Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant inherited disorder with an estimated prevalence of 1 in 5000.1 Caused by mutations in regulators of angiogenesis, HHT classically presents with a triad of recurrent epistaxis, mucocutaneous telangiectasias, and visceral arteriovenous malformations (AVMs).2 A wide range of clinical manifestations is observed; in its most severe form, patients may experience life-threatening hemorrhage, stroke, or high-output heart failure. HHT remains underdiagnosed, limiting access to life-saving screening.
HHT is caused by disruptions in angiogenesis signaling, leading to impaired vascular development. Three genes in the transforming growth factor beta (TGF-β) signaling pathway have been implicated, including endoglin (ENG), activin A receptor ligand type I (ACVRL1 or ALK1), and SMAD family member 4 (MADH4 or SMAD4).2
Epistaxis typically begins around ages 11 to 14, with 90% of patients experiencing epistaxis by age 40. For most patients, nosebleeds significantly impact their quality of life due to social stigma and disruptions at work or school. Recurrent nosebleeds contribute to iron deficiency anemia, and hemodynamically significant bleeding can occur.
Telangiectasias characteristically develop over the lips, oral and nasal mucosa, and fingers. Onset of telangiectasias is typically age-dependent, commonly appearing in the third decade of life or later. Cutaneous telangiectasias can impact a patient’s self-image and can occasionally bleed.
Arteriovenous malformations (AVMs)
Significant variability exists regarding the type, location, and severity of AVMs present in patients with HHT, contributing to a wide range of clinical manifestations.2
Gastrointestinal (GI) Tract: Up to 75% of patients with HHT over age 40 develop telangiectasias in the GI tract, which occur most frequently in the stomach and duodenum and to a lesser extent in the colon. The frequency of GI bleeding increases with age and can result in significant blood loss requiring support with iron infusions and blood transfusions.
Liver: Approximately 70% of patients with HHT will develop hepatic AVMs, although their clinical manifestations are highly variable and dependent on size, type, and location. While many hepatic AVMs are asymptomatic, large AVMs lead to high-output cardiac failure or portal hypertension due to vascular shunting. Increased shunting can be seen with pregnancy, exacerbating existing symptoms.
Brain and Spinal Cord: Cerebral AVMs are less common, affecting up to 15% of patients with HHT, and spinal AVMs are rare (<1%). The risk of rupture (and resulting hemorrhage and potential neurologic devastation) is estimated to be less than 2.5% per year.
Pulmonary: Pulmonary AVMs occur in up to 50% of patients with HHT, with new AVMs developing throughout the lifespan. Pulmonary AVMs may cause right-to-left vascular shunting, resulting in dyspnea, hypoxia, and chest pain. Less commonly, pulmonary AVMs can rupture, causing hemoptysis, hemothorax, or in rare cases, fatal hemorrhage. As the blood supply through the AVM bypasses the typical capillary filtering network, systemic paradoxical embolism of a bland thrombus or bacterial infection can occur, leading to complications such as cerebrovascular accident or abscess formation as well as osteomyelitis.
Iron Deficiency Anemia
Recurrent epistaxis and GI bleeding place patients at high risk of iron deficiency, with anemia observed in up to 50% of patients with HHT.3 Iron deficiency, even in the abscess of anemia, can result in fatigue, weakness, restless legs syndrome, and cognitive impairment, significantly impacting quality of life.
