinical implications. Acknowledgements None. Conflicts of interest The authors have no conflicts to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Gossage JR, Kanj G. Pulmonary arteriovenous malformations. A state of the art review. Am J Respir Crit Care Med 1998; 158:643–661. 2. Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 2006; 43: 97–110. 3. Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004; 363:852–859. 4. Santibanez JF, Letamendia A, Perez-Barriocanal F, et al. Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. J Cell Physiol 2007; 210:456–468. 5. Cottin V, Plauchu H, Bayle J-Y, et al. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med 2004; 169:994–1000. 6. Plauchu H, de Chadare´vian JP, Bideau A, et al. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989; 32:291–297. 7. Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet 1992; 29:527–530. 8. Berg J, Porteous M, Reinhardt D, et al. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet 2003; 40:585–590. 9. Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet 2011; 48:73–87. 10. van Gent MW, Velthuis S, Post MC, et al. Hereditary hemorrhagic telangiec&& tasia: how accurate are the clinical criteria? Am J Med Genet A 2013; 161A:461–466. This is the first study to address the validity of the Curac¸ao criteria as the main tool to rule out or in the diagnosis of HHT. Two hundred and sixty-three first-degree relatives of HHT patients were included. The study showed that a definite diagnosis of HHT can be made with 100% certainty in first-degree relatives of patients with a known mutation, although the NPV of the clinical diagnosis was 97.7% in patients with unlikely diagnosis. For patients with a possible clinical diagnosis as well as individuals at a young age, genetic testing is particularly helpful. 11. Prigoda NL, Savas S, Abdalla SA, et al. Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations. J Med Genet 2006; 43:722–728. 12. Bernhardt BA, Zayac C, Trerotola SO, et al. Cost savings through molecular & diagnosis for hereditary hemorrhagic telangiectasia. Genet Med 2012; 14:604–610. A very interesting analysis from University of Pennsylvania in Philadelphia comparing costs associated with genetic testing versus clinical approach in first-degree relatives at risk for HHT (charge and payment data were obtained for FY2010 from the three health insurers in the area, excluding Medicare). In a computer model, up to four siblings or children of 100 HHT probands were assigned to a repeated clinical screening approach until the diagnosis was either affirmed or excluded, although the other group included 100 HHT patients who were genetically tested for mutation followed by genetic testing of at-risk relatives (up to 4 per proband) and clinical monitoring only in those who test positive for the familial mutation. In the clinical model, the initial diagnostic evaluation cost $7984, a follow-up screening evaluation costs $5375 and total lifetime costs for one family for follow-up screenings were estimated at $117 936. In the genetic testing model, the cost estimated for a similar family of four was estimated at $18 655. The main advantage for using the genetic screening is that it helps eliminate the need for costly follow-ups in up to half of patients at risk for HHT.
13. Cottin V, Crestani B. [Evidence based respiratory medicine. 6th update workshop of SPLF March 30th, 2007. Interstitial lung diseases]. Rev Mal Respir 2007; 24:1162–1167. 14. Giordano P, Lenato GM, Suppressa P, et al. Hereditary hemorrhagic telan& giectasia: arteriovenous malformations in children. J Pediatr 2013; 163:179– 186. This study included 44 children with proven genetic mutation for HHT1 or HHT2, respectively, who were screened for arteriovenous malformations. Twenty children were found to have PAVM, nine had large PAVM (>3 mm) and seven of them had HHT1. 15. van Gent MW, Post MC, Snijder RJ, et al. Real prevalence of pulmonary rightto-left shunt according to genotype in patients with hereditary hemorrhagic telangiectasia: a transthoracic contrast echocardiography study. Chest 2010; 138:833–839. 16. Iqbal M, Rossoff LJ, Steinberg HN, et al. Pulmonary arteriovenous malformations: a clinical review. Postgrad Med J 2000; 76:390–394. 17. Cottin V, Dupuis-Girod S, Lesca G, Cordier JF. Pulmonary vascular manifestations of hereditary hemorrhagic telangiectasia (Rendu-Osler disease). Respiration 2007; 74:361–378. 18. Gossage JR. Role of contrast echocardiography in screening for pulmonary arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Chest 2010; 138:769–771. 19. Velthuis S, Vorselaars VM, van Gent MW, et al. Role of transthoracic contrast && echocardiography in the clinical diagnosis of hereditary hemorrhagic telangiectasia. Chest 2013; 144:1876–1882. This is a well designed study trying to integrate the presence of an intrapulmonary shunt on transthoracic echocardiography as an additional criterion for establishing a definite diagnosis in first-degree relatives at risk of HHT patients. Addition of a shunt grade of at least two to the current clinical criteria will improve the sensitivity to 90.1% with a PPV of 99% for a definite diagnosis of HHT, whereas the addition of a shunt grade 1 will decrease the criteria’s specificity and will only marginally increase sensitivity. The NPV was 100%. 