Hereditary Haemorrhagic Telangiectasia

Hereditary haemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease) is an autosomal dominant vascular dysplasia with a prevalence of about 1 in 5,000 to 8,000.

Pathogenic variants impair BMP9/TGF-beta signalling, producing telangiectasias and arteriovenous malformations (AVMs) that bypass the capillary bed. The genes involved are:

• ENG (endoglin; HHT1, about 40 to 50%; more pulmonary and cerebral arteriovenous malformations)
• ACVRL1 (ALK1; HHT2, about 40 to 50%; more hepatic AVMs)
• SMAD4 (juvenile polyposis-HHT overlap, about 2 to 3%; colon polyps, gastric polyps and cancer risk)
• rarely GDF2

Curacao criteria (definite with 3 or more; possible with 2): recurrent spontaneous epistaxis, multiple mucocutaneous telangiectasias (lips, oral cavity, fingers, nose), visceral lesions (gastrointestinal telangiectasia, pulmonary, hepatic, cerebral or spinal AVMs), and a first degree relative with HHT.

• Epistaxis (over 90%), usually beginning at about age 12; frequent and severe, causing iron deficiency anaemia and quality of life impact
• Telangiectasia on lips, tongue, face and fingers (develop with age, by 40 in most)
• Gastrointestinal bleeding (20 to 40%; from the age of 50, stomach and small bowel telangiectasia), causing chronic anaemia
• Pulmonary AVMs (30 to 50% in HHT1; 15 to 20% in HHT2): paradoxical emboli (stroke, TIA, brain abscess), hypoxaemia, dyspnoea, haemoptysis, haemothorax, and clubbing
• Hepatic AVMs (about 70% of adults on imaging, usually asymptomatic): high output heart failure, portal hypertension, biliary ischaemia, and pulmonary hypertension
• Cerebral AVMs (about 10% in HHT1): haemorrhage, seizures
• Pregnancy risk: pulmonary AVM haemorrhage and maternal death, and worsening during the second and third trimesters

Clinical (Curacao) criteria and genetic testing (ENG, ACVRL1, SMAD4, GDF2) for confirmation and family screening. Investigations:

• Full blood count, ferritin and iron studies
• Pulmonary AVM screening: contrast (bubble) transthoracic echocardiography at diagnosis (shunt grade 2 or more triggers CT), then thoracic CT angiography for confirmation and embolisation planning
• Hepatic AVM screening: Doppler ultrasound or multiphase CT
• Brain MRI with contrast (in adults at diagnosis and in children early, for HHT1 and unknown genotype)
• Colonoscopy and upper gastrointestinal endoscopy if SMAD4 mutation or iron deficiency anaemia is out of proportion to epistaxis
• Echocardiography for pulmonary hypertension

• Epistaxis: humidification, nasal saline spray and lubricating gel; topical therapy; tranexamic acid 500 mg to 1 g three times daily orally (reduces epistaxis); bevacizumab (intravenous 5 mg/kg every 2 weeks for 4 to 6 doses, then maintenance every 2 to 3 months, or intranasal or submucosal, with benefit in moderate to severe disease); pomalidomide 4 mg daily has recent evidence for efficacy (with thromboembolism prophylaxis and contraception); estrogen progesterone and tamoxifen have been used; avoid aspirin and anticoagulants where possible. Procedural: laser photocoagulation (Nd:YAG), sclerotherapy (sodium tetradecyl sulfate), septodermoplasty, and Young procedure (closure of nostrils) for refractory disease. Avoid nasal packing that causes trauma (use resorbable packs).
• Anaemia: oral ferrous sulfate 200 mg once daily or on alternate days; intravenous iron (ferric carboxymaltose 15 mg/kg up to 1,000 mg) for intolerance or severe disease; packed red cell transfusion for severe anaemia.
• GI bleeding: iron replacement, bevacizumab, octreotide, and endoscopic ablation (argon plasma coagulation) for accessible lesions.
• Pulmonary AVM: percutaneous embolisation (coils or vascular plugs) of feeding arteries 3 mm or larger, with excellent success; follow up CT at 6 to 12 months and every 3 to 5 years; all patients require antibiotic prophylaxis before dental and invasive procedures (amoxicillin 2 g orally, 1 hour before), air filters on intravenous lines, and avoidance of scuba diving.
• Hepatic AVM: treat heart failure and portal hypertension; bevacizumab for symptomatic disease; liver transplantation for refractory disease; avoid embolisation or ligation (risk of hepatic necrosis).
• Cerebral AVM: embolisation, radiosurgery or surgery.
• Pregnancy: screen for pulmonary AVM before conception, treat AVMs; deliver in a specialist centre; epidural anaesthesia is not contraindicated and screening spinal MRI is not required.
• Anticoagulation or antiplatelet therapy when strictly indicated at lowest effective dose.