What is Hereditary Hemorrhagic Telangiectasia (HHT) in older adults with a family history and pre-existing cardiovascular disease?

What is Hereditary Hemorrhagic Telangiectasia (HHT)

HHT is an autosomal dominant vascular disorder affecting approximately 1 in 5,000 people worldwide, characterized by abnormal blood vessel formation that creates telangiectasias (small dilated vessels) and arteriovenous malformations (AVMs) throughout the body, leading to chronic bleeding, anemia, and potentially life-threatening complications from vascular shunting. 1, 2

Genetic Basis and Inheritance

• HHT results from loss-of-function mutations in genes encoding proteins of the BMP signaling pathway, with 97% of cases caused by mutations in three primary genes: ENG (endoglin, HHT type 1), ACVRL1 (activin receptor-like kinase-1, HHT type 2), and SMAD4 (juvenile polyposis-HHT overlap syndrome) 1, 2

• As an autosomal dominant condition, each child of an affected parent has a 50% chance of inheriting the disease, allowing transmission through multiple generations 1

• ENG mutations (HHT type 1) account for approximately 54% of cases and are associated with more frequent and larger pulmonary AVMs and cerebral AVMs 1

• ACVRL1 mutations (HHT type 2) account for approximately 43% of cases and show substantially higher prevalence of symptomatic hepatic vascular malformations, particularly in females 1

• SMAD4 mutations (1-2% of cases) cause a combined syndrome of HHT and juvenile polyposis, with up to 76% manifesting HHT features including life-threatening AVMs and significantly higher risk of gastric cancer 1

Clinical Manifestations

Mucocutaneous Bleeding

• Epistaxis (nosebleeds) is the hallmark symptom, occurring in more than 90% of adults with HHT, typically beginning around age 11 years and worsening progressively with age 1, 2, 3

• Telangiectasias develop on characteristic sites including lips, oral cavity, fingers, nose, and gastrointestinal mucosa, with age-related expression patterns 1

• Chronic bleeding from nasal and gastrointestinal telangiectasias leads to iron deficiency anemia in approximately 50% of patients, causing fatigue, reduced exercise tolerance, and hair loss 1, 4

Visceral Arteriovenous Malformations

Pulmonary AVMs:

• Create right-to-left shunts causing hypoxemia and risk of paradoxical emboli, leading to ischemic stroke or cerebral abscess in nearly one in five HHT patients 1, 5

• More frequent and larger in HHT type 1 (ENG mutations) 1

Hepatic AVMs:

• Occur in 44-74% of HHT patients, but only 5-8% are symptomatic 1

• When symptomatic, cause high-output cardiac failure, portal hypertension, hepatic encephalopathy, and biliary ischemia through left-to-right shunting 1, 6

• Substantially more common and symptomatic in HHT type 2 (ACVRL1 mutations) with marked female predominance 1

Cerebral AVMs:

• Occur more commonly in HHT type 1 and can cause hemorrhagic stroke or seizures 1

Gastrointestinal telangiectasias:

• Cause chronic bleeding contributing to iron deficiency anemia, particularly in older adults 1, 5

Diagnostic Approach: Curaçao Criteria

A definite diagnosis requires 3 of 4 criteria; possible/suspected diagnosis with 2 criteria; unlikely with fewer than 2 criteria: 1

1. Spontaneous and recurrent epistaxis
2. Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose)
3. Visceral lesions (pulmonary AVMs, hepatic AVMs, cerebral AVMs, spinal AVMs, or gastrointestinal telangiectasias)
4. First-degree relative with HHT diagnosed using these criteria

Genetic Testing

• Should be performed particularly for asymptomatic persons from families with known HHT, allowing early screening and preventive treatment 1

• Simultaneous sequencing and deletion/duplication analysis of ENG, ACVRL1, and SMAD4 identifies causative mutations in 97% of clinically definite cases 1, 2

• Clinical Curaçao criteria remain the diagnostic foundation—negative genetic testing does not exclude HHT 1

Mandatory Screening for Visceral AVMs

Pulmonary AVM 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 and cerebral abscess 1, 5

