Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs

INTRODUCTION — Hereditary hemorrhagic telangiectasia (HHT; also called Osler-Weber-Rendu syndrome) is a vascular disorder inherited as an autosomal dominant trait, with a variety of clinical findings and range of severity, even within relatives who have the same HHT pathogenic gene variant.

Arteriovenous malformations (AVMs) frequently affect the pulmonary, hepatic, and/or cerebral circulations, demanding knowledge of the risks and benefits of screening for these complications. Additional common problems include mucocutaneous telangiectasia, epistaxis, gastrointestinal bleeding, and iron deficiency anemia. Despite these disease manifestations, some patients may present with pulmonary AVMs only and have a paucity or absence of clinical signs and symptoms [1]. (See 'PAVM screening' below.)

This topic review discusses an approach to screening of individuals with HHT for disease complications for which they are asymptomatic, as well as genetic testing and counseling of at-risk family members.

●Any symptoms related to HHT should be investigated, as discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".)

●The pathophysiology, epidemiology, and diagnosis of HHT are also discussed separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

OVERVIEW

Definition of terms — Any vascular lesions can be observed in individuals with HHT. Vascular abnormalities seen at a higher prevalence than in the general population include:

●Arteriovenous malformation – An arteriovenous malformation (AVM) is an abnormal vascular structure that provides a direct communication between one or more arteries and one or more veins. These may be sacs (eg, for pulmonary AVMs [PAVMs]), small collections of intervening vessels (nidal AVMs), or direct high-flow connections between the arterial and venous side (arteriovenous fistulas [AVFs]). AVMs result in arteriovenous shunting. Shunting may also be observed secondary to dilatation of existing normal capillaries (eg, intrapulmonary shunting in the hepatopulmonary syndrome and as part of normal physiologic responses).

●Telangiectasia – A telangiectasia is a small, dilated blood vessel (arteriole, venule, or capillary). The term is descriptive and refers to telangiectasia of many anatomic types and etiologies. HHT telangiectasia usually contain small arteriovenous communications and are commonly located near the surface of the skin or mucous membranes.

These lesions can also be seen in other disorders besides HHT, or in otherwise healthy individuals, as part of a syndrome or in isolation. As discussed in detail below, additional vascular lesions are increasingly recognized, some seen more commonly in patients with HHT and others, such as aneurysms, present at similar or only marginally increased rates to the general population.

General principles of management — Major management issues in individuals with HHT span the full range of clinical manifestations (table 1) and include the following [2-13]:

●Patient education – Educational materials for patients with HHT and the location of specialized centers for diagnostic testing and management are available from the websites of Cure HHT, VASCERN (the European Reference Network on Rare Multisystemic Vascular Diseases) and country-specific patient groups. VASCERN, formed in 2016, has created videos to provide a brief overview of HHT (https://www.youtube.com/watch?v=0YjWf7Agn40) and a list of "Do's and Don'ts" that can be shared with patients [14].

●Clinician education regarding the following:

•Possible sites of AVMs, typical symptoms attributable to these lesions, indications for treatment, and risks and benefits of local versus systemic therapies. Importance of epistaxis as the main cause of anemia, the need for intervention for certain asymptomatic individuals, and the possibility that HHT vascular lesions may radiologically-mimic metastases to liver or lung. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Therapy for specific vascular lesions and iron deficiency'.)

•Role of screening and treatment for asymptomatic AVMs in certain circulations. It is especially important to identify PAVMs to prevent paradoxical thromboemboli, strokes, and brain abscesses. (See 'Overview of screening strategy' below.)

•Screening for iron deficiency and supplementing iron as needed, ideally before the patient becomes symptomatic from anemia. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Iron deficiency and iron deficiency anemia'.)

•Awareness that patients who require antiplatelet and/or anticoagulation (eg, for treatment of thromboembolic disease) should not be denied this simply due to the diagnosis of HHT. (See 'Individuals who require anticoagulation (VTE and AF)' below.)

•Awareness that some individuals with genetically confirmed HHT have a paucity of clinical signs, and that absence of symptoms does not provide reassurance that someone does not have HHT [1]. Molecular (genetic) testing is required for minimally symptomatic relatives of an affected individuals and patients with isolated pulmonary AVMs.

Many management recommendations are based on expert opinion and observational studies. Although randomized controlled trials are increasingly conducted, they have not delivered statistical support for several proposed treatments; results are awaited from larger studies and studies of longer duration that are underway. In the meantime, uniformity of expert opinion varies depending on the clinical situation and prevailing health care practices.

Updated guidance from the second International Consensus Guidelines on management of HHT was published in 2020 [13]. This followed the first International Consensus Guidelines, which were developed in 2006, and published in print in 2011 [3].

