Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions

INTRODUCTION — Hereditary hemorrhagic telangiectasia (HHT; also called Osler-Weber-Rendu syndrome) is an autosomal dominant vascular disorder associated with a variety of clinical manifestations including mucocutaneous telangiectasia, epistaxis, gastrointestinal bleeding, and iron deficiency anemia. Arteriovenous malformations (AVMs) commonly occur in the pulmonary, hepatic, and cerebral circulations.

This topic review discusses the management of vascular lesions in individuals with HHT, including epistaxis; gastrointestinal lesions; and pulmonary, hepatic, and cerebral AVMs.

Other aspects of HHT care are discussed separately:

●Pathophysiology, epidemiology, and diagnosis – (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

●Screening for asymptomatic AVMs and testing and counseling of family members – (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".)

OVERVIEW

Definition of terms — The following vascular lesions are seen in individuals with HHT:

●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), 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 skin or mucous membranes.

These lesions are not specific for HHT; they can also be seen sporadically in otherwise healthy individuals, associated with other disorders, or as part of a syndrome. 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 have been summarized in International Guidelines published in 2020 [1] and Consensus Statements from the European Reference Network (ERN) and other groups [2-5].

Important general elements include:

●Patient educational materials for individuals 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.

●Clinician education regarding the importance of epistaxis as the main cause of anemia, the need for intervention for certain asymptomatic individuals, and the paucity of clinical signs in patients with genetically confirmed HHT with visceral AVMs [6]. HHT vascular lesions may mimic metastases to liver or lung.

●Individuals with epistaxis (and less frequently, gastrointestinal bleeding) from sites that are accessible can receive dedicated local therapies; however, systemic therapies are sometimes used very successfully. (See 'Epistaxis' below and 'Gastrointestinal lesions' below and 'Hepatic AVMs' below.)

●Other localized vascular lesions should be assessed and treated (table 1). This may require subspecialist management. The interventions used are generally the same as the treatment of the lesion in the absence of HHT. (See 'Therapy for specific vascular lesions and iron deficiency' below.)

●Systemic treatments may be needed for those with refractory bleeding, usually manifested by requirements for multiple blood transfusions and/or iron infusions. When reviewing evidence for systemic therapies, it is important to prioritize data from randomized trials. Individuals on the placebo arm often experience improvement in symptoms, illustrating the challenges in using observational studies to ascribe benefit [7]. (See 'Tamoxifen and other non-guideline approaches' below and 'Bevacizumab and other systemic antiangiogenic therapies' below.)

●When anticoagulation or antiplatelet therapy is indicated (for prophylaxis or treatment of thromboembolic or cardiovascular disease), this therapy should not be denied simply due to the HHT diagnosis. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Individuals who require anticoagulation (VTE and AF)'.)

●An approach to screening for asymptomatic AVMs and other aspects of routine care are discussed separately. It is especially important to identify pulmonary AVMs (PAVMs) to prevent paradoxical emboli, strokes, and brain abscesses. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".)

Many management recommendations are based on expert opinion and observational studies; although data from randomized trials are emerging for several areas of management, randomized trials have not delivered statistical support for several proposed treatments, and larger and further studies are underway with results awaited. In the meantime, as described in the sections below, much of expert opinion and practice remains guided by observational studies [1,3-5]. The uniformity of expert opinion varies depending on the clinical situation and prevailing health care practices.

The second International HHT Guideline, published in 2020 by an international consensus group, was updated to take into account changes in evidence and advances in genetic testing [1]. The first International Guideline for the management of HHT was developed by the same group in 2006, made available online in 2007, and published in print in 2011 [8].

The 2020 International Guideline addressed six topics: epistaxis, gastrointestinal bleeding, anemia/anticoagulation, hepatic vascular malformations, pediatrics, and pregnancy [1]. This Guideline was more nuanced in separating the severity of indications for elements of care proposed in the first Guideline (presenting in a stepwise fashion according to the severity of the disease), and also incorporated some new recommendations.

●For evaluation and therapy, the main new item in the 2020 Guideline was the incorporation of systemic antiangiogenic therapies into the algorithms for epistaxis, gastrointestinal bleeding, and severe hepatic AVMs (data on antiangiogenic therapy in HHT were not available when the first Guideline was generated in 2006). (See 'Bevacizumab and other systemic antiangiogenic therapies' below.)

●While previous guidelines recommended referral to specialists with relevant expertise (eg, otorhinolaryngologists, centers with neurovascular expertise), the 2020 Guideline detailed structured approaches recommended for the specialty management.

●Anemia was discussed as a separate topic. Previous guidelines had discussed management with oral and intravenous iron: the 2020 Guideline included a specific recommendation for red blood cell transfusions in the settings of hemodynamic instability/shock; comorbidities that require a higher hemoglobin target; need to increase the hemoglobin acutely, such as prior to surgery or during pregnancy; and/or inability to maintain an adequate hemoglobin despite frequent iron infusions. (See 'Iron deficiency and iron deficiency anemia' below.)

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: PAVM screening, antibiotic prophylaxis prior to dental and surgical procedures for those with PAVMs, epistaxis advice, assessment of iron deficiency, and advice on pregnancy [3]. Subsequent manuscripts include evidence from HHT patients across the ERN [3,4,9,10].

Frameworks published in 2022 include guidance for general health care practitioners reviewing HHT patients in non-specialty care as well as providing summary data and pathophysiological integrations for HHT specialists [2].

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, and country-specific patient groups.

THERAPY FOR SPECIFIC VASCULAR LESIONS AND IRON DEFICIENCY

Epistaxis — Epistaxis is the most common site of blood loss in HHT, affecting more than 90 percent of patients. Very high proportions experience epistaxis on a daily or near-daily basis, and the iron losses are often sufficient to cause iron deficiency anemia, even in the absence of additional gastrointestinal bleeding. Management of epistaxis and iron deficiency anemia are therefore cornerstones of HHT management. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Epistaxis'.)

The 2020 International Guideline provides a stepwise approach to treatment of epistaxis, in the following sequence [1]:

●Topical therapies

●Oral tranexamic acid

●Ablative therapies by otorhinolaryngologists

●Systemic antiangiogenic therapy (eg, bevacizumab)

●Septal dermatoplasty

●Young's procedure (nostril closure)

As discussed below, there is evidence from randomized controlled trials for tamoxifen and tranexamic acid in HHT, and randomized trials are especially important in HHT (see 'General principles of management' above). Although tamoxifen was not addressed in the 2020 guideline, we suggest tamoxifen for individuals who require systemic therapy. Tranexamic acid is another reasonable option. (See 'Tamoxifen and other non-guideline approaches' below and 'Oral tranexamic acid' below.)

There has also been widespread adoption of bevacizumab, and two further drugs (raloxifene and thalidomide) have received European Medicine Agency orphan drug designation for use in HHT, despite not being the most commonly used agents and no supportive evidence from randomized trials. Bevacizumab can be useful for individuals with severe bleeding. However, the transiency of some responses, lack of randomized trial data, and adverse effects should also be considered. (See 'Bevacizumab and other systemic antiangiogenic therapies' below.)

The decision to use particular approaches depends on risk-benefit evaluations individualized to incorporate potential benefits and risks for the specific patient, as discussed in more detail below. Potential beneficial effects from systemic agents need to be balanced against the risks, and this is ideally conducted by clinicians with expertise using these agents in HHT.

When weighing risks and benefits, there are few randomized trials to guide care. Early randomized trials provided evidence of benefit for the following:

●Estrogen-progesterone [11]

●Tamoxifen [12,13]

●Tranexamic acid [14,15]

●Systemic propranolol [16]

However, other randomized trials have not shown convincing evidence of benefit in the treatment arm [7,17-22]. For two of the trials, there was marked improvement in the placebo arm, reflecting the benefit of saline and gel administration [17,18].

