Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an incidence of 1:5000. Recurrent, spontaneous epistaxis is the most common presenting symptom. Severity of epistaxis varies widely, from mild, self-limited nosebleeds to severe, life-threatening nasal hemorrhage. Treatment of HHT-related epistaxis presents a challenge to the otolaryngologist due to the recurrent, persistent nature of epistaxis often requiring multiple treatments. Treatment modalities range from conservative topical therapies to more aggressive surgical treatments.
Key learning points
At the end of this article, the reader will:
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Know how to diagnose a patient with HHT and discover the key examination findings.
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Know what additional workup is required in a patient with HHT.
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Understand the Epistaxis Severity Score and how it is used.
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Know the nonsurgical options for treatment of mild or moderate epistaxis related to HHT.
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Know the surgical options available for treatment of HHT.
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Understand the role of Avastin (bevacizumab) in treatment of HHT.
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Introduction
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HHT is hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu disease
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Autosomal dominant inheritance, approximately 1:5000 prevalence
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Recurrent, spontaneous epistaxis is most common presenting symptom
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Spontaneous formation of multiple mucocutaneous telangiectasias
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Patients are also at risk for multiorgan vascular dysplasia with formation of arteriovenous malformations (AVMs) in the brain, lungs, and gastrointestinal (GI) tract
HHT is a rare, autosomal dominant disease with prevalence of 1:5000 characterized by formation of multiple mucocutaneous telangiectasias as well as formation of AVMs within the pulmonary, cerebral, and gastrointestinal vasculature. Patients are particularly prone to formation of telangiectasias within the sinonasal mucosa, and recurrent, spontaneous epistaxis is the most common symptom at time of presentation. More than half of patients with HHT will develop troublesome epistaxis by the third decade of life, and severity of epistaxis increases with age. More than 90% of patients with HHT experience recurrent epistaxis at some point in life. Severity and frequency of epistaxis varies widely between patients, from mild, occasional epistaxis to severe, life-threatening nosebleeds. In general, severity of epistaxis increases with age.
Introduction
- •
HHT is hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu disease
- •
Autosomal dominant inheritance, approximately 1:5000 prevalence
- •
Recurrent, spontaneous epistaxis is most common presenting symptom
- •
Spontaneous formation of multiple mucocutaneous telangiectasias
- •
Patients are also at risk for multiorgan vascular dysplasia with formation of arteriovenous malformations (AVMs) in the brain, lungs, and gastrointestinal (GI) tract
HHT is a rare, autosomal dominant disease with prevalence of 1:5000 characterized by formation of multiple mucocutaneous telangiectasias as well as formation of AVMs within the pulmonary, cerebral, and gastrointestinal vasculature. Patients are particularly prone to formation of telangiectasias within the sinonasal mucosa, and recurrent, spontaneous epistaxis is the most common symptom at time of presentation. More than half of patients with HHT will develop troublesome epistaxis by the third decade of life, and severity of epistaxis increases with age. More than 90% of patients with HHT experience recurrent epistaxis at some point in life. Severity and frequency of epistaxis varies widely between patients, from mild, occasional epistaxis to severe, life-threatening nosebleeds. In general, severity of epistaxis increases with age.
Etiology
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Mutations in genes associated with transforming growth factor-beta (TGF-β) superfamily signaling pathway
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Dysregulation of vascular endothelial tissue remodeling results in weakened integrity of vessel wall leading to formation of telangiectasias and AVMs
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Three gene mutations have been identified: endoglin (ENG), activin receptor-like kinase (ACVRL1 or ALK1), and MADH4
Various members of the transforming growth factor (TGF)-β superfamily have been implicated in the pathogenesis of HHT. Remodeling of the vascular endothelium within mucosal vessels occurs in a dysregulated fashion, leading to loss of elasticity and dilation of arteriole-venule communications. As a result, fragile and thin-walled telangiectasias form within the nasal cavity in regions with high airflow prone to dryness or repeated mechanical trauma. Telangiectasias tend to congregate along the anterior septum, head of inferior turbinates, anterior lateral nasal wall, and anterior nasal floor. Recurrent and spontaneous epistaxis results from traumatic rupture of the ectatic vessel wall lacking contractile and elastic elements. Elevated plasma levels of vascular endothelial growth factor (VEGF) are present in patients with HHT, which has provided rationale for treatment with VEGF inhibitors in certain cases.