20. Gazzaniga P, Buscarini E, Leandro G, et al. Contrast echocardiography for pulmonary arteriovenous malformations screening: does any bubble matter? Eur J Echocardiogr 2009; 10:513–518. 21. Hart JL, Aldin Z, Braude P, et al. Embolization of pulmonary arteriovenous malformations using the Amplatzer vascular plug: successful treatment of 69 consecutive patients. Eur Radiol 2010; 20:2663–2670. 22. Zukotynski K, Chan RP, Chow C-M, et al. Contrast echocardiography grading predicts pulmonary arteriovenous malformations on CT. Chest 2007; 132:18–23. 23. Smith-Bindman R, Lipson J, Marcus R, et al. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med 2009; 169:2078–2086. 24. Blivet S, Cobarzan D, Beauchet A, et al. Impact of pulmonary arteriovenous malformations on respiratory-related quality of life in patients with hereditary haemorrhagic telangiectasia. PLoS One 2014; 9:e90937. 25. White RI Jr. Pulmonary arteriovenous malformations: how do I embolize? Tech Vasc Interv Radiol 2007; 10:283–290. 26. Andersen PE, Kjeldsen AD. Interventional treatment of pulmonary arteriovenous malformations. World J Radiol 2010; 2:339–344. 27. Milic A, Chan RP, Cohen JH, et al. Reperfusion of pulmonary arteriovenous malformations after embolotherapy. J Vasc Interv Radiol 2005; 16:1675– 1683. 28. Woodward CS, Pyeritz RE, Chittams JL, et al. Treated pulmonary arteriove& nous malformations: patterns of persistence and associated retreatment success. Radiology 2013; 269:919–926. This is a retrospective study of 23 patients with PAVM who underwent embolotherapy and were followed for 11 years. Multiple persistence patterns were seen in previously treated PAVM with recanalization having a higher success rate for retreatment. 29. Ference BA, Shannon TM, White RI, et al. Life-threatening pulmonary hemorrhage with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. Chest 1994; 106:1387–1390. 30. Ardelean DS, Jerkic M, Yin M, et al. Endoglin and activin receptor-like kinase 1 heterozygous mice have a distinct pulmonary and hepatic angiogenic profile and response to anti-VEGF treatment. Angiogenesis 2014; 17:129–146. 31. Buscarini E, Plauchu H, Garcia Tsao G, et al. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations. Liver Int 2006; 26:1040–1046. 32. Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010; 181:851–861. 33. Sopen˜a B, Pe´rez-Rodrı´guez MT, Portela D, et al. High prevalence of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. Eur J Intern Med 2013; 24:e30–e34. 34. Ginon I, Decullier E, Finet G, et al. Hereditary hemorrhagic telangiectasia, liver && vascular malformations and cardiac consequences. Eur J Intern Med 2013; 24:e35–e39. This is a cross-sectional, single-centre study that included 52 HHT patients with dyspnoea and liver vascular malformations at baseline. The authors confirmed a previously observed correlation between cardiac classification and hepatic artery diameter. Systematic echocardiography is recommended for HHT patients with dyspnoea to help guide therapy.
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Disorders of the pulmonary circulation 35. Faughnan ME, Granton JT, Young LH. The pulmonary vascular complications of hereditary haemorrhagic telangiectasia. Eur Respir J 2009; 33:1186– 1194. 36. Olivieri C, Lanzarini L, Pagella F, et al. Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia. Genet Med 2006; 8:183–190. 37. Letteboer TG, Mager JJ, Snijder RJ, et al. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet 2006; 43:371–377. 38. Lerut J, Orlando G, Adam R, et al. Liver transplantation for hereditary hemorrhagic telangiectasia: report of the European liver transplant registry. Ann Surg 2006; 244:854–862. 39. Dupuis-Girod S, Ginon I, Saurin J-C, et al. Bevacizumab in patients with && hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA 2012; 307:948–955. This is a single-centre phase 2 trial that included 25 patients who received bevacizumab 5 mg/kg every 14 days for total of six infusions. Data from 24 patients were analysed. Statistically significant improvement in cardiac parameters on echocardiogram, dyspnoea score, epistaxis and quality of life was seen at 6 months follow-up. A subsequent study showed continued improvement at 12 months. 40. Boillot O, Bianco F, Viale JP, et al. Liver transplantation resolves the hyperdynamic circulation in hereditary hemorrhagic telangiectasia with hepatic involvement. Gastroenterology 1999; 116:187–192. 41. Maggi U, Conte G, Nita G, et al. Arterial anastomosis in liver transplantation for Rendu-Osler-Weber disease: two case reports. Transplant Proc 2013; 45: 2689–2691. 42. Minai OA, Rigelsky C, Eng C, et al. Long-term outcome in a patient with pulmonary hypertension and hereditary hemorrhagic telangiectasia. Chest 2007; 131:984–987. 43. Bonderman D, Nowotny R, Skoro-Sajer N, et al. Bosentan therapy for pulmonary arterial hypertension associated with hereditary haemorrhagic telangiectasia. Eur J Clin Invest 2006; 36 (Suppl 3):71–72. 44. Raimondi A, Blanco I, Pomares X, Barbera` JA. Pulmonary arterial hypertension in a patient with hereditary hemorrhagic telangiectasia. Arch Bronconeumol 2013; 49:119–121. 45. Montani D, Price LC, Girerd B, et al. Fatal rupture of pulmonary arteriovenous malformation in hereditary haemorrhagic telangiectasis and severe PAH. Eur Respir Rev 2009; 18:42–46.