The degree of ill health and/or compromised quality of life due to HHT-associated bleeding not responding to all other measures means that the risks of systemic therapies may be considered justifiable [9]. However, it is important to recognize that most HHT patients with nosebleeds and anemia will not require such treatments that should be reserved for severe cases.

Although all drugs have their specific side effect profiles, the risk of venous thromboembolism (VTE) requires a special note. Concerns about VTE with systemic therapies have led to the development of investigational topical agents (see 'Topical therapies' below). The systemic agents used to treat HHT-related epistaxis also increase the risk of VTE; individuals who develop VTE would require full anticoagulation with its attendant risks [23-25]. Across Europe, these agents are therefore generally avoided in patients with a prior history of VTE and/or those at particularly high risk of cerebral sequelae (eg, due to concurrent atrial fibrillation).

Topical therapies — Additional information about local therapies for the management of epistaxis is presented separately. (See "Management of epistaxis in children" and "Approach to the adult with epistaxis".)

In HHT, accumulating evidence encourages the use of local (topical) preventive therapies [1]:

●Nasal humidification

●Ointments

●Saline spray [17]

●Gel [18]

These therapies are essentially free of significant adverse effects, although occasional individuals report that they seem to precipitate their nosebleeds, in which case they should be discontinued.

●Saline nasal sprays – Saline nasal sprays can be used to prevent drying, especially during winter and in dry environments such as airplanes. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Air travel'.)

Saline nasal sprays demonstrated significant benefits in two trials in which they were used as placebo:

•In one trial from 2016 involving 80 patients with HHT randomly assigned to receive intranasal bevacizumab or a saline nasal spray, the epistaxis severity score (ESS) in the 27 patients receiving nasal saline was reduced from 5.7 (95% CI 5.0-6.3) to 3.7 (95% CI 3.2-4.3) [7]. Other studies have demonstrated that the minimally important difference in the ESS is 0.7 [26].

•In a survey of 649 patients with HHT and epistaxis, there were positive (beneficial) scores for improvement of epistaxis with saline treatments, room humidification, and nasal lubrication [27].

•In another trial from 2016 involving 121 patients with HHT who were randomly assigned to receive one of several nasal sprays (active agents bevacizumab, estriol, tranexamic acid, or saline [placebo]), there were no significant between-group differences [17].

●Thermosensitive gel – In a randomized trial of 27 patients, benefit was seen in the placebo arm, which used a thermosensitive gel [18]. The median reduction in ESS was 1.96 (range, -0.91 to 5.98), and 9 of 12 participants (75 percent) receiving the placebo gel experienced a clinically meaningful improvement in ESS.

●Topical beta blockers – Topical betablockers have been shown to demonstrate efficacy in some but not all randomized controlled trials:

•Propranolol demonstrated efficacy in a 2020 trial in 20 participants with moderate-severe HHT-related epistaxis who were randomly assigned to eight weeks of propranolol gel (1.5%) or placebo [16]. Dosing used 0.5 mL, applied to each nostril twice daily; and propranolol was continued for eight weeks in an open-label study. For the propranolol group, the ESS improved significantly (-2.03±1.7, versus -0.35±0.68 for the placebo group, p = 0.009). Hemoglobin levels also improved significantly (10.5±2.6 to 11.4±2.02 g/dL, p = 0.009); and intravenous iron and blood transfusion requirement decreased. The change in nasal endoscopy findings was not significant. During the open-label period, the ESS score improved significantly in the former placebo group (-1.99±1.41, p = 0.005).

•There was not a significant benefit in a trial in which 27 participants were randomly assigned to use timolol gel or placebo gel; the median change in ESS was 2.32 (range, 0.22 to 5.97) with timolol gel versus 1.96 (-0.91 to 5.98) with placebo [18]. A clinically meaningful improvement in ESS was experienced by 9 of 11 (82 percent) in the timolol gel group versus 9 of 12 (75 percent) with placebo. In another trial that randomly assigned 58 individuals to receive timolol nasal spray (0.25 mg in each nostril twice a day for 28 consecutive days) or placebo, ESS did not improve with timolol administration [19].

●Topical estrogen or other agents – A 2016 trial in which 121 patients were assigned to apply a 0.1 percent estriol ointment (a low potency metabolite of estradiol), topical bevacizumab, topical tranexamic acid, or placebo to the nasal mucosa found no benefit of any of the active treatments [17]. However, the study was not sufficiently powered to rule out an effect, and a larger study of topical therapy may be warranted.

A 2018 meta-analysis that included eight randomized placebo-controlled clinical trials found that submucosal (delivered endoscopically) bevacizumab and oral tamoxifen delivered benefit [28]. All of the nasal sprays (bevacizumab, tranexamic acid, or estrogen) showed a trend towards reduced frequency of epistaxis that did not reach statistical significance. Despite these negative findings, responses vary in different individuals, and it is not possible to predict who will respond particularly well to a given intervention.

A 2020 randomized trial found that tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment [20].

Emergency nasal packing may be required for severe hemorrhage. (See "Approach to the adult with epistaxis", section on 'Nasal packing'.)

Oral tranexamic acid — Tranexamic acid is proposed in the 2020 HHT guidelines to be second-line therapy for HHT nosebleeds that do not respond to topical therapies. It can be taken orally two to three times per day.

Randomized trial evidence for efficacy of tranexamic acid with long-term use in HHT includes the following:

●In the 2014 ATERO trial, 118 individuals with HHT who had epistaxis for more than 60 minutes or 28 days in a month were randomly assigned to receive placebo or tranexamic acid (1.5 g orally twice per day for three months) followed by crossover to the other arm [14]. Compared with placebo, tranexamic acid was associated with a reduced duration of nosebleeds (106 versus 129 minutes per month) but no change in the number of nosebleeds (mean, 23 versus 22 per month).

●A randomized crossover trial from 2014 in which 22 patients received placebo or tranexamic acid, 1 g orally three times a day for three months, also found a significant reduction in nosebleeds with tranexamic acid, although hemoglobin levels were not improved [15].

Not all experts agree with such widespread use of tranexamic acid, given the generally lifelong nature of HHT nosebleeds and the possibility of side effects not captured by short-term clinical trial follow-up. In our experience, VTE has developed in patients with HHT, and ischemic strokes have occurred in patients with HHT and pulmonary AVMs (PAVMs) [24,29].

Aminocaproic acid is an antifibrinolytic agent with a similar mechanism of action as tranexamic acid, but the published clinical experience with aminocaproic acid in HHT is much less extensive [30].

Ablative therapies — For patients who continue to experience significant nosebleeds, review by an ear nose and throat (ENT) surgeon with expertise in this area is advisable to optimize interventional treatments. Dedicated local ENT treatments are generally directed to patients experiencing frequent epistaxis or less frequent massive hemorrhages [31]. In one survey, 326 of 666 unselected respondents with HHT (49 percent) required specialist invasive treatments, often requiring multimodality therapy [27].

●Different types of laser or argon plasma coagulation devices are available, with the choice of method depending on operator preference and availability.

●Laser therapy is generally preferred over cauterization, since cauterization can damage the nasal mucosa, which may prompt vascular regrowth; however, if cauterization is the only therapy available, it can have beneficial effects [27]. In a survey comparing 267 international HHT users of cauterization and 221 users of laser therapy, laser therapy was reported to be beneficial more frequently than cauterization [27].

●Sclerotherapy is another treatment that may be effective. A randomized crossover trial involving 17 patients with HHT and epistaxis found that sclerotherapy with sodium tetradecyl sulfate resulted in a greater reduction in ESS than standard care (moisturization, cautery) [32]. A retrospective study evaluating 67 patients with HHT found that use of sclerotherapy with sodium tetradecyl sulfate resulted in similar efficacy in controlling epistaxis as laser cautery, with fewer procedures required [33]. However, the otorhinolaryngology experts within the European Reference Network (ERN) have made the point that sclerotherapy carries well-documented risks of adverse events, including blindness in the non-HHT population, and full-patient counseling seems appropriate [2].

