What is hereditary hemorrhagic telangiectasia (HHT)?

Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)

Definition and Pathophysiology

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular disorder characterized by abnormal blood vessel formation that creates direct artery-to-vein connections bypassing normal capillaries, resulting in fragile, thin-walled vessels prone to rupture and bleeding throughout the body. 1, 2

• HHT affects approximately 1 in 5,000 to 8,000 individuals worldwide, making it a rare but clinically significant bleeding disorder 1, 3, 4
• The fundamental vascular defect involves enlarged vessels with thin walls that lack the normal capillary bed, creating telangiectasias (small lesions) and arteriovenous malformations or AVMs (larger lesions) 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

Genetic Basis

• In 97% of patients with definite clinical diagnosis, causative mutations are identified in one of three primary genes: ENG (endoglin, causing HHT type 1), ACVRL1 (activin receptor-like kinase-1, causing HHT type 2), or SMAD4 (causing juvenile polyposis-HHT overlap syndrome) 1, 3
• ENG mutations account for approximately 54% of HHT families, while ACVRL1 mutations account for approximately 43% 1
• SMAD4 mutations occur in 1-2% of HHT cases and create a combined syndrome with juvenile polyposis, requiring additional gastrointestinal surveillance 1
• A fourth gene, GDF2, accounts for rare cases, with these genes collectively identifying the vast majority of clinically definite HHT 1

Clinical Manifestations

Mucocutaneous Features

• Epistaxis (recurrent nosebleeds) is the hallmark symptom, occurring in more than 90% of adults with HHT, typically beginning around age 11 years and worsening with age 1, 3, 2, 5
• Telangiectasias appear as punctate, linear, or splinter-like red lesions on characteristic sites including lips, oral cavity, tongue, fingers, nose, and nail beds 1, 2, 5
• These mucocutaneous telangiectasias demonstrate age-related expression, becoming more prominent over time 1

Visceral Arteriovenous Malformations

• Pulmonary AVMs occur in 40-60% of HHT patients and create right-to-left shunts causing hypoxemia and risk of paradoxical emboli leading to stroke or brain abscess 1, 4
• Hepatic vascular malformations occur in 44-74% of patients, though only 5-8% become symptomatic, potentially causing high-output heart failure 1
• Cerebral AVMs occur in approximately 10% of patients, with nearly one in five HHT patients developing stroke or cerebral abscess 1, 4
• Gastrointestinal telangiectasias cause chronic bleeding and contribute to iron deficiency anemia 1, 2, 5
• Spinal AVMs occur in approximately 1% of affected individuals 4

Systemic Complications

• Chronic bleeding leads to iron deficiency anemia in approximately 50% of HHT patients, causing fatigue, reduced exercise tolerance, and hair loss 1, 2, 5
• Epistaxis significantly impacts quality of life, causing psychosocial morbidity, social isolation, and difficulties with employment, travel, and routine daily activities 1

Diagnostic Criteria (Curaçao Criteria)

The diagnosis of HHT is primarily clinical, requiring assessment of four features: (1) spontaneous and recurrent epistaxis, (2) multiple telangiectasias at characteristic sites, (3) visceral lesions (pulmonary, hepatic, cerebral, or gastrointestinal AVMs), and (4) first-degree relative with HHT. 1, 2, 5

• Definite diagnosis requires 3 of 4 criteria present 1
• Possible or suspected diagnosis with 2 criteria present 1
• Unlikely diagnosis with fewer than 2 criteria 1
• Genetic testing should be performed, particularly for asymptomatic persons from families with known HHT, to enable early screening and preventive treatment 1

Genotype-Phenotype Correlations

• HHT1 (ENG mutations) shows higher frequency of pulmonary and cerebral AVMs that tend to be larger 1
• HHT2 (ACVRL1 mutations) demonstrates substantially higher prevalence of hepatic vascular malformations with marked female predominance 1
• SMAD4 carriers have significantly higher risk of severe gastric polyposis, with all gastric cancers in one cohort occurring exclusively in SMAD4 carriers 1
• Despite these patterns, families with the same mutation exhibit considerable phenotypic variation 2

Screening Recommendations

Mandatory Screening for All HHT Patients

• 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
• Brain MRI should be performed to detect cerebral vascular malformations 1
• Doppler ultrasonography is recommended as first-line imaging for liver involvement 1
• Liver biopsy must be strictly avoided in any patient with proven or suspected HHT due to catastrophic hemorrhage risk 1, 5

SMAD4-Specific Screening

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

Management Approach

Stepwise Treatment Algorithm for Bleeding

The American College of Cardiology recommends a systematic escalation strategy: (1) begin with nasal moisturization using saline gels and humidification, (2) escalate to oral tranexamic acid if inadequate, (3) proceed to local ablative therapies (laser, electrosurgery, argon plasma coagulation), and (4) reserve systemic bevacizumab for refractory cases failing all other interventions. 1, 6, 2, 5

• Nasal moisturization with saline gels and air humidification prevents cracking and bleeding of fragile nasal telangiectasias but often proves inadequate as monotherapy 1
• Oral tranexamic acid reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54%, now recommended as standard treatment 1, 2
• Systemic bevacizumab (anti-VEGF therapy) produces a 50% reduction in epistaxis severity score and mean hemoglobin improvement of 3.2 g/dL for severe refractory bleeding 1, 5

Anemia Management

• All adults with HHT should be tested for iron deficiency and anemia regardless of symptoms 1
• Start with oral iron (35-65 mg elemental iron daily), escalating to intravenous iron for inadequate absorption, intolerance, or severe anemia 1
• Assess complete iron studies including hemoglobin, ferritin, and transferrin saturation, as iron deficiency without anemia still causes fatigue 1, 5

Pulmonary AVM Management

• Percutaneous transcatheter embolization is recommended for pulmonary AVMs regardless of feeding artery size due to paradoxical embolism risk 1, 7

Critical Management Principles

• Treatment decisions should prioritize quality of life, not just hemoglobin levels, as epistaxis causes significant psychosocial morbidity and impacts daily functioning 1
• All patients diagnosed with HHT should be referred to a multidisciplinary team with expertise in HHT management 1
• SMAD4 mutation carriers must be managed in conjunction with a specialist HHT center experienced in both HHT and juvenile polyposis complications 1

Medication Safety Considerations

• Standard allergy treatments including antihistamines, corticosteroids, and epinephrine can be safely used in HHT patients, as these do not worsen vascular malformations or bleeding tendency 6
• Avoid dual antiplatelet therapy and combination antiplatelet/anticoagulation therapy where possible, as these significantly increase bleeding risk 6
• If anticoagulation is required, prefer heparin agents or vitamin K antagonists over direct oral anticoagulants due to increased bleeding risk with DOACs 6