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46. Shovlin CL, Tighe HC, Davies RJ, et al. Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure. Eur Respir J 2008; 32:162–169. 47. Cottin V, Dupuis-Girod S, Lesca G, Cordier JF. Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: a series of 126 patients. Medicine (Baltimore) 2007; 86:1–17. 48. Gallitelli M, Pasculli G, Fiore T, et al. Emergencies in hereditary haemorrhagic telangiectasia. QJM 2006; 99:15–22. 49. Ishikawa T, Pollak S, Pflugradt R, et al. Pulmonary arteriovenous malformation causing sudden death due to spontaneous hemothorax. Int J Legal Med 2010; 124:459–465. 50. Lincoln MJ, Shigeoka JW. Pulmonary telangiectasia without hypoxemia. Chest 1988; 93:1097–1098. 51. Moriwaki A, Imanaga T, Hirota T, et al. [A case of Osler-Weber-Rendu syndrome: therapeutic embolization of the pulmonary artery and bronchial artery]. Nihon Kokyuki Gakkai Zasshi 2005; 43:384–388. 52. Lacombe P, Lacout A, Marcy PY, et al. Diagnosis and treatment of pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: an overview. Diagn Interv Imaging 2013; 94:835–848. 53. Shovlin CL, Sulaiman NL, Govani FS, et al. Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost 2007; 98:1031–1039. 54. Livesey JA, Manning RA, Meek JH, et al. Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/ deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia. Thorax 2012; 67:328–333. 55. Edwards CP, Shehata N, Faughnan ME. Hereditary hemorrhagic telangiec&& tasia patients can tolerate anticoagulation. Ann Hematol 2012; 91:1959– 1968. This is the first large series of HHT patients addressing the very delicate matter of anticoagulation in the setting of HHT. Patients were selected from Toronto HHT database if they ever had one of the following medications prescribed: warfarin, unfractionated heparin, low molecular weight heparin, aspirin or clopidogrel. Chart reviews were conducted on 64 patients who met the criteria and 43 of them agreed to complete a questionnaire regarding their experience during therapy. Fifty-eight percent of patients reported a minor bleeding complication and 23% reported a major complication such as the need for blood transfusion. However, the overall rate of severe complications was only 0.1 per patient-year and only 20% of anticoagulation courses had to be stopped early.
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Pulmonary vascular complications of hereditary haemorrhagic telangiectasia Sebastian Circo and James R. Gossage
Purpose of review The purpose of this study is to present the latest advances and recommendations in the diagnosis and treatment of pulmonary vascular complications associated with hereditary haemorrhagic telangiectasia (HHT): pulmonary arteriovenous malformations (PAVMs), pulmonary arterial hypertension (PAH), pulmonary hypertension associated with high output cardiac failure or liver vascular malformations, haemoptysis, haemothorax and thromboembolic disease. Recent findings Transthoracic contrast echocardiography has been validated as a screening tool for PAVM in patients with suspected HHT. Advancements in genetic testing support its use in family members at risk as a cost-effective measure. Therapy with bevacizumab in patients with high output cardiac failure and severe liver AVMs showed promising results. PAH tends to be more aggressive in HHT type 2 patients. Summary Patients suffering from this elusive disease should be referred to HHT specialized centres to ensure a standardized and timely approach to diagnosis and management. Keywords haemoptysis, haemothorax, hereditary haemorrhagic telangiectasia, pulmonary arteriovenous malformation, pulmonary hypertension
INTRODUCTION Hereditary haemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu disease, is a genetic disorder that may lead to abnormal development of arteriovenous communications in virtually every organ. Depending on the vessel calibre and anatomical location, these anomalous communications are prone to rupture and cause significant bleeding complications. Although epistaxis is the most common complication (seen in 90–95% of patients), pulmonary manifestations are the most common of the serious complications and include pulmonary arteriovenous malformation (PAVM) [1–3], pulmonary hypertension [4], haemoptysis, haemothorax and pulmonary embolism. The purpose of this review is to present the latest advances and recommendations in the diagnosis and treatment of pulmonary complications of HHT.