●Coblation therapy (a term derived from the words "controlled ablation") is another treatment reported to be effective; it involves use of radiofrequency ablation at low temperatures to remove problematic tissue. In a study that followed 57 patients with HHT who underwent 150 coblation treatments over the course of 12 years, the average duration of effectiveness was 25 months (range 1 to 86 months) [34]. Of the 26 patients (46 percent) who underwent multiple coblation treatments, the overall average duration of coblation effectiveness was 16.4 months (range, 1 to72 months).

Bevacizumab and other systemic antiangiogenic therapies

●Bevacizumab

•Indications – Bevacizumab is an antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF). It can be very useful for individuals with severe bleeding, and antiangiogenic therapies were prominent in the recommendations from the second International HHT Guideline recommendations for epistaxis and gastrointestinal bleeding [1]. The first randomized trial did not provide clear guidance, as discussed below. Before the randomized trial, across the European Reference Network (ERN), bevacizumab was considered a choice of last resort in extremely ill individuals with compromised quality of life, based on the evidence available at the time the guideline was published, which did not include randomized trials, and the known adverse effects in HHT and other settings [9]. Further evidence to guide practice is awaited.

•Dosing – Advice on when and how to use bevacizumab is provided in a document from the ERN [35].

This recommends a dose of 5 mg/kg body weight administered as an intravenous infusion at 14- to 21-day intervals. The initial dose should be given as a 90-minute intravenous infusion. If the first infusion is well tolerated, the second infusion may be given over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be given over 30 minutes. The recommended duration of induction treatment with bevacizumab is six infusions at 14- to 21-day intervals, resulting in 2.5 to 4 months of therapy. If bleeding is controlled after three infusions, maintenance treatment is used with an individualized schedule.

•Adverse effects – Adverse effects were evaluated in a 2019 study by the ERN on Rare Multisystemic Vascular Diseases (VASCERN) in 69 individuals with HHT who were treated with bevacizumab for a mean of 11 months for bleeding or high-output cardiac failure due to hepatic AVMs [9]. Adverse events were reported in 33 patients, more commonly in females (27 adverse events in 46 females versus 6 events in 23 males). The most common of these were joint pain (10 percent), headache (4 percent), and proteinuria (3 percent). Bleeding occurred in two patients (3 percent); one was an episode of grade 3 gastrointestinal bleeding, and one was a fatal event of catastrophic hemoptysis from a known but not monitored PAVM. This was considered possibly related to bevacizumab, as spontaneous rupture of PAVMs is highly unusual outside of pregnancy or pulmonary hypertension, which were absent in this individual. Adverse events affecting the heart valves were reported in another HHT study [36].

Other potential toxicities of bevacizumab identified in the general population (including cardiovascular effects [hypertension, thromboembolism, left ventricular dysfunction], non-cardiovascular effects [proteinuria, bleeding, delayed wound healing, gastrointestinal perforation, fatigue, and dysphonia], and fatal adverse events) are presented in more detail separately. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

•Supporting evidence – The only randomized trial of bevacizumab in HHT was a small trial that assigned 24 individuals with a high transfusion requirement (at least 4 units in the previous three months) to receive bevacizumab 5 mg/kg every 14 days for 6 infusions or placebo [37]. Individuals assigned to bevacizumab had a greater reduction in transfusions that did not reach statistical significance (64 percent of bevacizumab-treated patients reduced transfusion requirements by at least 50 percent compared with 33 percent of placebo-treated patients; p = 0.22); benefit was greatest in those with high bevacizumab concentrations (measured after the data on benefit were collected). Bevacizumab-treated patients did not have statistically significant improvements in hematologic parameters or epistaxis. Adverse events were also similar between groups. The high percentage of patients in the control group with reduced transfusion requirements serves to emphasize the fluctuating nature of bleeding in patients with HHT.

The second International HHT Guideline reported multiple uncontrolled, retrospective series that demonstrated intravenous bevacizumab reduced epistaxis, improved anemia, reduced transfusion requirements, or improved quality of life [1,38-46]. Further observational studies and surveys have been published since those reviewed in the Guideline [47].

A multicenter retrospective study from 2021 that included data from 238 individuals with HHT treated with systemic bevacizumab found favorable safety and efficacy profiles [48]. Dosing protocols varied; the majority received four to six treatments of 5 mg/kg every two weeks, followed by maintenance treatments on a regular schedule (5 mg/kg once every 4 to 12 weeks). Responses were apparent within three months; hemoglobin levels increased by a mean of 3.2 g/dL, the mean ESS decreased by 3.4 points, and the median number of transfusions decreased from six units in six months to zero. In patients who required intravenous iron infusions, the number of infusions decreased from eight infusions in six months to two. Adverse effects included hypertension in 18 percent, fatigue in 10 percent, proteinuria in 9 percent, myalgia or arthralgia in 6 percent, and venous thromboembolism (VTE) in 2 percent (none fatal). Five percent discontinued bevacizumab for adverse events. Previous smaller studies, some from the same authors who contributed to the 2021 study above, had also suggested efficacy [38-40,49].

●IMiDs – Thalidomide and lenalidomide have antiangiogenic and immunomodulatory properties [50-53]. There have not been randomized controlled trials of these drugs in HHT. A 2018 systematic review of observational studies found an association between the use of low-dose thalidomide and reduced frequency and duration of epistaxis and need for transfusions [54]. Thalidomide had previously received EMA orphan drug designation for HHT [55,56]. This was based on two small series of individuals with HHT (12 and 7 patients) [50,57]. Patients reported reductions in epistaxis, but many patients (approximately two-thirds and one-third, respectively) discontinued the drug due to side effects that included drowsiness, peripheral neuropathy, nausea, and constipation. Only a minority of patients continued taking thalidomide, primarily due to these side effects [50].

The safety of thalidomide in HHT was specifically evaluated by the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) [9]. Sixty-seven HHT patients received thalidomide, all for bleeding, and for a mean of 13.4 months, totaling 75 person-years of treatment. Adverse events related to thalidomide were reported in 34 individuals (51 percent), with an average incidence rate of 45.3 per 100 person-years. These were seen at similar rates in males and females. They were more common in individuals with an ENG mutation than an ACVRL1 mutation (all 17 with ENG versus 14 of 34 [41 percent] with ACVRL1). The most common reports were of peripheral neuropathy (18 percent), drowsiness (12 percent), and dizziness (9 percent). Three fatal, adverse events were possibly related to thalidomide (average incidence rate: 4 per 100 person-years).

As noted above, systemic therapies have demonstrated adverse effects of which the clinician and patient should be aware. Individuals with HHT who have a history of thromboembolic disease are excluded from clinical trials using these agents [14,41]. Clinical studies using systemic bevacizumab in HHT have also excluded individuals with cerebral arteriovenous malformations (AVMs), thrombocytopenia, or anticoagulant therapy [41]. The use of these drugs remains off-label, and reported experience is still very limited.

A number of additional antiangiogenic and other agents have appeared promising in uncontrolled studies, case reports, or preclinical models. Examples include the VEGF inhibitor pazopanib and the immunosuppressive agents sirolimus and interferon [58-62]. It has been suggested that their use should be restricted to selected, consenting individuals in randomized trials conducted at experienced HHT centers, due to the lack of evidence for benefit from randomized trials, potential side effects, and lack of long-term safety and efficacy data [63].

Further ENT options recommended in international guidelines — Other directed therapies include septodermoplasty and/or unilateral or bilateral surgical closure of the nostrils [31,64-69]. These invasive treatments are almost always used in patients who have also received laser therapy and/or cauterization [27,31].