Two distinct mutations account for 90% of cases of HHT: ENG mutation is known at HHT1, and ACVRL1 mutation is known as HHT2. Another gene, MADH4 (mothers against decapentaplegic homolog 4) has been implicated in both juvenile polyposis and a small proportion of cases of HHT. Recently, mutation in bone morphogenetic protein-9 (BMP9) has been described as resulting in a vascular anomaly syndrome with phenotypic similarity to HHT.
Distinct phenotypic variations have been described in HHT1 and HHT2. Patients with HHT1 are more likely to present with epistaxis earlier in life as well as pulmonary AVMs. Patients with HHT2 are more likely to develop hepatic AVMs.
Diagnosis
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The Curaçao criteria include 4 different clinical criteria: a definite diagnosis is made if 3 criteria are present ( Table 1 )
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Positive genetic testing may also provide a definite diagnosis, although testing is expensive and indicated in only a minority of cases
| Criteria | Description |
|---|---|
| Epistaxis | Spontaneous and recurrent |
| Telangiectases | Multiple, at characteristic sites: lips, oral cavity, fingers, nose |
| Visceral lesions | Gastrointestinal telangiectasia, pulmonary, hepatic, cerebral, or spinal arteriovenous malformations |
| Family history | A first-degree relative with HHT according to these criteria |
The diagnosis of HHT is based on various clinical and physical examination criteria known as the Curaçao criteria. The Curaçao criteria (see Table 1 ) were established in 2000 by an expert consensus panel, consisting of 4 different clinical criteria: recurrent and spontaneous epistaxis, mucocutaneous telangiectasias, visceral AVMs, and family history. Three positive criteria are necessary for a “definite” diagnosis, whereas 2 criteria allow for “possible/suspected” diagnosis. Diagnosis is “unlikely” with only 1 criterion present.
Genetic testing may also provide a definite diagnosis of HHT, and standard testing for ENG and ACVRL1 mutation is available. Current genetic testing may not be positive in all patients with HHT due to presence of an unrecognized genetic mutation. Routine genetic testing, therefore, is not recommended in patients with suspected HHT. Expert guidelines have established indications for testing in specific situations, such as prenatal screening, index cases within a family, and establishing or excluding a definite diagnosis in members with few symptoms in a family with known HHT.
Evaluation
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Multiple mucocutaneous telangiectasias involving skin (face, fingertips), lips, oral cavity (hard palate), tongue, and sinonasal cavity
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Differential diagnosis includes CREST syndrome (calcinosis, Raynaud disease, esophageal dysmotility, sclerodactyly, and telangiectasia), essential telangiectasia, ataxia-telangiectasia
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Telangiectasias vary in morphology from small, flattened, and stellate lesions to large, raised conglomerate lesions
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Crusting and dryness of nasal mucosa as well as septal perforation are common findings in patients with history of multiple nasal procedures for treatment of epistaxis
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Iron deficiency in conjunction with low ferritin and elevated transferrin is characteristic in patients with moderate to severe epistaxis
Patients with HHT will present to the otolaryngologist with a history of recurrent, spontaneous epistaxis. Some patients will identify particular triggers, such as dietary factors, emotional state, and seasonal variations. Other complaints include sequelae of recurrent epistaxis or prior treatments, such as crusting, foul odor, nasal obstruction, and septal perforation. In addition to the nasal cavity, mucosal telangiectasias involving the lips, hard palate, and tongue are characteristic, and patients may request treatment for these lesions as well. Multiple cutaneous telangiectasias are commonly seen on the skin of the face, ears, and fingertips, and referral to the dermatologist or facial plastic surgeon may be helpful in patients seeking treatment for these lesions. In a patient presenting with intranasal telangiectasias without a prior diagnosis of HHT, other conditions such as CREST syndrome, essential telangiectasia, and ataxia-telangiectasia syndrome should be considered in the differential diagnosis.
A complete examination of the upper aerodigestive tract should be performed during the initial evaluation of the patient with HHT. Anterior rhinoscopy and nasal endoscopy may detect presence of telangiectasias. Nasal endoscopy is performed in a careful, atraumatic manner to prevent bleeding. Patients with a history of severe, high-volume epistaxis may wish to defer nasal endoscopy in the office. Intranasal crusting and blood clots are typically present overlying larger telangiectasias, and debridement, if indicated, should be performed carefully to prevent bleeding. Nasal crusting is particularly prevalent in patients with a history of septodermoplasty. Cotton balls soaked with oxymetazoline or equivalent topical decongestant are a useful adjunct during the examination. Nasal endoscopy is useful to evaluate for septal perforation, scarring, and more posterior telangiectasias that may not be evident on anterior rhinoscopy.