[1,2] and higher in certain geographic areas. The highest prevalence in the world, one in 1331 inhabitants, is in the Afro-Caribbean population of the Netherland’s Antilles [2]. The pathophysiology of HHT is related to alterations in the transforming growth factor-b (TGF-b) signalling pathway leading to abnormal angiogenesis. Mutations in two major genes encoding endothelial surface proteins, the endoglin gene (ENG) causing HHT type 1 (HHT1) and activin receptor-like kinase 1 gene (ACVRL1) causing HHT type 2 (HHT2) are responsible for the majority of cases. Mutations in these two genes result in a significant reduction in the level of functional endoglin and activin receptor-like kinase 1 proteins and to dysregulation of the TGF-b signalling pathways. These alterations predispose to the formation of focal vascular lesions with fragile walls Georgia Regents University, Augusta, Georgia, USA
BACKGROUND OF HHT The transmission of HHT follows an autosomal dominant pattern and the incidence is thought to be on average one to two cases per 10 000 people
Correspondence to James R. Gossage, Georgia Regents University, BBR5521, 1120 15th street, Augusta, GA 30912, USA. Tel: +1 706 721 6789; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:421–428 DOI:10.1097/MCP.0000000000000076
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Disorders of the pulmonary circulation
KEY POINTS All patients with definite or suspected HHT should be screened for PAVMs. Transthoracic contrast echocardiography is the screening test of choice for PAVM. HHT patients who are pregnant should be referred to HHT specialized centres. Pulmonary hypertension, whenever suspected, should be immediately investigated, as these patients are at high risk for severe complications and may require specific therapies. Referral to an HHT specialized centre both for screening and for follow-up is of outmost importance.
The International Consensus guidelines for the Diagnosis and Treatment of HHT recommend screening for HHT in all first-degree family members of a patient who has been diagnosed with possible or definite HHT [9]. In paediatric patients and younger adults, the value of the Curac¸ao criteria may be limited by the lag in symptom onset. Genetic testing has emerged as an important tool to help make the diagnosis by identifying the causative mutation. Prigoda et al. [11] performed genetic analysis on 194 families and found a sensitivity of 80% for detection of a known genetic mutation. The remaining 20% may carry mutations too complex to detect or yet to be identified. Although genetic testing may not be readily available in most medical centres and has its own limitations, it may have a significant economic impact by decreasing healthcare costs as outlined in a study by Bernhardt et al. [12 ]. &
and arteriovenous shunting. Although the mechanisms are unclear, possible triggers such as hypoxia or local haemodynamic changes could promote tissue inflammation or endothelial cell injury [2], along with the influence of modifier genes. More recently, a combined syndrome of juvenile polyposis and HHT (JPHT) has been described, involving mutations to the downstream mediator SMAD family member 4 (SMAD4) [2–4]. The diagnosis of HHT is most commonly considered after recurrent episodes of epistaxis in a patient with a family history of the same. In a large study looking at pulmonary vascular complications in adults with HHT, the most common clinical findings were epistaxis and telangiectasias in 91.4 and 95.2% of patients, respectively [5]. In the same cohort, a family history of HHT was present in 88.9% of cases. The mean age of onset for epistaxis is about 12 years with up to 95% affected by age 40 [6–8]. The appearance of telangiectasias can be delayed 5–20 years after the onset of epistaxis and overall tend to appear earlier in patients with HHT type 1 than in those who have HHT type 2 [8]. The diagnostic criteria for HHT were first published in 2000 and are referred to as the Curac¸ao criteria that include spontaneous recurrent epistaxis, multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose), visceral AVMs (lung, brain, liver, spine, gastrointestinal) and a firstdegree family member diagnosed with HHT by these same criteria. Meeting three or more of these criteria makes the diagnosis definite [9]. A recent study of the Curac¸ao criteria reported a positive predictive value (PPV) of 100% for a definite diagnosis and a negative predictive value (NPV) of 97.7% for an unlikely diagnosis, when compared with DNA testing [10 ]. &&
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PULMONARY ARTERIOVENOUS MALFORMATIONS Pulmonary arteriovenous malformations (PAVMs) represent direct communications between pulmonary arteries and veins. This anomaly creates a right to left shunt that can cause a decrease in oxygen saturation and also increase the chance of paradoxical embolism by bypassing the lung’s natural filtration ability. PAVMs are simple if they have a single feeding artery (Fig. 1) or complex for two or more feeding arteries (Fig. 2). In HHT patients, the PAVMs tend to be multiple, bilateral and are mainly located in lower lobes [13]. Depending on the definition of PAVM and the underlying population, PAVM can be present in up to 85% of patients with HHT [1,5,14 ]. However, approximately 40% of all HHT patients will have a visible PAVM on computed tomographic (CT) scan. Table 1 represents data from the study published by van Gent et al. [15], showing an overall higher incidence of PAVM in HHT1 than in HHT2. On the contrary, 80–90% of patients with PAVM will have HHT as the underlying cause. Due to the serious nature of complications arising from untreated PAVM, screening is recommended. Common clinical features associated with the presence of PAVM are epistaxis, dyspnoea, telangiectasias, cyanosis, clubbing in the presence of significant right to left shunt, paradoxical embolism and brain abscess. As most of the PAVM tend to be located at the bases of the lung, orthodeoxia and platypnoea can be seen [16]. The presence of right to left shunting caused by PAVMs can cause severe hypoxemia. The shunt can be quantified by measuring the arterial blood gases after 15 min of inspiring 100% oxygen with deep &
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Hereditary haemorrhagic telangiectasia Circo and Gossage Table 1. Incidence of pulmonary arteriovenous malformation in genetically proven hereditary haemorrhagic telangiectasia patients [15] HHT patients screened for PAVM HHT 1
Artery
HHT 2
Positive TTCE
84.8%
35.1%
Visible PAVM on CT scan
58.2%
17.9%
29%
3%
Treatable PAVM
Patients with HHT1 are much more likely to have PAVM than those with HHT2. Treatable PAVMs are those with a feeding artery diameter of 3 mm. CT, computed tomography; HHT, hereditary haemorrhagic telangiectasia; PAVM, pulmonary arteriovenous malformation; TTCE, transthoracic contrast echocardiography.