Young's procedure (bilateral surgical closure of the nostrils) has not been evaluated in a randomized trial, but as published in a series of 100 cases, many seen by us in subsequent years, it can have remarkable long-term success in alleviating major nosebleeds and reversing transfusion dependency, as long as there is complete closure of nasal flow [70]. However, a small proportion of patients cannot tolerate the procedure and request reversal, and a larger number decline as they are concerned about the implication of anosmia and mouth breathing.

Some patients have been treated with submucosal injection of bevacizumab at the time of laser therapy; long-term results of this approach are awaited [71,72].

Tamoxifen and other non-guideline approaches — Additional elements that can be incorporated as part of general care include:

●Dietary changes for prevention – HHT nosebleeds usually come in clusters and vary in severity over a lifetime. A proportion of people with HHT (we estimate approximately one in three) may be able to identify dietary triggers of nosebleeds that can be avoided without detrimentally impacting their lifestyle [27,64,73]. We suggest keeping a food diary of items ingested in the hours immediately prior to an unusually severe bleed to aid identification of potential precipitants.

●Avoidance of over-the-counter supplements – Caution with over-the-counter dietary supplements offers another opportunity to avoid potential precipitants. An example is fish oil supplements, for which antiplatelet activity is not generally appreciated [74]. (See "Fish oil: Physiologic effects and administration".)

For individuals who require systemic therapy, the 2020 International HHT Guideline discussions did not incorporate tamoxifen (with evidence from randomized trials) and the two European Medicines Agency (EMA)-recommended drugs raloxifene and thalidomide.

●Tamoxifen – A 2018 meta-analysis of eight randomized placebo-controlled trials demonstrated that only tamoxifen was superior to placebo, reducing both the frequency and the severity of epistaxis [28]. Tamoxifen appears to be well tolerated, has evidence of efficacy from a double-blind, randomized controlled trial, and is our first treatment of choice when a systemic agent is used for treating epistaxis. In a 2018 meta-analysis of randomized, placebo-controlled trials, tamoxifen was the only systemic agent shown to be superior to placebo; it reduced epistaxis severity and frequency [28]. Tamoxifen also has a favorable side effect profile compared with tranexamic acid, bevacizumab, and raloxifene (wider HHT population use of raloxifene is awaited). However, tamoxifen would not be recommended for someone with a prior history of VTE, atrial fibrillation, or similar higher risk-factor status for venous or arterial thromboembolism. (See "Managing the side effects of tamoxifen and aromatase inhibitors".)

A benefit from tamoxifen was demonstrated in a 2009 trial that randomly assigned 25 individuals with HHT (men and women) to receive placebo or tamoxifen (20 mg daily) for six months [12]. Compared with placebo, tamoxifen was associated with a reduction in epistaxis, based on self-report and nasal endoscopy (improvement in 18 versus 90 percent). Some individuals assigned to tamoxifen also had an improvement in hemoglobin level or reduction in transfusion requirements. In an extended follow-up of patients completing the trial arm, in a total of 46 patients with mean 23.4 months of treatment, there were improvements in bleeding score, quality-of-life score, and hemoglobin concentration; none required blood transfusions [13]. These and other extended follow-up studies, as well as our experience, suggest sustained benefits from tamoxifen, and therapy has been well tolerated [13,23,75]. In contrast to other agents discussed below, we have yet to see VTE developing in HHT patients using tamoxifen [23,75].

Premenopausal females taking tamoxifen should be aware of the effects on other organ systems. (See "Managing the side effects of tamoxifen and aromatase inhibitors".)

●Raloxifene – Raloxifene is a selective estrogen receptor modulator (SERM) that has received European Medicine Agency (EMA) orphan drug designation for HHT based on a small pilot study [76,77]. There is no evidence from randomized trials in HHT. Raloxifene is associated with an increased risk of VTE events, particularly during the first four months of treatment, and is contraindicated in people with a history of VTE, hepatic impairment, cholestasis, severe renal impairment, unexplained uterine bleeding, or endometrial cancer.

●Estrogens – High-dose estrogens have been beneficial in the setting of gastrointestinal bleeding from AVMs (see 'Gastrointestinal lesions' below); however, we do not use high-dose estrogens due to their side effect profiles, particularly the increased risk of VTE. The 50 mg estradiol dose that was effective in one study is not tolerated by men, and we consider the risk of VTE too great to use systemic estrogens [11].

●N-acetylcysteine – A pilot study in 43 patients suggested a possible benefit of N-acetylcysteine [78].

●Pazopanib – A retrospective review of 13 patients who received pazopanib for transfusion-dependent anemia due to HHT bleeding reported that all 13 became transfusion independent, with evidence for reduction in ESS, decreased intravenous iron use, and improvement in hemoglobin [79]. Compared with pretreatment hemoglobin, those treated with pazopanib for 12 months had an increase in their mean hemoglobin by 4.8 g/dL (95% CI 3.6-5.9), from 7.8 to 12.7 g/dL, and decreased mean ESS by 4.77 points (95% CI 3.11-6.44 points; from 2.43 to 7.20 points). As stated by the authors, these findings require confirmation in a randomized trial.

●Oral itraconazole – In an observational assessment of 21 patients treated with oral itraconazole, four discontinued therapy due to side effects; the remaining 17 had a decrease in mean ESS from 6.0 to 3.8 points (IQR decreased from 5.1-7.2 to 3.1-5.2) [80]. Hemoglobin levels did not change significantly.

Gastrointestinal lesions — Gastrointestinal lesions in HHT are common (seen in up to 20 percent of patients), but in the majority of cases, treatment is not required, as iron deficiency is primarily due to under-replacement of iron losses from nosebleeds. That said, a small population of patients with HHT have very severe, recurrent gastrointestinal bleeding, and some suggest this is more common in patients with SMAD4 HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Individuals with SMAD4 HHT'.)

Bleeding gastrointestinal lesions in HHT may be accessible for local therapies administered endoscopically. As for epistaxis, local treatments allow the patient to avoid systemic therapies with potential prothrombotic or other risks.

●Repeated endoscopic ablation of gastrointestinal lesions may be used to control bleeding in the short term (picture 1), although the results are not as good as in the non-HHT population [81]. Additionally, local therapies carry a potential risk of causing visceral perforations and other complications. In a 2009 guidance, repeated therapies were therefore not recommended [8].

●Embolization and/or surgery has limited success due to recurrent disease but may be useful for emergency control of hemorrhage from discrete lesions. This is also the preferred option for diffuse or endoscopically inaccessible severe gastrointestinal bleeding.

Gastrointestinal bleeding requiring frequent endoscopic interventions, transfusions, or iron infusion may be treated with systemic agents, and additional studies are ongoing. (See 'Bevacizumab and other systemic antiangiogenic therapies' above and 'Tamoxifen and other non-guideline approaches' above.)

Additional information about management of accessible vascular lesions in the gastrointestinal tract is presented separately. (See "Angiodysplasia of the gastrointestinal tract" and "Argon plasma coagulation in the management of gastrointestinal hemorrhage", section on 'Angiodysplasia'.)

Where bleeding from an obscure source is considered (eg, due to iron deficiency anemia or a positive stool guaiac test), under-appreciated epistaxis loss is almost always the cause (see 'Epistaxis' above). The possibility of other hematologic causes of anemia should also be considered.

Iron deficiency and iron deficiency anemia — Iron deficiency and iron deficiency anemia are common in individuals with HHT. The usual cause is epistaxis due to the vascular lesions of HHT. Other common non-HHT-related causes include heavy menstrual bleeding, dietary iron insufficiency, regular blood donation, pregnancy, surgery, and other traumatic events, all of which increase the requirement for iron (the hemorrhage-adjusted iron requirement [HAIR]) [82]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Iron deficiency'.)