Cerebral AVM Screening

• Brain MRI is recommended to detect cerebral vascular malformations, particularly in HHT type 1 1

Hepatic Screening

• Doppler ultrasonography is first-line imaging for liver involvement, assessing hepatic artery diameter (>6 mm abnormal), peak flow velocity (>80 cm/sec abnormal), and resistivity index (<0.55 abnormal) 1

• Liver biopsy must never be performed in HHT patients due to catastrophic hemorrhage risk 1, 3

Gastrointestinal Evaluation

• Upper endoscopy should be performed in patients with unexplained anemia disproportionate to epistaxis severity 1

• SMAD4 mutation carriers require upper GI surveillance every 1-3 years starting at age 18 years due to 73% prevalence of gastric polyposis and high gastric cancer risk 1

Management Approach

Stepwise Treatment of Epistaxis

The treatment algorithm prioritizes quality of life over hemoglobin levels alone, as epistaxis causes significant psychosocial morbidity, social isolation, and employment difficulties: 1

1. First-line: Nasal moisturization with saline gels and air humidification to prevent cracking of fragile telangiectasias 1, 3

2. Second-line: Oral tranexamic acid (antifibrinolytic) when moisturization fails, producing 17.3% reduction in epistaxis duration and 54% reduction in composite epistaxis endpoints 1, 2

3. Third-line: Local ablative therapies (laser treatment, electrosurgery) for refractory bleeding 1

4. Fourth-line: Systemic bevacizumab (anti-VEGF antibody, 5 mg/kg IV every 2 weeks for 4-6 doses) for severe refractory cases, producing 50% reduction in epistaxis severity score and mean hemoglobin improvement of 3.2 g/dL 1, 2, 7

Iron Deficiency and Anemia Management

• All adults with HHT should be tested for iron deficiency and anemia regardless of symptoms, assessing complete iron studies including hemoglobin, ferritin, and transferrin saturation 1

• Start with oral iron (35-65 mg elemental iron daily), escalating to intravenous iron for inadequate absorption, intolerance, or severe anemia 1

• Fatigue severity correlates with iron deficiency and anemia—ferritin and transferrin saturation must be normalized, not just hemoglobin 1

Pulmonary AVM Treatment

• Percutaneous transcatheter embolization is recommended for pulmonary AVMs regardless of feeding artery size due to paradoxical embolism risk 1

Hepatic AVM Management

• Invasive therapies including liver transplantation should only be considered after failure of intensive medical therapy, as most hepatic involvement is asymptomatic 1, 6

Special Considerations for Older Adults with Cardiovascular Disease

• Avoid dual antiplatelet therapy and combination antiplatelet/anticoagulation therapy where possible, as these significantly increase bleeding risk 3

• If anticoagulation is required, prefer heparin agents or vitamin K antagonists over direct oral anticoagulants (DOACs), as DOACs may be less well tolerated due to increased bleeding risk 3

• High-output cardiac failure from hepatic AVMs can worsen fatigue and cardiovascular symptoms beyond anemia alone, creating additional hemodynamic burden 1

• The mean age of patients with hepatic vascular malformations is 52 years, indicating age-dependent manifestation particularly relevant in older adults 1

Critical Pitfalls to Avoid

• Never perform liver biopsy in proven or suspected HHT due to catastrophic hemorrhage risk from vascular malformations 1, 3

• Do not rely solely on hemoglobin levels for treatment decisions—prioritize quality of life and normalize complete iron stores 1

• Recognize that families with the same mutation exhibit considerable phenotypic variation, requiring individualized screening protocols 8

• All patients with SMAD4 mutations must be managed in conjunction with a specialist HHT center due to combined HHT and juvenile polyposis complications 1

Multidisciplinary Care Requirement

• Patients diagnosed with HHT should be referred to a multidisciplinary team with expertise in HHT management, coordinating care across otolaryngology, gastroenterology, interventional radiology, hematology, and genetics 1, 8

• Genetic counseling is essential given the 50% inheritance risk for offspring 1

• Early diagnosis in at-risk family members through genetic testing allows appropriate screening and preventive measures before complications develop 1, 5