The 2020 Guidelines focused on six topics and provided greater nuance than the first Guidelines in separating the severity of indications for elements of care and presenting guidance in a step-wise fashion, according to the severity of the disease [13]. The six topics addressed were:

●Epistaxis

●Gastrointestinal bleeding

●Anemia and anticoagulation

●Hepatic vascular malformations

●Pediatrics

●Pregnancy

Several other recommendations from the first International Guideline were not reassessed and remain in place [3]. Details from these Guidelines, including new recommendations and affirmation of existing recommendations, are discussed below. (See 'Overview of screening strategy' below.)

As noted above, consensus statements on good practice in HHT have also been developed by the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN). This group has identified core Outcome Measures suitable to be implemented by all clinicians evaluating a patient with HHT: pulmonary AVM (PAVM) screening, antibiotic prophylaxis prior to dental and surgical procedures for those with PAVMs, epistaxis advice, assessment of iron deficiency, and advice on pregnancy [15,16]. Subsequent manuscripts include evidence from HHT patients across the ERN [17,18], address nuances of cerebral screening [19], and are summarized in a single Frameworks manuscript targeting general and speciality care [20].

Overview of screening strategy — Screening to diagnose AVMs in individuals at risk for HHT, or those with HHT but without symptoms relevant to the AVMs, is distinct from investigation of a symptomatic patient.

Some countries have historically placed particular emphasis that screening within clinical practice should be clearly linked to a proven patient-recognizable benefit [21,22]. In some cases, such as identification of PAVMs, results of screening may lead to risk-reducing interventions. In other cases where risk cannot be altered, the stated or implied purpose of screening can be that it allows information considered valuable about the risk to be provided to the patient and/or family [21,22].

It is good practice, prior to screening patients, to counsel them on how the screening could impact their health and management. The challenge for all screening programs is to establish whether, across the selected population, the expected benefits are likely to outweigh the harms and burdens of screening.

Clinicians should be cognizant of the significant radiation exposure that can occur during a lifetime of imaging studies [23] and should minimize these risks by restricting imaging studies to individuals for which the results will affect evidence-based management [5]. (See "Radiation-related risks of imaging".)

New recommendations for screening in the 2020 International Consensus Guidelines included a clearer recommendation for hepatic AVM screening for all adults and discussion of preconception and prenatal diagnostic options, including preimplantation genetic testing [13]. Additional screening recommendations for children and during pregnancy were similar to the first International Consensus Guidelines, published in 2011, including cerebral and pulmonary screening and genetic testing [3]. There was no discussion of these topics for other adults, although cerebral AVMs have been addressed in a 2020 Position Statement from VASCERN on cerebral vascular malformations [19,20]. The British Thoracic Society provided a 2017 Position Statement on pulmonary AVMs [24].

Recommendations for evaluation of iron deficiency, anemia, and symptomatic lesions, as well as recommendations for therapy, are presented separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".)

In general, protocols for screening asymptomatic individuals depend upon the importance attached to the detection of asymptomatic lesions in particular viscera, the diagnostic and therapeutic expertise available locally, and the degree to which establishment of the extent of HHT is important in the particular health care system. Assuming the individual is in agreement, screening of adults with HHT typically consists of the following:

●Clinical evaluation – History and physical examination may identify clinically significant features that would modify subsequent management [3]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".)

●Anemia and iron deficiency – All individuals are evaluated for anemia and iron deficiency, with treatment if identified. This is an Outcome Measure to define good clinical HHT practice from VASCERN [16]. It was also recommended in the second International HHT Guidelines in 2020 [13]. (See 'Iron status' below.)

●Pulmonary AVMs (PAVMs) – PAVMs are always considered worthy of treatment, and screening should be offered for all adult patients over 16 years with known or suspected HHT [13]. All individuals with PAVMs should receive advice on antibiotic prophylaxis and many proceed to interventions to occlude the AVMs, which have been shown to reduce PAVM complications [25-27]. This is an Outcome Measure to define good clinical HHT practice from VASCERN [16]. It was also addressed in a British Thoracic Society Clinical Statement in 2017 and recommended in the 2006 International HHT Guideline, published in 2011 [3,24]. (See 'PAVM screening' below.)

●Cerebral AVMs – There is widespread agreement that any HHT patient with neurologic symptoms potentially attributable to a cerebral AVM should be investigated (see "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions'). However there has been significant controversy and ongoing debate regarding the optimal management of asymptomatic cerebral vascular malformations and the role of cerebral screening in asymptomatic individuals with HHT. The first International Guidelines recommended brain AVM screening in adults, with lower agreement than most of the other recommendations; this recommendation was not reassessed and remains in place [3,13]. Important considerations were addressed in a 2020 Neurovascular-led Position Statement from VASCERN and are discussed in more detail below [19,20].

●Hepatic AVMs – There is consensus that any HHT patient with symptoms potentially attributable to hepatic AVMs should be investigated, and in the 2020 International Guidelines, this was extended to all adults [13]. Asymptomatic, incidentally discovered hepatic AVMs are not treated, but the value of early detection to guide management in symptomatic patients has been increasingly recognized. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Hepatic AVMs'.)

