Hereditary Hemorrhagic Telangiectasia (HHT): Comprehensive Management
What is HHT?
HHT is an autosomal dominant bleeding disorder affecting approximately 1 in 5000 persons worldwide, characterized by abnormal blood vessel formation leading to telangiectasias and arteriovenous malformations (AVMs) throughout the body. 1, 2
Genetic Basis
- Mutations occur in three primary genes: ENG (HHT type 1), ACVRL1 (HHT type 2), and SMAD4 (juvenile polyposis-HHT overlap), accounting for 97% of definite clinical cases 2, 3
- Each child of an affected parent has a 50% chance of inheriting the disease 3
- These genes encode proteins that modulate transforming growth factor-beta superfamily signaling in vascular endothelial cells 4
Clinical Manifestations
Epistaxis (nosebleeds) is the hallmark symptom, occurring in more than 90% of adults with HHT, often lasting hours per day and causing significant psychosocial morbidity, social isolation, and employment difficulties 1, 2, 3
Additional manifestations include:
- Mucocutaneous telangiectasias on lips, oral cavity, fingers, and nose (age-related expression) 3
- Pulmonary AVMs requiring presymptomatic screening to prevent life-threatening complications 3
- Hepatic AVMs (more common and symptomatic in females) 3
- Cerebral and spinal AVMs 4
- Gastrointestinal telangiectasias causing chronic bleeding and anemia 4, 5
Diagnosis
Curaçao Clinical Criteria
Diagnosis requires assessment of four clinical features, with three criteria needed for a definite diagnosis: 1, 3
- Spontaneous and recurrent epistaxis 3
- Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose) 3
- Visceral lesions (pulmonary, hepatic, cerebral, spinal AVMs, or GI telangiectasias) 3
- First-degree relative with HHT diagnosed by these criteria 3
- Definite diagnosis: 3 or more criteria present 3
- Possible/suspected diagnosis: 2 criteria present 3
- Unlikely diagnosis: Fewer than 2 criteria 3
Genetic Testing
Genetic testing should be performed, particularly for asymptomatic persons from families with known HHT, targeting mutations in ENG, ACVRL1, and SMAD4 2, 3
- Simultaneous sequencing and deletion/duplication analysis identifies approximately 96% of mutations when strict Curaçao criteria are applied 3
- SMAD4 testing is essential when juvenile polyposis features coexist 3
Screening for Organ Involvement
Pulmonary Screening
All HHT patients must undergo screening for pulmonary AVMs using contrast echocardiography or chest CT, as these can be treated presymptomatically to prevent stroke, brain abscess, and massive hemoptysis 3
Hepatic Screening
Doppler ultrasonography is the first-line imaging for liver involvement in all HHT patients 3
- Liver involvement is graded 0-4 based on hepatic artery diameter, peak flow velocity, resistivity index, and peripheral hepatic hypervascularization 3
- Liver biopsy must be strictly avoided in any patient with proven or suspected HHT due to catastrophic hemorrhage risk 3
Cerebral Screening
MRI of the brain is recommended to detect cerebral vascular malformations 3
Gastrointestinal Evaluation
Upper endoscopy should be performed to evaluate for GI telangiectasias, especially in patients with unexplained anemia disproportionate to epistaxis severity 3
Management Approach
Systemic Therapies: The New Standard of Care
The Second International HHT Guidelines (2020) now recommend systemic therapies including antiangiogenics and antifibrinolytics as standard treatment options on equal standing with surgical interventions, representing a paradigm shift in HHT management. 1, 2
Antifibrinolytic Therapy
Tranexamic acid (oral) demonstrated efficacy in reducing epistaxis in two randomized controlled trials in 2014 1
Antiangiogenic Therapy
Bevacizumab (anti-VEGF monoclonal antibody) has emerged as a promising systemic therapy based on the hypothesis that VEGF excess supports telangiectasia growth 1, 5
- Can be administered systemically (intravenous) for severe bleeding or topically/submucosally for localized nasal disease 6, 5
- Eliminates bleeding telangiectasias and achieves hemostasis 1, 2
- Not curative but reduces bleeding complications 5
Local Therapies for Epistaxis
Nasal mucosal moisturization through air humidification and topical application of saline solution or gels is a mainstay of epistaxis prevention to reduce cracking and bleeding of fragile telangiectasias 1
Additional local interventions include:
- Sclerotherapy of telangiectasias (including in-office applications) has proven safe and effective 6
- Resorbable packing materials should be used to reduce rebleeding risk during packing removal 3
- Laser therapy and surgical interventions for severe or refractory bleeding 3, 6
Anemia Management
Iron replacement therapy and monitoring for anemia should be implemented for all patients with recurrent bleeding 3, 5
- Chronic bleeding leads to iron deficiency anemia requiring aggressive supplementation 3, 5
- Hormonal treatment may be considered for menorrhagia-related anemia 5
Interventional Radiology
Pulmonary AVMs require embolization to prevent stroke, brain abscess, and massive hemoptysis 7
- Interventional radiology techniques are particularly important for managing pulmonary AVMs 7
Multidisciplinary Care
Patients diagnosed with HHT must be referred to a multidisciplinary team with expertise in HHT management 3, 6
- Optimal treatment requires coordination between hematology, otolaryngology, interventional radiology, gastroenterology, and genetics 6, 5
Critical Pitfalls to Avoid
Never perform liver biopsy in HHT patients due to catastrophic hemorrhage risk 3
Avoid invasive hepatic therapies unless patients have failed intensive medical therapy 3
Do not delay pulmonary AVM screening, as presymptomatic treatment prevents life-threatening complications 3
Recognize that phenotypic variation is considerable even within families sharing the same mutation, requiring individualized screening protocols 5