AVM sac
!
FIGURE 1. Noncontrasted computed tomographic scan in a patient with a single small ‘simple’ pulmonary arteriovenous malformation in the right lower lobe. The feeding artery and AVM sac are visible. On other cuts, the draining vein is seen to connect to the AVM sac.
inspirations at every minute. Various formulas are available for calculating shunt, but it is important to include both paO2 and SaO2 in these calculations to optimize accuracy. A shunt value of 5% or less is considered normal. This relatively easy test is not recommended for screening due to poor reproducibility and low sensitivity (62%) [17]. Radionuclide
Draining vein
Artery
AVM sac
FIGURE 2. Contrasted computed tomographic scan in a patient with a large ‘complex’ pulmonary arteriovenous malformation in the left lower lobe. Both feeding arteries and a large and convoluted AVM sac are visible. A huge draining vein is seen exiting from the sac; although the vein appears to connect to the lateral most artery, this is an artefact of volume averaging and is easily differentiated on other cuts.
lung scanning has also been used to assess and quantify right-to-left shunting. After injection of 99mTc-labelled albumin particles, radioactivity is detected over cerebral, renal and thyroid areas in patients with significant right to left shunt. Being an expensive test and having poor sensitivity (79%) are the main reasons why it is no longer recommended in HHT [17]. Contrast echocardiography is the screening test of choice with sensitivity up to 98.6% [18]. More recent studies have proven the excellent reproducibility and safety of this noninvasive test. Grading systems to characterize the shunt have been developed to help guide the clinical approach [15,19 ,20]. Velthuis et al. [19 ] demonstrated a direct relationship between shunt grade on transthoracic contrast echocardiography (TTCE) and prevalence of cerebral manifestations in patients screened for HHT. A pulmonary shunt grade 1 (100 microbubbles) pulmonary shunt were independent predictors of cerebrovascular events and brain abscess [19 ]. The methodology of TTCE includes placement of a peripheral intravenous line with two 10 ml syringes connected to a three-way stopcock, one containing 8 ml isotonic saline and the other 1 ml air. Some authors additionally drew 1 ml of blood into the air-filled syringe. Subsequently, the air and saline are rapidly flushed between the two syringes to create an agitated saline solution. The patient should be positioned in the left lateral position and 5–10 ml of agitated saline is injected within 3 s, although projecting the four-chamber apical view. A pulmonary right to left shunt is considered present if one or more microbubbles appear in the left ventricle after three to four cardiac cycles [19 ].
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A noncontrasted high-resolution CT scan of the chest remains the gold standard for identification of PAVM and to help select those suitable for embolization therapy [15,21]. The morphology of a PAVM is highly characteristic and shows a feeding artery and draining vein with a sacular or fistulous communication in between (Figs 1 and 2). For all but the smallest PAVM, this is easily demonstrated without contrast. Our own practice is to perform a CT scan of the chest in all patients with possible HHT and a grade 2 or 3 right to left shunt on TTCE. However, in most patients with a grade 1 shunt or less, we defer a CT scan unless the shunt worsens in the future [18]. This is based on data published in three separate studies [15,20,22] on prevalence of PAVM by shunt grading on TTCE that used a quantitative measurement with less than 30 bubbles as an upper limit for grade 1 right to left shunt. The combined data from all three studies showed the upper limit of finding a treatable PAVM to be 2.1% in patients with a grade 1 shunt [18]. In addition, the lifetime risk of malignancy associated with ionizing radiation delivered during CT is one in 330 for a 20-year-old woman who received CT chest to rule out a pulmonary embolus and can be as high as 1 in 90 for a poorly designed imaging protocol [23]. Furthermore, for the sake of the Curac¸ao criteria, we consider a grade 2–3 right to left shunt as diagnostic for PAVM even in the presence of a negative HRCT scan. The mainstay of therapy for PAVM is catheterbased embolization therapy (embolotherapy). On the basis of data by Rosenblatt and others, the current recommendation of the Consensus Guidelines – and our own practice – is to embolize all PAVMs with a feeding artery diameter of at least 2–3 mm. In patients with a feeding artery of at least 3 mm, embolization of PAVM achieves normalization of the respiratory-related quality of life score as shown in a recent study by Blivet et al. [24]. Embolization can be done either by using MRI safe coils or by placing an endovascular plug. There are no randomized studies to evaluate the success rate of one procedure versus the other. The coils come in various shapes and sizes, and are easily delivered via catheter using the ‘anchor’ or ‘scaffold’ technique [25]. The endovascular plug is a selfexpandable occlusion device that can be delivered via catheter. It is more time saving than coiling, as one vascular plug can occlude a vessel that would otherwise require multiple coils, but its use is limited in the presence of small tortuous vessels in which situation coils are more easily delivered [26]. After embolotherapy, the PAVM sac will shrink and in time will form a fibrous scar. The risk of recanalization varies from 5 to 15% [26,27] and seems to be associated more with coil embolization than 424