●Spinal AVMs – Screening has performed in pregnancy in countries where epidurals may be withheld due to a perceived risk of spinal AVMs and often for patients undergoing surgery when epidural analgesia may be required [28]. The 2020 International HHT Guidelines recommended against withholding an epidural because of a diagnosis of HHT, and stated that screening for spinal vascular malformations is not required [13].

Additional investigations are performed based upon patient symptoms, results of the initial assessment, and sometimes specific family issues [3].

Screening in children is discussed below. (See 'Children' below.)

Individuals with SMAD4 HHT — Individuals with SMAD4-related HHT require more extensive surveillance due to the risk of juvenile polyposis and aortopathy [29,30]. A discussion of SMAD4-specific issues related to polyposis and aortopathy screening is presented separately. (See "Juvenile polyposis syndrome", section on 'Management'.)

Other management does not differ from that for individuals with ENG or ACVRL1 HHT.

Other elements of genomic variability — A 2022 study highlighted that the severity of hemorrhage is higher in HHT patients with rare, high-impact deoxyribonucleic acid (DNA) variants in genes associated with bleeding diatheses [31]. HHT patients with concurrent changes in T-helper lymphocytes may be more at risk of infectious complications [32]. These associations may lead to additional investigation of patients with more severe phenotypes, but there has been no recommendation to screen all individuals with HHT for such changes.

IRON STATUS — Assessment of iron stores and optimization of iron status is crucial in HHT. As noted separately, the major cause of iron deficiency is bleeding, including bleeding from epistaxis and gastrointestinal arteriovenous malformations (AVMs), with insufficient iron supplementation for the degree of bleeding. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Iron deficiency'.)

A survey of 50 individuals with HHT emphasized that epistaxis is usually sufficiently severe to account for the iron deficiency [33]. The approximate blood loss from epistaxis was in the order of 277 mL per month resulting in hemorrhage-adjusted iron requirements (HAIR) that could not be met from dietary sources alone in 80 percent of the study participants. Forty-three patients (86 percent) met their recommended dietary allowance of iron, but only 10 (20 percent) met their HAIR.

Regular complete blood counts (CBCs) are recommended [3]. Review of other red blood cell (RBC) indices such as the mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) are also important [34]. This is particularly true for patients who have hypoxemia due to pulmonary arteriovenous malformations (PAVMs), when a "normal" hemoglobin may be inappropriately low for the expected degree of polycythemia [34,35]. Regular assessment of iron status is recommended regardless of the hemoglobin level, to detect iron deficiency that is likely to progress to anemia if not treated [13,16]. We routinely measure serum iron and transferrin saturation index in addition to ferritin. While a low ferritin confirms the presence of iron deficiency, a normal or high ferritin does not exclude iron deficiency since it is an acute phase protein and can be elevated despite iron deficiency being present [36]. More information regarding the use of iron studies to assess iron status and thresholds for determining iron deficiency are presented separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Stages of iron deficiency' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

Iron deficiency can lead to symptoms related to the deficiency and/or to anemia (eg, fatigue, lethargy, dyspnea); it is also associated with an increased risk of other complications of HHT including venous thromboembolism (VTE), high-output cardiac failure and/or cardiac arrhythmias, and ischemic stroke [35,37-40].

Iron replacement and supplementation was also addressed in the 2020 Guideline [13]. This subject is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Iron deficiency and iron deficiency anemia' and "Treatment of iron deficiency anemia in adults".)

PAVM SCREENING — Adults with HHT should be screened for pulmonary arteriovenous malformations (PAVMs) because of the high incidence of unsuspected PAVMs and the high rates of complications in otherwise asymptomatic adults [41,42] and evidence that treatment reduces stroke and brain abscess risks in adults [25]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Principles of PAVM management' and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Embolotherapy'.)

Initial PAVM screening

●Adults (non-pregnant) – One algorithm for PAVM screening is provided by the British Thoracic Society (BTS) following modification at public consultation [24]. The 2020 second International Consensus Guideline did not provide additional discussion of PAVM screening in non-pregnant adults [3,13].

Key points emphasized by the BTS include the following [24]:

•All adults over the age of 16 years with known or suspected HHT should be offered screening for PAVMs (this is also an Outcome Measure from the European Reference Network [ERN] for Rare Vascular Diseases [VASCERN] and a recommendation from the 2006 International HHT Guideline, which was published in 2011) [3,16].

•Although trans-thoracic contrast echocardiography (TTCE; bubble echocardiography) is commonly recommended by international groups, the BTS Clinical Statement Group considered it was difficult to recommend contrast echocardiography as the preferred first-line screen, as a number of British Respiratory Medicine units noted that inexpert operators may miss clinically significant shunts. Thus, unless there is very strong local expertise in contrast echocardiography, the preference was for the definitive study to be by computed tomography (CT). However, the decision regarding the appropriate screening approach is approached on a case-by-case basis, mindful of the prevailing expertise in detection of intrapulmonary shunts by contrast echocardiography.

•A positive CT scan is diagnostic for PAVMs, whereas contrast echocardiography is frequently positive for reasons unrelated to PAVMs (such as functional shunting in response to exercise or hypoxemia) and notably is positive in at least 8 percent of the general population at rest [3,43-45].