Most patients with iron deficiency anemia secondary to blood loss from the vascular lesions of HHT are managed conservatively by repletion of the lost iron. Evidence for responses to 35 mg elemental iron tablets (ferrous gluconate) has been published, and this is our preference for initial oral dosing for reasons described below [83]. Recommended treatment regimens for iron supplementation and education regarding supplementary ways to improve iron absorption, such as avoiding ingestion of absorption inhibitors such as tea within an hour of iron ingestion based on general population considerations, are discussed separately. If iron absorption is impaired due to concurrent inflammation or disease, and/or bleeding is severe enough, parenteral iron therapy and/or blood transfusions may be required. (See "Treatment of iron deficiency anemia in adults".)

HHT patients have important additional considerations relative to the general population:

●Ongoing blood losses and higher HAIR should be expected in individuals with HHT [82].

●Data indicate that treatment of anemia (together with treatment of AVMs) improves epistaxis in approximately one-third of patients with HHT [84].

●Importantly, a smaller proportion of HHT patients (approximately 5 percent) report that iron treatments and blood transfusions make their nosebleeds worse [84,85]. We are concerned this may relate to supranormal serum iron concentrations evident in people ingesting iron tablets [74,85] and induction of endothelial injury [85,86], but this awaits clinical confirmation. Additional studies are ongoing.

Heavy menstrual bleeding is a very common problem for the female HHT population and can exacerbate iron deficiency. Heavy menstrual bleeding in patients with HHT is generally managed the same as in patients without HHT, though applying the prothrombotic concerns outlined above for systemic therapies (see 'Bevacizumab and other systemic antiangiogenic therapies' above). This information is presented in detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)

Iron deficiency is the most common form of anemia in HHT, but as for any population, individuals may also be at risk for concurrent pathologies causing anemia, and these should be evaluated as appropriate for the patient. (See "Diagnostic approach to anemia in adults".)

Data from a series of HHT patients with severe anemia out of proportion to calculated hemorrhagic iron losses emphasize that low-grade hemolysis may contribute to severe anemia in HHT [87].

Pulmonary AVMs

Potential complications of PAVMs — Pulmonary AVMs (PAVMs) are of concern in HHT because patients can develop a number of potentially life-threatening and life-changing cerebral complications including ischemic stroke caused by a paradoxical embolus to the brain and brain abscess caused by paradoxical septic emboli [88]. As noted, PAVMs affect over one-half of individuals with HHT. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary AVMs'.)

●Hypoxemia versus hypoxia – PAVMs commonly cause hypoxemia (low partial pressure of oxygen [PaO₂] and low hemoglobin saturation by oxygen [SaO₂]) due to impaired gas exchange, though this is usually asymptomatic [89]. These changes are due to hypoxemia and not hypoxia. Individuals with HHT maintain their arterial oxygen content (CaO₂), and they do not have the same physiology as patients who have low PaO₂/SaO₂ due to parenchymal lung disease [89]. Standard recommendations for individuals with hypoxic lung disease are not applicable since individuals with hypoxemia due to right to left shunting are not specifically at risk of hypoxic pulmonary hypertension [90].

Two studies evaluating exercise capacity in individuals with HHT-associated PAVMs demonstrated that reduced exercise capacity reflects low hemoglobin and/or airflow limitation rather than hypoxemia [91,92].

Nevertheless, it was a surprise when the evidence on how well airline flights were tolerated was published [93]. Using a retrospective questionnaire-based study, the authors examined in-flight complications and predictors in 145 HHT patients (96 with PAVMs) who reported 3950 flights, totaling 18,943 flight hours. Dyspnea and thrombotic complications were less common than expected and could not be predicted from sea-level oxygen saturations or hemoglobin concentrations (anemia) [93].

Where there are concurrent pathologies such as parenchymal lung disease or pulmonary hypertension, standard guidance should be followed; this may include supplemental oxygen in certain settings (as an example, airline flights) or continuously. Where patients with PAVMs have successfully traveled by air on many occasions when hypoxemic, and there is no change in their medical state, we do not prohibit flying, based on published evidence [93]. (See "Assessment of adult patients for air travel" and "Evaluation of patients for supplemental oxygen during air travel".)

●Silent cerebral infarcts and stroke – Silent cerebral infarcts are also a concern; these silent infarcts have been identified on cerebral magnetic resonance images (MRIs) performed for another indication (cerebral AVM screening), emphasizing the risk in individuals with PAVMs [94,95]. In a study from the United States involving 353 individuals with HHT who had brain magnetic resonance imaging (MRI) for any reason, silent cerebral infarcts were more common in individuals with PAVMs than those without PAVMs (overall prevalence, 10 percent; with PAVMs in 81 percent of the silent infarction patients and 53 percent of the individuals without silent infarction) [95]. In a study from Europe in a group of 29 individuals with PAVMs and no history of stroke, one to five silent infarcts were found in 16 individuals (55 percent) [94]. The most frequently affected sites were the cerebellum (40 percent) and thalamus (14.3 percent), and the age-adjusted odds ratio for an infarct was 21.6 (95% CI: 3.7, 126) [94].

Septic embolism to the brain causing brain abscess is also a risk. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Neurologic'.)

●Bleeding – Occasionally, PAVMs may bleed; this event is rare unless PAVMs have developed a systemic arterial supply (spontaneously or post-treatment), the individual is pregnant, or the individual has pulmonary hypertension. PAVM hemorrhage may lead to hemoptysis or hemothorax.

These and other complications of PAVMs are discussed in more detail separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary AVMs' and "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".)

PAVM screening — PAVMs are present in over one-half of individuals with HHT. Any relevant symptoms should be investigated. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Clinical manifestations'.)

The approach to screening is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'PAVM screening'.)

Principles of PAVM management — Management of PAVMs should be performed by clinicians with expertise in this area and should include the following, which are in keeping with a 2017 good practice statement from the British Thoracic Society and the European Reference Network for HHT (VASCERN HHT) [3,96].

●Individuals with PAVMs should receive prophylactic antibiotics prior to dental procedures, other potentially nonsterile procedures (eg, endoscopy), and surgery, to reduce post-procedural bacteremias implicated in brain abscess pathogenesis [97]. This is one of the five VASCERN HHT Outcome Measures, where good practice is 100 percent of all PAVM patients advised in writing [3,97]. It is also important to maintain good dental care to reduce the risk of bacteremia. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Antibiotic prophylaxis'.)

●For PAVMs of a size amenable to embolization, embolotherapy is recommended based on evidence from observational studies that suggests reduced morbidity and mortality [75,98-101]. These data are also supported by practice standards from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) and a Cochrane database review [5,101]. Information about the details of the procedure and evidence to support its efficacy in reducing cerebral complications are presented separately. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Patients suitable for embolotherapy'.)

There are occasional circumstances (eg, severe pulmonary hypertension [PH]) when risk-benefit analyses are generally not in favor of embolization or where surgery may be preferred due to a greater likelihood of complete obliteration of shunting through the lesion [101-103]. Patients with in situ metallic coils and Amplatzer vascular plugs used to treat PAVMs can safely undergo MRI [104].

●For PAVMs that are not amenable to embolization anatomically, surgery may occasionally be warranted. While the risks of removing normal lung in an individual likely to have multiple PAVMs may in the past have outweighed the benefits, parenchymal-sparing surgical techniques mean this is less of a concern, and at our center, surgery is increasingly offered to selected patients.

●Lung transplantation has been performed in very occasional cases, but in major HHT/PAVM centers, this has not been considered an option for even the majority of complicated PAVM cases, due to longevity of patients with severe hypoxemia who do not receive lung transplantation. Of five where transplantation was considered and not performed, by 2017, survival ranged from 16 to 27 (median 21) years, with surviving patients restating a preference for their ongoing medical issues [105]. Since that publication, at our institution, one patient has been referred and meets the criteria for lung transplantation; however, they are not actively transplant-listed as their quality of life is considered by the patient and the transplant team to be too high to justify the risks of lung transplantation. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Surgical excision'.)