Intranasal telangiectasias vary widely with regard to morphology and number of lesions present. Mahoney and Shapshay described 3 distinct vessel patterns associated with nasal telangiectasias in HHT: small, punctate isolated telangiectasias (type I) ( Fig. 1 ), diffuse interconnecting lesions with “feeder” vessels (type II) ( Fig. 2 ), and large, solitary AVM (type III). Type I lesions are more likely associated with mild epistaxis, whereas type II and type III lesions are often associated with moderate or severe epistaxis. Morphologic characterization and quantifying number of lesions may be useful for treatment planning. For example, smaller punctate type I lesions tend to respond well to laser treatment, whereas larger, raised type II and III lesions are better addressed with coblation or electrocautery. Additionally, patients with fewer, predominantly anterior lesions are better candidates for in-office treatment as compared with patients with more numerous, more posterior telangiectasias.
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Nasal endoscopy performed atraumatically, with careful debridement of crusts so as to characterize number and size of telangiectasias
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The Epistaxis Severity Score is a normalized, validated scoring tool used to quantify severity of epistaxis
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Patients with HHT should undergo pulmonary AVM screening with bubble echocardiogram at time of diagnosis and every 5 to 10 years thereafter. Brain MRI is indicated at time of diagnosis. Gastrointestinal (GI) endoscopy is indicated in patients with anemia disproportionate to degree of epistaxis
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Complete blood count and type and cross are recommended before any surgical intervention. Patients with unknown pulmonary AVM status undergoing surgery should undergo bubble echocardiogram screening before surgery
A careful history with attention to family history as well as symptoms of visceral AVMs should be performed. A history of stroke, heart failure, and GI bleeding warrant further investigation. The Curaçao criteria expert guidelines recommend screening for pulmonary AVMs and cerebrovascular malformations in all patients with HHT at time of diagnosis. Bubble echocardiogram is a screening test recommended every 5 to 10 years following initial screening to rule out formation of new AVMs. If positive, bubble echocardiogram is followed by chest computed tomography (CT) scan to fully characterize size and number of AVMs. Patients with pulmonary AVMs should be referred to a pulmonologist, interventional radiologist, or thoracic surgeon for treatment. Brain MRI is recommended at time of diagnosis, and presence of cerebrovascular malformations warrants referral to neurosurgery. Routine GI endoscopy is not indicated; however, patients with a history of GI bleeding and/or anemia disproportionate to epistaxis severity should undergo GI endoscopy for diagnosis and treatment of GI AVMs. The wide range of organ systems potentially affected in patients with HHT underlines the need for a multidisciplinary approach.
The Epistaxis Severity Score (ESS) is a validated, normalized scoring tool composed of questions related to nosebleed frequency, severity, presence of anemia, need for medical treatment, and need for blood transfusion. This is the only validated patient questionnaire for HHT-related epistaxis, and is a useful tool for evaluating treatment success as well as following nosebleed severity over time.
Severity of HHT-related epistaxis ranges from mild, occasional nasal bleeding to severe, life-threatening epistaxis. Mild nosebleeds are primarily a quality-of-life issue, whereas moderate bleeding may be associated with anemia or iron deficiency. Microcytic iron deficiency anemia with elevated transferrin and low ferritin is characteristic of moderate or severe HHT-related epistaxis. Expert guidelines recommend annual hemoglobin and hematocrit screening in patients older than 35 years.
Laboratory testing before surgical intervention should include a complete blood count with type and screen or type and crossmatch. Patients should be questioned regarding need for recent blood transfusions, and prepared for possible transfusion during surgery. Patients with unknown pulmonary AVM status should be screened with bubble echocardiogram before surgery. Patients with a positive or unknown history of pulmonary AVM should receive antibiotic prophylaxis before any procedure. Additionally, intravenous filters should be considered in patients with a positive or unknown history of pulmonary AVMs to prevent air embolism.
Management
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Nosebleed prevention is the mainstay of therapy for any patient with HHT-related epistaxis
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Nonmedicinal prevention measures include avoidance of triggers, use of nasal emollients, proper nasal hygiene, and avoidance of blood thinning medications if possible
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Pressure tamponade and use of topical spray decongestants are useful for nosebleed treatment
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Nondissolvable nasal packing should be avoided in most cases
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Topical medical treatments include bevacizumab (Avastin), estriol, tranexamic acid, thalidomide, and timolol
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