What is hereditary hemorrhagic telangiectasia?

What is Hereditary Hemorrhagic Telangiectasia?

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disorder characterized by abnormal blood vessel formation that creates telangiectasias (small dilated vessels) and arteriovenous malformations (AVMs) throughout the body, affecting approximately 1 in 5,000 people worldwide. 1

Genetic Basis and Inheritance

• HHT results from mutations in genes that regulate blood vessel formation, with 97% of clinically definite cases caused by mutations in one of three 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

• Each child of an affected parent has a 50% chance of inheriting the disease, as it follows an autosomal dominant pattern 2

• ENG mutations account for approximately 54% of HHT families, while ACVRL1 mutations account for 43% 2

Pathophysiology

• The fundamental pathology involves abnormal direct connections between arteries and veins that bypass normal capillaries, creating vessels with thin walls that are prone to rupture and bleeding 3, 4

• These vascular malformations can develop in multiple organ systems including the nose, skin, mucous membranes, lungs, brain, liver, gastrointestinal tract, and spinal cord 4

• HHT has age-dependent penetrance, meaning symptoms typically emerge and worsen over time rather than being present from birth 4

Clinical Manifestations

Most Common Presentation

• Recurrent spontaneous epistaxis (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, 5

• Epistaxis results from rupture of fragile telangiectasias in the nasal mucosa 5

Characteristic Skin and Mucosal Findings

• Multiple telangiectasias appear at characteristic sites including the lips, oral cavity, tongue, fingers, nose, and nail beds, presenting as punctate, linear, or splinter-like red lesions 2, 5

• These telangiectasias have age-related expression, often appearing later in life 2

Visceral Organ Involvement

• Pulmonary AVMs create right-to-left shunts that can cause hypoxemia, dyspnea with exertion, and risk of paradoxical emboli leading to stroke or brain abscess 2, 4

• Cerebral AVMs occur more commonly in HHT type 1 and can cause intracranial hemorrhage or stroke 2, 4

• Hepatic AVMs are substantially more common in HHT type 2 with marked female predominance, and when symptomatic can cause high-output heart failure or liver complications 2, 4

• Gastrointestinal telangiectasias cause chronic bleeding leading to iron deficiency anemia 5, 4

Diagnostic Approach: Curaçao Criteria

• Diagnosis requires 3 of 4 clinical criteria: (1) spontaneous and recurrent epistaxis, (2) multiple telangiectasias at characteristic sites, (3) visceral AVMs (pulmonary, hepatic, cerebral, spinal, or gastrointestinal), and (4) first-degree relative with HHT 2

• A diagnosis is definite with 3 criteria, possible/suspected with 2 criteria, and unlikely with fewer than 2 criteria 2

• Genetic testing identifies causative mutations in 97% of clinically definite cases but is not required for diagnosis, which remains primarily clinical 1, 6

Major Complications and Morbidity

• Chronic bleeding leads to iron deficiency anemia in approximately 50% of patients, causing fatigue, reduced exercise tolerance, and hair loss 2

• Life-threatening complications include ischemic stroke, cerebral bacterial abscesses, intracranial hemorrhage, pulmonary hypertension, high-output heart failure, and liver failure 4

• Epistaxis causes significant psychosocial morbidity, social isolation, and difficulties with employment, travel, and routine daily activities, impacting quality of life beyond just hemoglobin levels 2

Screening for Asymptomatic AVMs

• All patients with confirmed HHT must undergo comprehensive screening for asymptomatic but potentially life-threatening AVMs to prevent stroke, cerebral abscess, and hemorrhage 2

• Pulmonary AVM screening with contrast echocardiography or chest CT is mandatory, as these lesions can be treated presymptomatically 2

• Brain MRI to detect cerebral vascular malformations is recommended, particularly in HHT type 1 where cerebral AVMs are more common 2

• Doppler ultrasonography as first-line imaging for liver involvement, though most hepatic AVMs are asymptomatic 2

• Never perform liver biopsy in patients with proven or suspected HHT due to catastrophic hemorrhage risk 2

Management Principles

Stepwise Treatment of Epistaxis

• First-line: Nasal moisturization with saline gels and air humidification to prevent cracking of fragile telangiectasias 2

• Second-line: Oral tranexamic acid (antifibrinolytic), which reduces epistaxis duration by 17.3% and composite endpoints by 54% 1, 2

• Third-line: Local ablative therapies including laser treatment, electrosurgery, or radiofrequency ablation 5

• Fourth-line: Systemic bevacizumab (anti-VEGF therapy) for severe refractory bleeding, producing a 50% reduction in epistaxis severity score 1, 2

Anemia Management

• All adults with HHT should be screened for iron deficiency and anemia regardless of symptoms, with complete iron studies including hemoglobin, ferritin, and transferrin saturation 2

• Oral iron replacement (35-65 mg elemental iron daily) as first-line therapy, with intravenous iron for severe anemia or inadequate oral response 2

Gastrointestinal Bleeding

• Systemic bevacizumab produces mean hemoglobin improvement of 3-4 g/dL and 82% reduction in red cell transfusions for GI bleeding 2

• Argon plasma coagulation should be reserved for emergent, brisk bleeding rather than systematic repeated use 2

Genotype-Phenotype Correlations

• HHT type 1 (ENG mutations) has higher incidence of pulmonary AVMs (up to 40%) and cerebral AVMs 7

• HHT type 2 (ACVRL1 mutations) has substantially higher prevalence of hepatic AVMs with marked female predominance but lower pulmonary AVM incidence (14%) 2, 7

• SMAD4 mutations cause combined HHT and juvenile polyposis syndrome, requiring intensive gastrointestinal surveillance starting at age 18 years due to 73% prevalence of gastric polyposis and high gastric cancer risk 2

Critical Clinical Pitfalls

• Treatment decisions should prioritize quality of life, not just hemoglobin levels, as chronic bleeding causes profound psychosocial impact 2

• Negative genetic testing does not exclude HHT—clinical Curaçao criteria remain the diagnostic foundation 2

• Families with the same mutation exhibit considerable phenotypic variation, so each patient requires individualized screening and management 6

• Optimal care requires multidisciplinary management through specialized HHT centers with expertise in evaluating and treating multiple organ system involvement 2