●Experts in some countries have recommended filters to prevent paradoxical embolization of particulate material present in an intravenous solution. In other countries such as the United Kingdom, where air embolism is a "never event" (ie, one that should not occur if the available preventive measures have been implemented), insertion of such a filter is considered likely to be detrimental, compared with judicious following of safe practices for intravenous solutions [106].

●Individuals with PAVMs are generally advised to avoid scuba diving. Having been informed of the additional risks, in our experience, some patients choose to make an informed choice of the level of risk that they would consider acceptable to them. The field is awaiting formal guidance to take into account the one in three of the general population who will also shunt through a patent foramen ovale during a dive.

●Management of complications of PAVMs (eg, ischemic stroke, brain abscess) is discussed separately. Importantly, brain abscess is often not accompanied by leukocytosis, and a low threshold for making the diagnosis should be used to ensure that there is immediate referral for neurosurgical review and that appropriate intravenous antibiotics are given [75,107]. As noted above, MRI can be performed in patients who have undergone PAVM embolization and should not be delayed in emergency situations [104]. (See "Initial assessment and management of acute stroke" and "Treatment and prognosis of bacterial brain abscess".)

Pulmonary hypertension is a separate pathology (usually, pulmonary artery [PA] pressures are low to normal in patients with PAVMs). Data from two large series published in 2017 (3176 HHT patients, pulmonary artery hypertension in <2 percent) demonstrated that when pulmonary hypertension was present, it was usually part of a broader picture of hepatic AVMs, anemia, atrial fibrillation, and symptoms [108,109]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary hypertension' and "Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults".)

Additional discussion of the management of PAVMs is presented separately. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".)

Hepatic AVMs — Hepatic AVM management has been assisted by the 2020 International HHT Guidelines where the expert panel recommended the following [1]:

●Screening for liver AVMs in adults with definite or suspected HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Hepatic AVM screening'.)

●Diagnostic testing in HHT patients with symptoms and/or signs suggestive of complicated liver AVMs (including heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension, or encephalopathy), using Doppler ultrasound, multiphase contrast CT scan, or contrast abdominal MRI. (See 'Identifying hepatic AVMs and determining need for treatment' below.)

●Estimation of the prognosis of liver AVMs using available predictors, to identify patients in need of closer monitoring.

●An intensive first-line management only for patients with complicated and/or symptomatic liver AVMs, tailored to the type of complication(s). (See 'Initial management of hepatic AVMs' below.)

●Co-management of HHT patients with high-output cardiac failure and pulmonary hypertension by an HHT Center of Excellence and an HHT cardiologist or pulmonary hypertension specialty clinic.

●Systemic bevacizumab is considered for patients with symptomatic high-output cardiac failure due to liver AVMs for whom first-line management is unsuccessful. For those with refractory high-output cardiac failure, biliary ischemia, or complicated portal hypertension, referral for consideration of liver transplantation is appropriate. (See 'Role of liver transplantation' below.)

●Liver biopsy should be avoided in any patient with proven or suspected HHT.

●Hepatic artery embolization be avoided in patients with liver AVMs as it is only a temporizing procedure associated with significant morbidity and mortality.

Identifying hepatic AVMs and determining need for treatment — Hepatic AVMs are common in HHT, identified in approximately 50 percent of people; they are substantially more prevalent in patients with HHT2 due to pathogenic variants in ACVRL1 [110,111]. Longitudinal series have shown that complications occur at an incidence of 3.6 percent per year and that 1 percent annual mortality is due to hepatic AVMs in HHT [112].

Hepatic AVMs vary in size from small telangiectasia to large AVMs and constitute three separate types of aberrant intrahepatic communications. The most common are between hepatic arteries and hepatic veins. Other types of communications include hepatic-portal shunts (between hepatic arteries and portal veins) and portohepatic shunts (between portal and hepatic veins).

Typical symptoms include reduced exercise tolerance, dyspnea, edema, ascites, and/or other consequences from high-output cardiac failure. These symptoms should prompt hepatic imaging to identify these lesions.

Despite the high prevalence of hepatic AVMs and the significant symptoms they cause, clinicians often do not suspect that the driving pathology leading to these symptoms is sited in the liver rather than the heart. Thus, diagnosis of hepatic AVMs may be delayed.

Other challenges related to identifying hepatic AVMs include the following:

●Such patients usually present to cardiologists, who may focus on a potential cardiac cause of their symptoms. Portal hypertension and its consequences including encephalopathy and varices and symptoms from mesenteric or biliary ischaemia (resulting from blood flow steal) are more likely to result in an acute picture within gastroenterology and hepatology disciplines. (See "Portal hypertension in adults", section on 'Clinical manifestations'.)

●Symptoms may differ according to the nature of the vascular malformations, particularly whether the portal vein is involved, and whether there is a blood flow steal through arteriovenous (AV) shunts.

●It may be difficult to separate out the majority of patients who will never require specific treatment of their hepatic AVMs, from the significant minority for whom the consequences of hepatic AVMs will come to dominate the clinical picture and who will require high-level specialist support that needs to be delivered in a timely fashion to intervene at the optimal time [113].

●Clinicians may not recognize the importance of correcting anemia, atrial fibrillation, and otherwise modest cardiac pathologies to improve the clinical picture. Longitudinal studies have demonstrated that symptoms of hepatic AVMs can be exacerbated in the presence of concurrent anemia and/or atrial fibrillation [112].

●Data from two large series published in 2017 (3176 HHT patients, pulmonary artery hypertension in <2 percent) demonstrated that hepatic AVMs may be accompanied by a constellation of findings including pulmonary hypertension, anemia, atrial fibrillation, and symptoms [108,109]. Hepatic AVMs (and resultant high-output cardiac states) are responsible for the most common form of pulmonary hypertension in HHT [108,109]. These data were reviewed in a consensus statement from the European Association for the Study of the Liver (EASL) and an HHT workshop held in 2017 [113]. Updated guidance from the HHT International Guidelines Committee is awaited.

●For any HHT patient undergoing imaging of the liver, it is most important for clinicians to be aware of the possibility that hepatic AVMs may occur in individuals with HHT. We are aware of three cases in which hepatic AVMs were initially mistaken for cancer metastases (in one case resulting in a fatal outcome) and of two further cases where liver biopsies (performed without appreciating the presence of AVMs) resulted in catastrophic hemorrhage.

Initial management of hepatic AVMs — International consensus is that all patients with HHT should be offered screening for hepatic AVMs; however, only symptomatic hepatic AVMs should be treated [114,115]. A 2016 practice guideline from the EASL and a 2011 observational study involving 154 patients with HHT who had vascular malformations in the liver concluded that in the small proportion (approximately 8 percent) who became symptomatic, medical therapy was beneficial in most [112,113]. For most of the 39 individuals who had a clinical event related to a hepatic AVM, treatment resulted in complete response or stable disease, although eight individuals died of disease complications over the 15-year period of observation.

For those who do require treatment, therapy is individualized and should be performed by clinicians with expertise in this area. First-line treatments involve the following, as detailed in selected case series [113,115]:

●Treatment of high-output heart failure, in a similar way to treatment of heart failure in non-HHT patients, with emphasis on escalating diuretics and correcting anemia [112,113,116]. Iron deficiency anemia was the precipitant of high-output cardiac failure in seven of the eight cases in the largest prospective series [112]. (See "Causes and pathophysiology of high-output heart failure" and "Evaluation and management of anemia and iron deficiency in adults with heart failure".)

●Treatment of portal hypertension, in a similar way to treatment of portal hypertension in other circumstances. (See "Portal hypertension in adults", section on 'Treatment'.)

●Antibiotics in case of cholangitis. (See "Acute cholangitis: Clinical manifestations, diagnosis, and management".)

The efficacy of these treatments are evaluated within 6 to 12 months, although earlier assessments will be required in individuals with rapid clinical deterioration [113,115].