Clinical diagnosis rests on the Curaçao Diagnostic Criteria, which include evaluations for the presence of (1) recurrent, spontaneous epistaxis; (2) mucocutaneous telangiectasias; (3) visceral AVMs; and (4) family history in first-degree relatives. In patients meeting at least three of these criteria, a clinical diagnosis of definite HHT is made.4,5 Over 90% of patients who meet all Curaçao criteria will harbor a pathogenic variant in ENG, ACVRL1, or less commonly SMAD4. Alterations in RAS p21 protein activator 1 (RASA1) and growth differentiation factor 2 (GDF2) can cause HHT-like syndromes and should be considered in the event of negative testing. Identification of pathogenic variants allows for screening of at-risk family members.2
Multimodal management is customized to each patient’s symptoms and treatment preferences. The Epistaxis Severity Score is a validated semi-objective outcome measure that captures the frequency, duration, and severity of nosebleeds and may be used to monitor treatment response.6 Firstline behavioral and environmental interventions for epistaxis include avoiding personal triggers, limiting manipulation of nasal passages, applying topical moisturizers, and preventing dryness with overnight humidifier use. Estrogen (0.1% estriol) compounded in petroleum jelly may be applied to provide additional moisturization and protection against vessel rupture.7
Hormonal agents, antifibrinolytics, and antiangiogenic medications have all been evaluated in HHT. Estrogen-containing oral contraceptives, selective estrogen receptor modulators, and tamoxifen have all shown efficacy in small case series and may be considered for appropriately selected patients with a low risk of thrombosis.8 Tranexamic acid and aminocaproic acid may be used on an ongoing basis and titrated to the lowest effective dose.2 Among antiangiogenic agents, the vascular endothelial growth factor (VEGF) inhibitor bevacizumab is the most studied and has shown efficacy in controlling epistaxis and GI bleeding when used systemically.9 Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide have antiangiogenic properties, with the latter two agents carrying a more favorable side effect profile. Randomized controlled trials of pomalidomide (PATH-HHT; 1UG3HL140097-01A1; NCT03910244) and pazopanib (STOP-HHT; NCT03850964) are ongoing.10,11
Surgical interventions to control bleeding, carried out by experienced surgeons, are used to complement and augment medical management.4 Recommended options include endonasal laser ablation and sclerotherapy.12 Electrical and chemical cautery are rarely recommended. Dermatoplasty (i.e., grafting skin onto the nasal mucosa) can be effective but requires considerable maintenance and is seldom pursued at present. Arterial embolization is used for life-threatening acute hemorrhage. The modified Young’s procedure (surgical closure of external nares) is reserved for severe, refractory cases.
Visceral AVM Screening & Management
Screening is critical for identifying AVMs that require intervention and preventing complications. Magnetic resonance imaging with and without contrast is recommended for cerebral AVM screening at diagnosis, as intracranial hemorrhage has been reported even in infants and young children.4 Children with negative MRI findings should undergo repeat screening in adulthood, while adults with negative findings do not require repeat brain screening. For cerebral AVMs requiring intervention, potential options include embolization, surgical resection, and stereotactic radiation. Pulmonary AVM screening using contrast echocardiography (“delayed bubble study”; preferred approach) or computed tomography of the chest is recommended at diagnosis, with repeat screening at five-year intervals when no lesions are detected. Embolization is recommended for pulmonary AVMs with a feeding artery diameter greater than 2.5 to 3 mm. Most recent international guidelines also recommend hepatic AVM screening, although the optimal frequency and imaging modality remain to be established.5 Antiangiogenic therapy with bevacizumab can be used to improve heart failure in patients with hepatic AVMs, and liver transplantation may be considered in patients with severe or refractory symptoms. Hepatic artery embolization carries a high rate of complications.2
Management of Iron Deficiency Anemia
Aggressive iron repletion, often requiring intravenous iron, is warranted in patients with HHT. Ongoing monitoring of hemoglobin and iron stores should be performed, with a target serum ferritin level of 30 to 50 ng/mL. Blood transfusions may be necessary for patients with severe anemia.2
HHT is a complex inherited vascular disorder with a range of clinical manifestations, many of which can be life-threatening. Untreated patients are at risk of significant morbidity and mortality, while patients who receive appropriate screening and care may have normal life expectancy.13 There are currently 30 HHT Centers of Excellence throughout North America, which model integrative care for HHT and promote the development of dedicated research.14
Drs. Berkowitz and Kasthuri indicated no relevant conflicts of interest.