•A normal chest radiograph does not exclude clinically significant PAVMs, even if accompanied by normal oxygen saturations and no clinical symptoms [3,16,24]. PAVMs are commonly seen "below the diaphragm" on posterior-anterior chest radiographs, due to their lower lobe predilection; their enlarged feeder arteries and draining veins may also be obscured.

•Either a negative thoracic CT scan, with or without contrast, or negative contrast echocardiography (if performed at a center with expertise in this type of study and no evidence of hypoxemia) excludes clinically significant PAVMs [3,16,24].

•Radiation exposure from the recommended protocol screening is high, and a key component of the BTS statement was that CT scanning should not be repeated based on protocol alone, as this increases radiation exposure [3,24,46]. However, there may be an indication to perform a repeat CT scan, such as post-pregnancy (a time of PAVM growth), or based on other clinical concerns.

It is considered particularly important that women with HHT undergo screening before becoming pregnant, since PAVMs can bleed in later pregnancy, leading to life-threatening hemoptysis or hemothorax [28,47-49]. In a series of 484 pregnancies, this occurred in 1 percent (95% CI 0.1-1.9 percent) [28]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary AVMs' and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pregnancy'.)

●Pregnant women – The 2020 HHT Guideline recommends screening of women for PAVMs during pregnancy if they have not been recently screened before becoming pregnant [13]. However, this is not our practice unless the tests are performed as investigations of symptoms or other abnormal findings, and in the United Kingdom, pregnant women are managed assuming PAVMs are present [28].

●Children – The 2020 International Guideline recommends screening of asymptomatic children for pulmonary AVMs, typically at five-year intervals, using various modalities including CT, TTCE, and oximetry [13]. This is not the practice across many ERN HHT centers, based on clinical experience and the absence of any complications from PAVMs in asymptomatic children within extensive European cohorts and subsequent re-review of the pediatric data. A study cohort that followed 436 children from HHT families screened consecutively for HHT over a period of 18 years found that postponing transthoracic contrast echocardiography and subsequent chest CT scanning (to detect any smaller PAVMs) until adulthood did not appear to be associated with major risk [50]. Within this study, 175 of 436 children (40 percent) had a diagnosis of HHT. PAVMs were detected in 39 of these 175 (22 percent), and 33 of the 39 required treatment by embolotherapy.

In the expert European HHT centers, PAVM investigations of younger children are generally performed only if there is a symptomatic concern after evaluation by a pediatrician. Reperfusion rates are higher in treated children who may then require further treatment as an adult; pediatric studies have also raised the possibility of additional complications [51].

Management of PAVMs is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Principles of PAVM management' and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".)

Repeat screens — The risk of subsequent PAVM development in an individual who previously screened negative by thoracic CT or contrast echocardiography in adult life is unclear, although accumulating evidence suggests that the risk is very small [24].

Key points from the BTS Clinical Statement include the following:

●For asymptomatic individuals with a negative initial screen during childhood, a repeat evaluation is needed in adulthood.

●For individuals with a negative screen during adulthood, we suggest review every five years (or if new symptoms develop). We initially evaluate using a history of the individual's symptoms and imaging with radiation-sparing strategies, restricting further thoracic CT scans for patients who have a specific clinical indication. Evaluation by CT may be reserved for those with signs or symptoms that suggest a PAVM. This practice is consistent with the BTS Clinical Statement [24].

●Even if an initial screen was negative, PAVM reassessment is essential if the patient develops neurologic symptoms suggestive of a transient ischemic attack, or if they have a stroke or brain abscess.

●PAVM reassessment is also essential if there is a radiologic finding such as a new opacity on chest radiography, noting this is more likely to be a different pathology, and the importance is not to assume PAVMs are the cause. The approach is discussed separately. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".)

●PAVM growth or development may be included in the differential diagnosis of new respiratory symptoms such as dyspnea or hemoptysis, again noting that these symptoms are more likely to be due to non-PAVM pathologies (eg, anemia, airflow obstruction) [52,53]. These other conditions may be more amenable to treatment than very small PAVMs.

A normal chest radiograph does not exclude clinically significant PAVMs [24]. The details of contrast ("bubble") echocardiography and other tests for PAVMs are presented separately. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".)

CEREBRAL AVM SCREENING — Evaluation of symptoms potentially attributable to a cerebral arteriovenous malformation (AVM) is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions'.)

The types of cerebral lesions include vascular malformations with a risk of hemorrhage and lesions with minimal risk, as detailed in data from the European Reference Network [19,20]. Discussions of these lesions and their prevalence are presented separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

As with other complex decision-making, it is essential that cerebral screening is discussed so that each patient can make an informed decision, weighing risks and benefits, about whether to screen [19]. It may also be beneficial to consult with local neurosurgery or neuroradiology colleagues regarding whether they would treat an asymptomatic brain lesion and to share this information with the patient.