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vascular plugging, especially if too few coils or poorly sized coils are used. The main mechanisms are related to persistence of feeding vessels due to inadequate occlusion, development of accessory feeding vessels and migration of endovascular material. The study by Woodward et al. [28 ] found recanalization through previously placed coils as the main pattern for PAVM persistence at 1-year follow-up. Several long-term follow-up series showed that these procedures have low morbidity, but these reports have come mainly from specialized and experienced centres. An HRCT of the chest at 6–12 months after embolotherapy is currently recommended to assess the continued success of the procedure [9]. Antibiotic prophylaxis prior to dental work below the gum line and some invasive procedures, and use of air filters for placing peripheral intravenous access remain crucial recommendations for any HHT patient with PAVM due to their increased risk for brain abscess and air embolism [19 ,20]. Special consideration should be given to the paediatric and pregnant populations. The presence of PAVM in the pregnant population carries significant morbidity, especially during the third trimester. The increased cardiac output associated with pregnancy is thought to be directly related to increased risk for rupture and secondary haemorrhagic complications such as massive haemoptysis, haemothorax and even death [29]. The greatest risk is in women who have not undergone screening for PAVM prior to pregnancy. TTCE is well tolerated during pregnancy and we recommend screening after the first trimester in all pregnant HHT patients who have not been screened in the last 2–3 years. If treatable PAVMs are discovered, we recommend embolotherapy after 16 weeks of pregnancy. If PAVMs are too small to treat, counselling and close follow-up are extremely important. In the paediatric population, there is still a lot controversy in terms of screening for PAVM and treatment. Given the limitations of the Curac¸ao criteria in this population, genetic testing is the gold standard to make the diagnosis of HHT. There are few examples in the literature of patients less than 12 years old who suffered cerebral events from asymptomatic PAVM. There is also some concern that treatment of PAVM in paediatric patients may be associated with a higher incidence of reperfusion. Our own practice is to screen for PAVM with TTCE in patients after the age of 10–12 years or in younger patients with dyspnoea or hypoxemia. If PAVMs with a feeding artery diameter of at least 3 mm are found, we discuss the pros and cons of treatment and make a decision on a case-by-case basis. &
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Hereditary haemorrhagic telangiectasia Circo and Gossage
The current therapeutic approach for PAVM may change in the future. A recent study [30] describing the effects of antivascular endothelial growth factor mAb in mice models showed some significant improvement in the vascular architecture by stabilizing and improving previously formed PAVM.
PULMONARY HYPERTENSION Pulmonary hypertension is seen in patients with HHT and can occur by several mechanisms. Postcapillary pulmonary hypertension can be related to high output cardiac failure due to liver AVM and/or anaemia, while precapillary pulmonary hypertension can be related to thromboembolic disease or PAH. The gold standard for making the diagnosis remains right heart catheterization (RHC). In patients with hepatic AVM and pulmonary hypertension, RHC will typically show elevated pulmonary artery wedge pressure, high cardiac index and normal pulmonary vascular resistance (PVR) [31], although in patients with PAH, the pulmonary artery wedge pressure is normal, the cardiac index is normal or low, and the PVR is elevated [32]. Various studies have identified patients at risk using transthoracic echocardiogram as a screening test [33,34 ,35], although given the small numbers of patients reported and the lack of RHC data, the true prevalence remains uncertain. Olivieri et al. [36] found a systolic pulmonary artery pressure (PAP) of at least 40 mmHg in 13% of 68 unselected patients with HHT; the value rose to 20% in the 44 patients who had a reliable estimate of PAP. In a small series of 29 patients with a definite HHT who were hospitalized, 45% had possible or probable pulmonary hypertension by echocardiography [33]. Pulmonary hypertension is more prevalent in HHT2, being related to a higher prevalence of hepatic AVM and subsequent development of high output heart failure [35,37]. Ginon et al. [34 ] performed TTCE in 52 patients with hepatic AVM and cardiac symptoms and found an elevated cardiac index in 85% of patients. About 25% had a systolic PAP of at least 40, all of whom had an elevation in cardiac index and left ventricular filling pressure, and normal PVR. Common signs and symptoms include exertional dyspnoea, fatigue, leg oedema and atrial fibrillation. Medical therapy has been directed towards improvement in haemodynamics by controlling salt intake, correcting anaemia and use of antihypertensive and antiarrhythmic agents when clinically indicated [31,38]. In a recent study by Dupuis-Girod et al. [39 ], therapy with bevacizumab, an angiogenic inhibitor, was tried in a series of 25 patients with high output cardiac failure and &&