For complicated liver AVMs that are refractory to first-line treatment, interventions directed at the hepatic arterial bed such as embolization, ligation, or banding of the hepatic artery are generally no longer advised for the majority of patients because of the high rate of complications (including potentially fatal hepatic necrosis) and up to a 20 percent acute mortality rate compared with transplantation [113]; the 10-year survival rate for transplantation is 82.5 percent [117].

Options for severe patients not responding to therapy include bevacizumab and liver transplantation. (See 'Role of bevacizumab for liver AVMs' below and 'Role of liver transplantation' below.)

Role of bevacizumab for liver AVMs — Bevacizumab has observational studies of efficacy and is a first-line choice in many HHT centers in the United States. However, earlier suggestions that this reversed the need for liver transplantation have not been supported by longer-term follow-up studies in those individuals.

Bevacizumab is usually reserved for individuals with severe liver disease for which management is ineffective and in many countries where liver transplantation is not possible. It is proposed for older patients (over age 65) who will not meet transplantation criteria (and for patients younger than 65 years who are not medically fit for transplantation) as a "bridge to transplantation" if patients experience a response [115].

The efficacy of bevacizumab in the setting of severe hepatic AVMs was demonstrated in a series of individuals with HHT who had hepatic AVMs and increased cardiac output [41]. Bevacizumab (5 mg/kg intravenously once every 14 days for a total of six doses) was associated with an improvement in cardiac index in 20 of 24 evaluable patients (83 percent); this included cardiac output normalization in five individuals and improvement in 15 others. Additional benefits included resolution of pulmonary hypertension in five of eight (63 percent) and improvement in epistaxis. Case reports and observational studies have also described improvements (in some cases dramatic) in disease manifestations attributable to hepatic AVMs (and pancreatic AVMs) with bevacizumab [41,113,118-120]. Benefits from continued use have been published [121].

Notably, the reported follow-up for these patients has been relatively short compared with the decades-long follow-up post-liver transplantation discussed below (see 'Role of liver transplantation' below). Thrombotic complications of bevacizumab have been reported in individuals with HHT [122]. These and other safety concerns such as those observed in a study from the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) are discussed above. (See 'Bevacizumab and other systemic antiangiogenic therapies' above.)

Role of liver transplantation — Liver transplantation in countries where very good long-term survival of HHT patients is reported can be lifesaving for those who develop acute hepatic failure (eg, acute biliary necrosis syndrome), intractable heart failure, or portal hypertension [117,123-125].

Available data suggest that liver transplantation should be proposed in a timely fashion, before pulmonary resistances become fixed, and taking into account that complicated liver AVMs in HHT represent a model for end-stage liver disease (MELD) exception for transplantation [113,115]. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

A 2006 series from the European Liver Transplant Registry reported outcomes in 40 individuals with HHT and severe liver disease who underwent liver transplantation [117]. Ten-year actuarial patient and graft survival rates were 82.5 percent. There were seven perioperative deaths, six due to bleeding and one due to heart failure, and one late death (at 11 years) due to chronic rejection.

Pulmonary involvement through portopulmonary hypertension is considered a transplant priority and proposed as a MELD exception [126]. Right-heart catheterization to evaluate the severity of pulmonary hypertension prior to transplant is advised [113].

Cerebral lesions — Lesions in the cerebral (or spinal) vasculature in individuals with HHT may include telangiectasia, AVMs, and aneurysms. These lesions result in varying degrees of hemorrhagic risk. They may also cause symptoms related to their size or location such as headache, focal neurologic deficit, or seizures; however, the majority of patients will have no complications from cerebral lesions.

Significant effort has been invested in trying to identify the patients at higher risk of future complications in whom the known risks of neurologic intervention are more justifiable. Most patients will never have a specific complication from their cerebral AVMs, but for others, the consequences of cerebral AVMs will lead to life-changing or life-limiting consequences.

For a small group of patients, symptoms may be used to indicate a higher likelihood of AVM presence, and an AVM that has already bled is usually treated. For highly symptomatic or ruptured cerebral AV shunts for which treatment is appropriate and feasible, therapeutic options include surgical excision, a number of endovascular techniques, or stereotactic radiotherapy. The risks associated with these interventions should not be underestimated [127]. The risk of rupture and details of therapy are discussed separately. (See "Brain arteriovenous malformations", section on 'Acute management issues'.)

Management of cerebral lesions that have not bled is complex and should be performed by clinicians with expertise in this area who are aware of the results of the ARUBA (A Randomized trial of Unruptured Brain AVM therapy) trial [128]. The interpretation of this trial and its applicability to the HHT population has remained highly controversial, and in our experience, it is applied differently in Europe and the United States. Across the ERN, cerebral AVMs that have not bled are usually not treated [129]. A 2020 position statement on cerebral screening in HHT published by VASCERN suggested that data do not support routine intervention for unruptured AVMs, acknowledging the controversies that may arise and individual patients may have different preferences [4]. Some clinicians may weigh the risks and benefits differently.

The ARUBA trial randomly assigned individuals with a cerebral AVM (not knowingly HHT related) to receive or not to receive an interventional procedure (surgery, embolization, stereotactic radiotherapy) in addition to standard medical therapy [128]. The trial was halted early after accrual of 223 patients when the data and safety monitoring board noted a threefold increased risk of adverse outcomes in the intervention group. At a median follow-up of 33 months, the primary composite endpoint of death or symptomatic stroke was seen in 35 of 114 intervention patients (31 percent) versus 11 of 109 controls (10 percent). Individuals in the intervention group also had worse functional outcomes and a higher risk of hemorrhagic stroke. In a follow-up report that described an additional period of observation (mean follow-up of approximately 50 months total), there were 41 deaths or strokes in the intervention group and 15 deaths or strokes in the medical management group (incidence rate per 100 person-years, 12.3 versus 3.4, respectively) [130]. However, follow-up data were only available for one-half of the original participants.

There is no evidence that the risks associated with cerebral AVMs in HHT are higher or lower than the risks in non-HHT cerebral AVMs [131].

There are other central nervous system vascular malformations that pose a very low risk of hemorrhage and usually no intervention is recommended. (See "Vascular malformations of the central nervous system", section on 'Capillary telangiectasias'.)

For the HHT patients with cerebral vascular malformations who do not fall into either of these groups, assessments of the risks and benefits of intervention are based on clinical judgment, which can be highly specific to the individual.

SPECIAL POPULATIONS

Children — Symptomatic children require specialist evaluation and treatment, as discussed in the sections above.

It is important that neurologic symptoms are promptly investigated and that parents with HHT are educated about the potential significance of these symptoms or clinical signs of cardiac failure/hydrovenous dysfunction in their children [132]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Sites of large arteriovenous malformations'.)

Screening of asymptomatic children is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Children'.)

Pregnancy — Case reports have highlighted major complications of pregnancy in individuals with HHT. However, our series of 484 pregnancies in 199 individuals indicated that the vast majority are able to have a healthy pregnancy. This is an important observation since individuals with HHT are sometimes led to believe that pregnancy is too dangerous to undertake. That said, a small proportion did experience life-threatening complications, even in those who previously had only minor symptoms of HHT.

In this series, the following complications were noted [133]:

●Pulmonary arteriovenous malformation (PAVM) hemorrhage – 1.4 percent (95% CI 0.2-2.5)

●Stroke – 1.2 percent (95% CI 0.3-2.2)

●Maternal deaths – 1.0 percent (95% CI 0.1-1.9)

●Myocardial infarction – 0.2 percent (one case)

General recommendations for the management of HHT during pregnancy include:

●High risk status – All pregnancies in women with HHT should be considered "high risk," and local obstetric services should be alerted to the need for greater than normal vigilance and pre-planning.

●Education – All individuals with HHT who become pregnant should receive written advice on pregnancy management; this is one of the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) HHT's five Outcome Measures defining good practice [3].