For individuals who engage in shared decision-making and determine that brain imaging would be useful (even if it does not result in an invasive intervention), brain imaging is appropriate and reasonable and should be pursued. In contrast, if the perception is that at the current time, screening information would create more harms than benefits, we support the patient's decision to forgo imaging. This decision can be revisited if circumstances change.

The role of screening for cerebral AVMs in asymptomatic individuals is more controversial than screening in other sites [19]. The controversy largely focuses on differing opinions about the risk-benefit ratio of screening, as discussed in a series of responses to the 2020 International Consensus Guidelines [54-56].

Considerations, advantages, and disadvantages of cerebral AVM screening in asymptomatic individuals with HHT include the following:

●Risk of bleeding – Cerebral hemorrhages in HHT patients are usually life-changing and may be fatal. However, many HHT-related cerebral vascular malformations rarely bleed, including several types that may be identified by cerebral imaging [19]. The absolute risk of bleeding for any particular lesion has been evaluated across the European Centres of excellence in VASCERN and may be estimated from the literature [19,20]. Precise angioarchitecture and location of the lesion are also relevant [57,58]. Children are at a small risk of an arteriovenous fistula, which have higher hemorrhagic rates than the adult-type nidus AVMs. Younger individuals also have more life-years to live with their vascular abnormalities, with attendant hemorrhage risks per annum.

●Risks from imaging studies – Computed tomography (CT) is not sufficiently sensitive, and CT carries risks of radiation. Magnetic resonance imaging (MRI) is the preferred screening modality, though while this eliminates the risk of radiation for the initial screen, radiation may be used for subsequent evaluations and treatment. Imaging in young children may require sedation or general anesthesia [19].

●Outcomes following identification of different types of lesions:

•Brain AVF – These are usually considered for treatment.

•Brain AVM – Symptomatic cerebral AVMs are usually considered for treatment. Asymptomatic AVMs are less likely to be treated according to the results of a consensus from European interventional neuroradiologists and neurosurgeons in three specialist societies spanning the three forms of treatment: the European Association of Neurosurgical Societies (EANS), the European Society of Interventional Therapy (ESMINT), and the European Society for Radiosurgery (EGKS) [19,59].

The expert authors specifically integrated review of the ARUBA trial (A Randomized trial of Unruptured Brain AVM), which found that in unruptured cerebral AVMs, conservative management was less harmful than interventional treatments [60]. There were several concerns with this trial, and participants were mainly adults with non-HHT-related AVMs. (See "Brain arteriovenous malformations", section on 'Unruptured AVMs'.)

Following expert joint review, neurosurgical, interventional neuroradiological, and radiosurgical teams may elect not to treat a lesion for other reasons [59]. However, those managing HHT families are aware there may be value in knowing of the presence of a cerebral AVM, either for early intervention should it become symptomatic, or for other aspects of health planning. There may also be negative implications from the awareness of a cerebral AVM for which treatment is not recommended.

•Other lesions – Other lesions more commonly seen in HHT patients include capillary malformations/telangiectases (sometimes referred to incorrectly as "micro-AVMs"), cavernous malformations (formerly known as "cavernomas") and developmental venous anomalies (DVA) [19]. (See "Vascular malformations of the central nervous system".)

For these, management in HHT patients follows general population guidance; these lesions are usually not treated due to low risks of hemorrhage [19].

•Cerebral aneurysm – The rate in HHT patients is similar to the general population [19,61] and management follows general population guidance.

Across European expert centers, these issues are discussed with all patients as part of formal pretest counseling. Our preferred practice is to enable any HHT patient to have a screening brain MRI scan if that is their wish following pretest counseling [41]. A 2020 Position Statement from the European Reference Network stated that discussions of potential screening are undertaken for asymptomatic patients and noted that MRI scans are performed in only a proportion of patients having the screening discussions [19].

One center's experience stratifying 603 HHT patients with no neurologic symptoms of concern according to whether there was a positive family history of cerebral hemorrhage were reported in 2018 [41]. Screening scan uptake was higher after publication of the ARUBA trial, and patients with a family history of cerebral hemorrhage were 4-fold to 14-fold more likely to have a screening scan than patients with no such family history [41]. In a survey of 28 North American HHT Centers of Excellence, all reported screening adults with HHT for vascular lesions in the brain; 25 of 28 routinely screen children [62].

If screening is performed, brain MRI with contrast is recommended; this may entail general anesthesia in young children. The optimal timing and frequency of MRI is not established, and it is important to recognize that small lesions may be missed without catheter cerebral angiography.

Other important considerations related to the incidence of cerebral AVMs include the following:

●The risk of a new AVM developing after a previous negative scan is unknown.

●Screening scans commonly detect silent cerebral infarction due to pulmonary AVMs (PAVMs) [19]. At our institution, these considerations are openly discussed with the patient [41].

●While cerebral AVMs lesions are more common in HHT1 (ENG) and SMAD4 families, they also are present and may hemorrhage in individuals from ACVRL1 families [29,63-68]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genotype-phenotype correlations and variable penetrance'.)