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severe liver AVM. The results after 3 months of follow-up showed a significant decrease in cardiac output and a marked improvement in quality of life [39 ]. Although bevacizumab may be useful in the management of high output heart failure due to liver AVM, it has no current role in the management of precapillary PAH. Other therapies such as trans-jugular intrahepatic porto-systemic shunt or trans-arterial embolization of hepatic AVM failed to produce significant improvement in symptoms or haemodynamic parameters and had a high rate of complications [31,40]. For patients with refractory high output hear failure, liver transplantation remains the best option to resolve the hyperdynamic circulatory state [31,38,41]. There have been a few case reports in literature that identified the presence of classic PAH in HHT patients that did not appear to be related to the presence of hepatic AVM [42–44]. These patients have normal filling pressures and a high PVR, so RHC is necessary to accurately make the diagnosis. In a study by Girerd et al. [32], patients with PAH who were carriers of a bone morphogenetic protein receptor type 2 (BMPR2) mutation or an ACVRL1 mutation were compared. Although patients with ACVRL1 mutations were found to be significantly younger at time of diagnosis and to have better baseline haemodynamic parameters, they had a worse prognosis when compared with BMPR2 carriers. None of the 23 ACVRL1 patients showed an acute response to pulmonary vasodilators. These patients appear to respond to the typical therapies used for PAH. Seven out of nine patients from French PAH network included in this study were found to have PAH before developing clinical manifestations suggestive of HHT. The coexistence of pulmonary hypertension and PAVMs has specific clinical and therapeutic implications. The presence of PAVM may have a protective role in the setting of underlying PAH by providing a low resistance system, which can attenuate right ventricular afterload. In time, as the pulmonary hypertension worsens, the risk of associated PAVM rupture increases, carrying significant mortality and morbidity [45]. Shovlin et al. [46] looked at the haemodynamic effect of PAVM embolization in 43 patients with HHT. Overall, embolization had no significant effect on pulmonary artery pressure; however, worsening pulmonary hypertension was documented in older patients [46]. All patients who underwent embolization had statistically significant improvement in their resting oxygen saturation [46]. Although this study supports embolotherapy in the setting of mild to moderate pulmonary hypertension, there is a paucity of studies examining its role in severe pulmonary
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hypertension. Embolization of PAVM in the setting of severe pulmonary hypertension may potentially worsen pulmonary hypertension and thus increase the risk of PAVM rupture, or alternatively it may decrease cardiac output and thus improve pulmonary hypertension. Each patient should be considered individually, but the higher the mean PAP and PVR at baseline, and the larger the PAVM, the greater is the likelihood of worsening pulmonary hypertension after embolization. As PAH also appears to be more aggressive in this population, we favour an aggressive approach with earlier consideration of prostacylins. We also recommend referral of these patients to centres that have expertise in both HHT and PAH.
HAEMOTHORAX Given the high incidence of PAVM in the HHT population, they are at particularly high risk for life-threatening complications such as haemothorax. In a retrospective study by Cottin et al. [47] in 126 patients with at least one PAVM, four were found to have a history of haemothorax, one being during pregnancy. Ference et al. [29] found that out of 159 patients with HHT and PAVM, 11 had massive haemoptysis or haemothorax requiring hospitalization. Seven women experienced haemothorax– three of them during pregnancy [29]. Although the prevalence of haemothorax tends to be lower than haemoptysis [48], the rupture of a PAVM has a life-threatening potential [45,49]. The majority of PAVM ruptures during pregnancy have occurred during the third trimester. If a treatable PAVM is identified in a pregnant patient, it is recommended to perform embolotherapy as soon as possible after the 16th week [17] to avoid rupture. In life-threatening cases, surgical lobectomy can be considered if local expertise with embolotherapy is not available.
usually a contrasted CT of the chest. If this does not show obvious PAVM or pulmonary embolism, bronchoscopy to screen for telangiectasias is reasonable. Treatment is mainly supportive for PAVM, and in severe cases, embolotherapy or surgical intervention can be considered. In case of bronchial telangiectasias, endobronchial cauterization can be performed, but the long-term response is unknown.
