What is hereditary hemorrhagic telangiectasia (HHT)?

What is Hereditary Hemorrhagic Telangiectasia (HHT)?

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, 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, iron deficiency anemia, and potentially life-threatening complications from visceral organ involvement. 1, 2

Genetic Basis and Inheritance

• HHT is caused by loss-of-function mutations in genes encoding proteins of the BMP signaling pathway, with 97% of clinically definite cases having identifiable mutations 1, 2
• The primary causative genes are:
  • ENG (endoglin) on chromosome 9 - causes HHT type 1, found in approximately 54% of HHT families 1
  • ACVRL1 (activin receptor-like kinase-1) on chromosome 12 - causes HHT type 2, found in approximately 43% of HHT families 1
  • SMAD4 - causes juvenile polyposis-HHT overlap syndrome in 1-2% of cases 1
  • GDF2 - less commonly responsible 3
• Each child of an affected parent has a 50% chance of inheriting the disease, allowing transmission through multiple generations 1

Clinical Manifestations

Mucocutaneous Features

• 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, 2, 4
• Telangiectasias appear as punctate, linear, or splinter-like lesions on characteristic sites including lips, oral cavity, tongue, fingers, nose, and nail beds 1, 5
• These vascular lesions have age-dependent expression, with telangiectasias developing progressively over time 1

Visceral Arteriovenous Malformations

• Pulmonary AVMs create right-to-left shunts causing hypoxemia and risk of paradoxical emboli leading to ischemic stroke or brain abscess 1, 6, 3
• Cerebral AVMs occur more commonly in HHT type 1, with nearly one in five HHT patients developing stroke or cerebral abscess 1
• Hepatic AVMs occur in 44-74% of HHT patients but only 5-8% are symptomatic, potentially causing high-output heart failure, portal hypertension, hepatic encephalopathy, and biliary ischemia 1, 6, 7
• Gastrointestinal telangiectasias lead to chronic bleeding and iron deficiency anemia 1, 5, 3
• Spinal AVMs can occur but are less common 6

Genotype-Phenotype Correlations

• HHT type 1 (ENG mutations) has higher incidence of pulmonary AVMs (up to 40%) and cerebral AVMs 1, 4
• HHT type 2 (ACVRL1 mutations) has lower incidence of pulmonary AVMs (14%) but substantially more common and symptomatic hepatic involvement with marked female predominance 1, 4

Pathophysiology

• The fundamental pathology involves abnormal blood vessel formation with enlarged vessels having thin walls that are prone to rupture and bleeding 8
• AVMs are characterized by direct artery-to-vein connections that bypass the normal capillary bed 1
• This creates vascular shunting: right-to-left through pulmonary AVMs and left-to-right through systemic AVMs 3

Clinical Impact and Complications

Bleeding and Anemia

• Recurrent epistaxis and gastrointestinal bleeding lead to chronic iron deficiency anemia affecting approximately 50% of HHT patients 1
• Typical symptoms include fatigue, reduced exercise tolerance, and hair loss 1

Life-Threatening Complications

• Ischemic stroke from paradoxical emboli through pulmonary AVMs 6, 3
• Cerebral bacterial abscesses from septic emboli 6, 3
• Intracranial hemorrhage from cerebral AVMs 6
• High-output heart failure from hepatic AVMs 6, 3
• Pulmonary hypertension and chronic hypoxemia 6
• Liver failure from hepatic vascular complications 6, 7

Quality of Life Impact

• Epistaxis causes significant psychosocial morbidity, social isolation, and difficulties with employment, travel, and routine daily activities 1
• Treatment decisions should prioritize quality of life, not just hemoglobin levels 1

Diagnostic Approach

Curaçao Clinical Criteria

• Diagnosis requires 3 of 4 criteria for definite HHT, 2 criteria for possible/suspected HHT 1:
  • Spontaneous and recurrent epistaxis
  • Multiple telangiectasias at characteristic sites
  • Visceral lesions (pulmonary, hepatic, cerebral, spinal AVMs, or GI telangiectasias)
  • First-degree relative with HHT

Genetic Testing

• Genetic testing identifies causative mutations in 97% of clinically definite cases 1, 2
• Particularly important for asymptomatic persons from families with known HHT 1
• SMAD4 testing should be included when juvenile polyposis features coexist 1

Screening for Visceral AVMs

• All HHT patients require screening for asymptomatic but potentially life-threatening AVMs 1
• Pulmonary AVM screening with contrast echocardiography or chest CT 1
• Brain MRI to detect cerebral vascular malformations 1
• Doppler ultrasonography as first-line imaging for liver involvement 1
• Critical pitfall: Never perform liver biopsy in HHT patients due to catastrophic hemorrhage risk 1, 5

Management Overview

Epistaxis Management Algorithm

• First-line: Nasal moisturization with saline gels and air humidification 1, 8
• Second-line: Oral tranexamic acid (reduces epistaxis duration by 17.3% and composite endpoints by 54%) 1, 8
• Third-line: Local ablative therapies (laser treatment, electrosurgery, radiofrequency ablation) 1, 8, 5
• Fourth-line: Systemic bevacizumab for refractory cases (produces 50% reduction in epistaxis severity score) 1, 8, 5

Iron Deficiency and Anemia Management

• All adults with HHT should be screened for iron deficiency and anemia regardless of symptoms 1
• Oral iron replacement (35-65 mg elemental iron daily) as first-line therapy 1
• Intravenous iron for severe anemia, oral intolerance, or inadequate absorption 1
• Systemic bevacizumab can produce mean hemoglobin improvement of 3.2 g/dL 1

Multidisciplinary Care

• Patients diagnosed with HHT should be referred to a multidisciplinary team with expertise in HHT management 1
• Screening for pulmonary and cerebral AVMs should begin in childhood 1
• Genetic counseling is important given the 50% inheritance risk 1