●The lifelong risk of hemorrhage is higher for younger patients because of their longer predicted lifespan. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Cerebral vascular abnormalities' and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Children'.)

HEPATIC AVM SCREENING — Symptomatic liver lesions should be investigated, as discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Hepatic AVMs'.)

Screening for liver lesions was recommended in the 2020 International Guideline on HHT [13]. Reasons included the fact that diagnosis of symptomatic hepatic AVMs may be delayed because symptoms are incorrectly attributed to other causes (eg, high output cardiac failure attributed to "heart" disease). Hepatic vascular malformations are most common in individuals with HHT2 due to ACVRL1 variants.(See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.)

In terms of approaches to hepatic AVM screening, data are not available to guide the choice of imaging modality or the frequency of monitoring; additional study of these questions is needed. The choice of imaging modality may depend on local expertise and should be discussed with the radiology team who will be performing liver imaging. A Practice Guideline from the French Association for the Study of the Liver (AFEF) and European Reference Network (ERN) provides details of the types of lesions that may be found [69].

Management is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Initial management of hepatic AVMs'.)

SPECIAL SCENARIOS

Individuals who require anticoagulation (VTE and AF)

●Appropriate use of anticoagulation

•VTE prophylaxis – Patients with HHT are at increased risk for venous thromboembolism (VTE) [37]. They should have prophylactic anticoagulation at high-risk times as for the general population.

•AF or VTE treatment – Patients may also receive full anticoagulation if needed for conditions such as atrial fibrillation (AF) or VTE, or other indications; HHT is not an absolute contraindication, as discussed in the HHT 2020 Guideline and the 2022 VASCERN Framework manuscript [13,20]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management".)

•Cautions – While some caution is required during anticoagulation (particularly because nosebleeds may increase), anticoagulant or antithrombotic therapy should not be withheld purely on a presumption of potential bleeding risk in HHT [13,18,70]. Patients can be alerted that for approximately one-half of individuals, nosebleed severity may increase, but there is no evidence that AVM hemorrhage has been precipitated by therapeutic anticoagulation [18,70]. Securing additional ear, nose, and throat (ENT) treatments may be required [18]. Occasionally patients report that their nosebleeds improve.

●Choice of anticoagulant

•Conventional heparin and warfarin have been first-choice anticoagulants in HHT in International and European guidance [13]. However, a 2023 study found rates of dose reduction or discontinuation with warfarin and direct oral anticoagulants (DOACs), and the consensus for anticoagulant choice may shift to include DOACs [71]. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Treatment of bleeding'.)

•If DOACs are considered, apixaban appears to be associated with less risk of bleeding complications than rivaroxaban.

•If an HHT patient has excessive nosebleeds with one particular anticoagulant, they may successfully switch to an alternate agent, although it is not possible to predict which agent will best suit any particular individual [18].

●Supporting evidence

•Heparin and warfarin – Several studies have reported that heparin and warfarin are generally well-tolerated [18,70,72,73].

•DOACs – In a detailed audit of the use of anticoagulants across the European Reference Network (ERN), none of the eight VASCERN HHT Reference Centers had recommended DOACs [18,70]. There were 32 reports of the use of a DOAC prescribed to HHT patients by other clinicians, 16 times for VTE and 16 times for AF (apixaban in 15, rivaroxaban in 14, and dabigatran in 3). HHT nosebleeds increased in severity in 24 of 32 treatment episodes (75 percent), leading to treatment discontinuation in 11 (34 percent); 8 (25 percent) patients had extreme hemorrhage with nosebleeds lasting hours and requiring hospital admissions, blood transfusions, and in all cases, anticoagulant discontinuation [18].

•Discontinuation rates – In a cohort of 119 individuals with HHT, 59 (50 percent) reduced the dose or prematurely discontinued therapy due to worsening bleeding [71]. Multivariable analysis identified prior gastrointestinal bleeding as a risk factor for discontinuation. The choice of anticoagulant (warfarin, heparin, or a DOAC) did not affect dose reduction or anticoagulant discontinuation.

Air travel — As noted separately, air travel is generally well-tolerated in HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Potential complications of PAVMs'.)

Traveling by air raises issues in the general population and these have particular relevance for people with HHT.

●VTE – Individuals with HHT can follow advice for the general population regarding reducing the likelihood of VTE associated with prolonged immobility during air travel. It is important to recognize that HHT nosebleeds (that may prohibit flying) may occur before or during flights whether antiplatelet or anticoagulant agents are prescribed. (See "Prevention of venous thromboembolism in adult travelers".)

●Epistaxis – The risk of nosebleeds during airline travel may be increased due to reduced humidity and air pressure: in a series of 145 individuals with HHT who replied to a questionnaire about airline flight-related complications, significant nosebleeds occurred in approximately 14 percent of long-haul flights [74]. In our institution, we advise patients to use Vaseline or other nasal lubricants and to be prepared with tissues.