THROMBOEMBOLIC DISEASE There are data to suggest that patients with HHT are at an increased risk for venous thromboembolism. In a study by Shovlin et al. [53], factor VIII and von Willebrand antigen levels were found to be elevated in an HHT population compared with a non-HHT group. This association proved to be even higher in patients who developed thromboembolic events [53]. Due to the nature of the disease and recurrent bleeding, iron deficiency is common in HHT patients. A more recent prospective study by Livesey et al. [54] showed that the elevation in factor VIII levels and secondary increased risk for thromboembolism were directly related to low serum iron levels. The retrospective analysis of Lacombe et al. [52] over a period of 12 years showed that even though the overall incidence of PAVM thrombosis is fairly low (2.5%), it is associated with an increased rate of neurological complications such as ischemia or abscess formation. Given the underlying increased risk for bleeding associated with HHT, treatment is very challenging. A retrospective chart review study by Edwards et al. [55 ] found 64 HHT patients who had been prescribed antithrombotic medication; interview of 43 of these patients showed that bleeding complications were only minor in 58%. The authors concluded that HHT patients can be treated with antithrombotic medications as long as they have very close follow-up and had been previously screened and treated for PAVM or cerebral AVM [55 ]. &&
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HAEMOPTYSIS Potential causes of haemoptysis in HHT patients include rupture of a parenchymal PAVM or bronchial telangiectasias, and thromboembolic disease (see next section) [50,51]. Haemoptysis may sometimes be massive, especially with PAVM rupture. On the basis of studies published so far, the incidence is thought to vary between 4 and 20% for both adult and paediatric population [29,35,47]. However, in a retrospective analysis on 425 patients with known PAVM by Lacombe et al. [52], only six patients were found to have presented with haemoptysis secondary to spontaneous rupture of PAVM. After medical stabilization, the initial diagnostic approach is 426
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CONCLUSION HHT is a chronic and potentially disabling disease with a significant social and economic impact in the affected families. Recurrent nosebleeds in children should be a consideration for referral to a specialized HHT centre, although the Curac¸ao criteria in adults have proven to be an excellent screening tool. Most of the pulmonary vascular complications associated with this disease are secondary to the development of PAVM or liver AVM. The collaboration between the clinician and the interventional radiologist has established catheter embolotherapy as the preferred method of intervention both for prophylactic and Volume 20 Number 5 September 2014
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Hereditary haemorrhagic telangiectasia Circo and Gossage
therapeutic reasons. Patients with HHT should be referred to an HHT specialized centre, receive genetic counselling and be fully educated about their condition and its clinical implications. Acknowledgements None. Conflicts of interest The authors have no conflicts to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Gossage JR, Kanj G. Pulmonary arteriovenous malformations. A state of the art review. Am J Respir Crit Care Med 1998; 158:643–661. 2. Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 2006; 43: 97–110. 3. Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004; 363:852–859. 4. Santibanez JF, Letamendia A, Perez-Barriocanal F, et al. Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. J Cell Physiol 2007; 210:456–468. 5. Cottin V, Plauchu H, Bayle J-Y, et al. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med 2004; 169:994–1000. 6. Plauchu H, de Chadare´vian JP, Bideau A, et al. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989; 32:291–297. 7. Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet 1992; 29:527–530. 8. Berg J, Porteous M, Reinhardt D, et al. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet 2003; 40:585–590. 9. Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet 2011; 48:73–87. 10. van Gent MW, Velthuis S, Post MC, et al. Hereditary hemorrhagic telangiec&& tasia: how accurate are the clinical criteria? Am J Med Genet A 2013; 161A:461–466. This is the first study to address the validity of the Curac¸ao criteria as the main tool to rule out or in the diagnosis of HHT. Two hundred and sixty-three first-degree relatives of HHT patients were included. The study showed that a definite diagnosis of HHT can be made with 100% certainty in first-degree relatives of patients with a known mutation, although the NPV of the clinical diagnosis was 97.7% in patients with unlikely diagnosis. For patients with a possible clinical diagnosis as well as individuals at a young age, genetic testing is particularly helpful. 11. Prigoda NL, Savas S, Abdalla SA, et al. Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations. J Med Genet 2006; 43:722–728. 12. Bernhardt BA, Zayac C, Trerotola SO, et al. Cost savings through molecular & diagnosis for hereditary hemorrhagic telangiectasia. Genet Med 2012; 14:604–610. A very interesting analysis from University of Pennsylvania in Philadelphia comparing costs associated with genetic testing versus clinical approach in first-degree relatives at risk for HHT (charge and payment data were obtained for FY2010 from the three health insurers in the area, excluding Medicare). In a computer model, up to four siblings or children of 100 HHT probands were assigned to a repeated clinical screening approach until the diagnosis was either affirmed or excluded, although the other group included 100 HHT patients who were genetically tested for mutation followed by genetic testing of at-risk relatives (up to 4 per proband) and clinical monitoring only in those who test positive for the familial mutation. In the clinical model, the initial diagnostic evaluation cost $7984, a follow-up screening evaluation costs $5375 and total lifetime costs for one family for follow-up screenings were estimated at $117 936. In the genetic testing model, the cost estimated for a similar family of four was estimated at $18 655. The main advantage for using the genetic screening is that it helps eliminate the need for costly follow-ups in up to half of patients at risk for HHT.
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