●PAVMs – PAVMs will enlarge during pregnancy, and fatal hemorrhage from maternal PAVMs has been described [133,134]. As a result, individuals with HHT should be screened for PAVMs and treated maximally before pregnancy, although treatment may be safely undertaken in late pregnancy if required [135]. Hemoptysis of any degree or sudden severe dyspnea should be considered a medical emergency, prompting urgent hospitalization and institution of appropriate treatment. In the series described above, hemorrhages occurred in both treated and untreated patients, including four individuals who had previous PAVM embolization at four different institutions [133].

●Other AVMs – Anecdotal data suggest that epistaxis may get worse and skin telangiectasia become more prominent during pregnancy; there are no firm data regarding effects on hepatic or cerebral AVMs. Screening for other types of AVMs in asymptomatic individuals is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Initial PAVM screening'.)

●Epidural anesthesia – There is no evidence of hemorrhage from spinal AVMs in individuals with HHT who receive epidural anesthesia. Nevertheless, since spinal AVMs affect approximately 1 to 2 percent of HHT patients, some anesthetists will not perform epidural analgesia in HHT mothers unless magnetic resonance imaging (MRI) scans have excluded this possibility.

●Second stage of labor – Obstetricians advise that a prolonged second stage of labor should be avoided in individuals in whom cerebral AVMs have not been excluded. In some countries, it is assumed that cerebral AVMs may be present, and this advice is given to all individuals with HHT. In others, or if there would be specific separate recommendations were a cerebral AVM to be found, cerebral magnetic resonance imaging (MRI) is performed in pregnancy.

●Antibiotic prophylaxis – In keeping with the general advice for patients with PAVMs and/or HHT, antibiotic prophylaxis should be provided during delivery [75,107,136].

●Genetic counseling and testing – The patient should also be made aware that any offspring will have a 50 percent risk of inheriting HHT. Prenatal genetic testing is possible in families where the pathogenic variant has been identified in the family but is not necessary for proper pregnancy and delivery management [129]. Decisions about prenatal genetic testing are the choice of the parents, but discussion of all related issues is appropriate. The usual antenatal scans will be offered, and sonographers aware of the presence of HHT in the family will detect most major AVMs.

PROGNOSIS — When managed by treatment of nosebleeds, iron deficiency anemia, and screening/treatment for pulmonary arteriovenous malformations (PAVMs), life expectancy in individuals with HHT is normal on a population basis [137].

However, in settings in which optimal management is not pursued on a nationwide basis, life expectancy is modestly reduced. For example, in a 2015 case-control series from a primary care database, 675 individuals with HHT demonstrated a three-year reduction in survival (median age of death of 77 years, compared with 80 years in 6696 age- and sex-matched controls) [138]. An important limitation was that the rates were overall survival rather than disease-specific survival. Causes of death could not be confirmed, but the most frequent serious complications included stroke and heart disease.

HHT can be life-limiting on an individual basis. Patients can die in childhood and young-adult life from HHT complications such as cerebral hemorrhage [139,140], pulmonary hemorrhage in pregnancy [133], and cerebral abscess from PAVMs [88,141]. Causes of death in older patients include sepsis and cardiac failure in studies from 2006 and 2018 that surveyed HHT patients asking for causes of death in their deceased relatives [142,143]. A reduced survival of 6.8 years in the affected parent compared with the non-affected parent was identified in the 2006 study, based on median age at death of 63.2 years (HHT parent) versus 70.0 years (non-HHT parent) [143]. Where HHT does contribute to death, the mean life expectancy reduction has been calculated at 19 years (based on 55 of 73 deceased patients selected because HHT was considered implicated in the cause of death) [142].

We interpret these data for the patient, stating that while HHT can result in early deaths (that medical care strives to reduce), overall life expectancy is surprisingly good in HHT and is increasing with improved medical care. The reason for the good survival figures is that deaths due to HHT seem to be balanced by protection conferred by HHT from common causes of death in the general population such as certain cancers and myocardial infarction [137,144-147].

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

●Epistaxis – Epistaxis affects over 95 percent of individuals with hereditary hemorrhagic telangiectasia (HHT) and is the usual cause of iron deficiency anemia. Topical, systemic, and surgical treatments are available. We generally try to avoid toxicity of systemic therapies by using local preventive therapies (nasal humidification, ointments) and dietary changes; however, management is individualized. Expert otorhinological review and management is important and often the only additional treatment required. (See 'Overview' above and 'Epistaxis' above.)

Rarely, patients may require systemic therapies such as tamoxifen, tranexamic acid, or bevacizumab if epistaxis is recurrent or localized interventions are insufficient. For these individuals, we continue to suggest tamoxifen (Grade 2C). Other options are reasonable and may be preferred due to their differing side effect profiles or patient preference. Systemic agents are generally avoided in individuals with prior venous thromboembolism (VTE) and should be used with caution if there are additional risk factors for VTE or arterial thromboembolism. (See 'Bevacizumab and other systemic antiangiogenic therapies' above and 'Tamoxifen and other non-guideline approaches' above.)

●Gastrointestinal lesions – Gastrointestinal lesions are present in up to 20 percent of patients but rarely require treatment. If bleeding occurs, local therapies may be administered endoscopically, but gastrointestinal bleeding requiring transfusions or iron administration is often due to multiple lesions and is treated with systemic agents rather than frequent endoscopic interventions. (See 'Gastrointestinal lesions' above and 'Bevacizumab and other systemic antiangiogenic therapies' above.)

●Iron deficiency – Iron deficiency and iron deficiency anemia are common, usually from epistaxis. Most individuals are treated with oral iron, but parenteral iron and/or blood transfusions may be required. (See 'Iron deficiency and iron deficiency anemia' above.)

●Pulmonary AVMs – Pulmonary arteriovenous malformations (PAVMs) are especially concerning because of potentially life-threatening cerebral complications including ischemic stroke caused by a paradoxical embolus to the brain or brain abscess caused by a paradoxical septic embolus or hypoxia. Bleeding leading to hemoptysis or hemothorax is much less common but can occur. (See 'Pulmonary AVMs' above.)

•We screen all adults with HHT for PAVMs. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'PAVM screening'.)

•For PAVMs of a size amenable to embolization, we use embolotherapy, unless there are complications such as significant pulmonary hypertension that require more individualized therapy. (See 'Principles of PAVM management' above and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Patients suitable for embolotherapy'.)

•Antibiotic prophylaxis is required for all PAVM patients prior to dental and surgical procedures. PAVM management is discussed above and separately. (See 'Principles of PAVM management' above and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".)

●Hepatic AVMs – Hepatic AVMs are usually asymptomatic but can require intense, informed specialist care. In our experience, one major risk is of misdiagnoses as metastases. Symptoms attributable to high-output heart failure (often indolent) are seen in <10 percent of patients; acute presentations with portal hypertension and/or biliary disease are less common. For symptomatic liver involvement, initial treatment includes optimizing cardiac status, iron stores, and emergency management as needed. If intense medical management fails, liver transplantation is the treatment of choice. Bevacizumab may also be helpful for nontransplant candidates. (See 'Hepatic AVMs' above.)

●Brain AVMs – Management of cerebral lesions is complex. Symptomatic lesions and lesions that have bled are managed by specialized units with neurology expertise. For nonsymptomatic patients, management is more challenging since the ARUBA (A Randomized trial of Unruptured Brain AVM therapy) trial indicated that intervention results in worse outcomes than expectant management in unselected cases. Expertise in this area is required for optimal management. (See 'Cerebral lesions' above and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Cerebral AVM screening'.)

●Children and pregnancy – (See 'Special populations' above.)

●Prognosis – Prognosis is variable. Most patients can expect very good life expectancy, and life expectancy continues to improve. (See 'Prognosis' above.)

●Diagnosis and routine screening – (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)" and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".)

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