SCREENING AND GENETIC TESTING OF AT-RISK FAMILY MEMBERS — Data from a 2022 study emphasize the paucity of clinical symptoms in many patients with genetically-confirmed HHT [1]. Of 152 unrelated adults with genetically confirmed HHT due to a pathogenic variant in ACVRL1, ENG, or SMAD4, only 104 (68 percent) met a clinical diagnosis of HHT with three Curaçao criteria. Of 83 unrelated probands with one or more PAVMs and genetically-confirmed HHT, 20 (24 percent) had few, if any, features of HHT. Unaffected status should not be assumed based on the absence of nosebleeds or other HHT symptoms.

Children — Children in HHT families who have symptoms should be investigated, as discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".)

Determining what should happen to healthy children within HHT families is much more controversial.

●Genetic testing – The 2020 second International Consensus HHT Guideline recommended genetic screening to be offered to all children of a parent with HHT (96 percent agreement) and all who are diagnosed with HHT based on clinical criteria [13]. Where genetic testing is offered, this should always be in the context of counseling and informed decision-making, with discussions of the potential implications for the child. If the familial disease-causing (pathogenic) variant is known and the child tests negative for that variant, parents can be reassured that the child does not have HHT. However, if the familial variant is not known, a negative test cannot exclude the diagnosis of HHT. Those who do not undergo genetic testing should be considered to have possible HHT. (See 'Genetic counseling and testing of family members' below and "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)

If formal genetic testing and exclusion of a familial variant has not (or cannot) be done, it is not possible to eliminate the possibility of HHT in a child, since symptoms and vascular lesions may not become apparent until later in life [13]. There are differences in practice for children for whom it is not possible to use formal genetic testing, ranging from screening for all manifestations of HHT to deferring any screening in asymptomatic children until after puberty, unless dictated otherwise by family history [57].

●Clinical evaluation – Across practices, for children with HHT, recommendations range from evaluating for all manifestations of HHT to deferring the evaluation in most asymptomatic children until post-puberty, unless dictated otherwise by family history [57]. Similar variation in practices applies to children for whom it is not possible to use formal genetic testing [57].

•Pulmonary AVMs – For pulmonary arteriovenous malformations (PAVMs), the first International HHT Guideline recommended screening all patients with possible or confirmed HHT for PAVMs and included children in the screening recommendation [3]. The second International Guideline specifically addressed children and recommended pulmonary AVM screening at the time of diagnosis, and in those at risk for HHT based on a parent's diagnosis (94 percent agreement from the clinician and patient expert panel), and a repeat pulmonary AVM screening in children with an initial negative screen, at an interval of every five years (86 percent agreement) [13].

•Cerebral AVMs – For cerebral AVMs, the first International HHT Guideline recommended screening children with possible or definite HHT for CVMs in the first six months of life or at time of diagnosis (64 percent agreement) [3]. The second International HHT Guideline also recommended screening for brain vascular malformations in asymptomatic children with HHT or at risk for HHT, at the time of presentation or diagnosis (87 percent agreement) [13].

It should be noted that the pulmonary and cerebral screening recommendations contrast with other position statements (eg cerebral AVMs from the European Reference Network for Rare Vascular Diseases [VASCERN] [19]), particularly regarding the indication for repeated screening, imaging, and treatment of asymptomatic pulmonary AVMs. Further data on the outcomes post treatment are expected.

Based on the latest evidence, pediatric-specific risks and benefits of screening include the following:

●Greater burdens and risks – Burdens and risks of screening may be greater in children than in adults.

•Greater risks from exposure to ionizing radiation, including increased risk of cancer [23,75-77]

•Possible need for general anesthesia to enable imaging

•Inability to give full informed consent and/or to understand the implications of screening

●Less evidence for benefit – There is less evidence for benefits of screening in children, especially for pulmonary AVMs.

•Risk of complications from pulmonary AVMs in children is less well-documented than risk of complications in adults.

Some of these considerations are discussed in more detail separately. (See "Radiation-related risks of imaging", section on 'Children and adolescents' and "Genetic testing", section on 'Testing children'.)

Briefly, as for adult screening, all experts are in agreement that decisions to screen children should be made with shared decision-making to allow all concerns and questions to be addressed and implications of screening decisions understood, including by the child when they are near the age of consent in the particular country (age varies from 16 to 21 years in different countries). The key considerations are:

●Whether asymptomatic children are at similar or different risks to asymptomatic adults if rationales for screening programs are based on data in adults (for example, pulmonary arteriovenous malformation [PAVM] screens given almost all complications occur in adult life).

●Whether treatment of asymptomatic children modifies the natural history of the development of their condition in a detrimental manner [51].

Practice variations in the aggressiveness of testing and screening reflect the uncertainty as to whether silent AVMs pose sufficient danger in childhood to balance the risks of childhood radiation exposure from imaging studies. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Onset of disease manifestations' and 'Cerebral AVM screening' above.)

Pediatric treatment recommendations (as opposed to screening of asymptomatic children) are discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Children'.)

Genetic counseling and testing of family members — Individuals with HHT should be aware of the autosomal-dominant transmission and the possibility of having an affected child or other affected first-degree relative, which is approximately 50 percent. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.) Individuals with HHT should be aware of that data [1] absence or paucity of nosebleeds does not exclude HHT: of 83 unrelated probands genetically screened for HHT due to the presence of PAVM(s), 20 (24 percent) had few, if any, features of HHT.

Genetic testing of family members is complicated in HHT because there are several potential genes involved, there are no common pathogenic variants, founder members may be mosaic with challenging molecular diagnostics, and the causative pathogenic variant is not identified in all families, highlighting that additional HHT genes or genomic regions are yet to be characterized [3]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.)

If genetic testing is pursued, an affected individual in the family should be tested first, followed by testing of selected family members for the specific variant that has been identified to be pathogenic or likely pathogenic in that family. If a familial disease-causing variant for HHT has been identified, genetic testing for this variant can reliably identify family members who have and have not inherited the variant. Individuals with the HHT genotype can be evaluated as described above. However, this is only possible if a specific familial gene variant has been tested [3]. Details of this testing are presented separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics' and "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Diagnosis'.)

Practices vary regarding the age at which to perform genetic testing, reflecting the ethical considerations involved in screening an asymptomatic child who is too young to give consent and will likely not understand the implications of testing. (See 'Children' above and "Genetic testing", section on 'Testing children'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

SUMMARY AND RECOMMENDATIONS

●Symptomatic individuals – Individuals with hereditary hemorrhagic telangiectasia (HHT) who are symptomatic should be investigated. Clinicians should be aware of typical arteriovenous malformation (AVM) symptoms. Many recommendations are based on expert opinion and observational studies; the uniformity of expert opinion varies depending on the clinical situation and prevailing practices. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".)

●Asymptomatic individuals; general principles – Education and screening are important.

Educational materials and specialized testing and management centers are available from the European Reference Network on Rare Multisystemic Vascular Diseases and country-specific patient groups. (See 'General principles of management' above.)

●Screening – AVM screening in individuals at risk of HHT or asymptomatic individuals with HHT is recommended universally for PAVMs. For other AVMs, screening is more controversial than evaluating symptomatic lesions. It is good practice to counsel patients on risks and benefits prior to screening. Assuming the individual agrees, screening generally consists of an examination, evaluation for anemia and iron deficiency, pulmonary AVM (PAVM) screening, and discussions of screening for AVMs at other sites (hepatic, cerebral). Individuals with SMAD4-related HHT require more extensive surveillance due to the risk of juvenile polyposis and aortopathy. (See 'Overview of screening strategy' above and 'Cerebral AVM screening' above and 'Individuals with SMAD4 HHT' above.)

•Iron deficiency – We obtain regular complete blood counts (CBC) and examine serial trends and red cell indices, particularly for patients who have hypoxemia due to PAVMs, for whom a "normal" hemoglobin may be inappropriately low for the expected degree of polycythemia. We regularly assess iron status regardless of the hemoglobin level, since iron deficiency is likely to progress to anemia if not treated. (See 'Iron status' above.)

•PAVMs – Adults with HHT should be screened for PAVMs. Unsuspected PAVMs are common, and treatment reduces risks of stroke and brain abscess in adults. Females with HHT should undergo screening before becoming pregnant, since PAVMs can bleed in later pregnancy leading to life-threatening hemoptysis or hemothorax. Screening may consist of contrast (bubble) echocardiography in institutions with very strong local expertise, or with chest computed tomography (CT). Negative contrast echocardiography in experienced hands or negative CT can rule out PAVMs; a negative chest radiograph cannot. The timing and repeat screening in individuals with a negative initial screen depends on patient age and other findings. (See 'PAVM screening' above.)

•Cerebral AVMs – Screening for cerebral arteriovenous (AV) shunts can be undertaken, noting the importance of shared decision-making and other considerations discussed above. (See 'Cerebral AVM screening' above.)

•Children – Screening asymptomatic children within HHT families differs between institutions due to variable risk-benefit assessment. Evidence of benefit is generally lacking, and certain risks are recognized (radiation exposure from some imaging studies). All specialists agree on the importance of informed consent that weighs risks and benefits for each individual. Other considerations include uncertainty about the risk of complications from silent AVMs in children, concerns about the ethics of screening children, and lack of information about how treatment affects the natural history of disease in children. (See 'Children' above.)

●VTE risk – Individuals with HHT have an increased risk of venous thromboembolism (VTE) and should follow general population guidance for VTE treatment and prophylaxis. (See 'Individuals who require anticoagulation (VTE and AF)' above and 'Air travel' above.)

●Reproductive counseling and testing – Individuals with HHT should be aware of the autosomal dominant transmission and possibility of having an affected child. Genetic testing of family members can be complicated. The possibility of disease can be excluded in relatives only if a familial pathogenic variant has been identified. (See 'Genetic counseling and testing of family members' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Vijeya Ganesan, MD, who contributed to an earlier version of this topic review.