How is Hereditary Hemorrhagic Telangiectasia (HHT) diagnosed and managed in patients without epistaxis (nosebleeds)?

HHT Without Nosebleeds: Diagnosis and Management

Diagnostic Approach

HHT can be definitively diagnosed even without epistaxis if the patient meets 3 of the 4 Curaçao criteria: multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose), visceral arteriovenous malformations, and a first-degree relative with HHT. 1

Clinical Diagnosis Using Curaçao Criteria

• Definite diagnosis requires 3 of 4 criteria present, possible/suspected with 2 criteria, and unlikely with fewer than 2 criteria 1
• The four criteria are:
  • Spontaneous and recurrent epistaxis (absent in your patient)
  • Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose) 1
  • Visceral lesions (pulmonary AVMs, hepatic AVMs, cerebral AVMs, spinal AVMs, or GI telangiectasias) 1
  • First-degree relative with HHT diagnosed by Curaçao criteria 1

Physical Examination Findings to Identify

• Examine lips, tongue, hard palate, oral mucosa, and fingertips for telangiectasias - these are small, red-to-purple vascular lesions that blanch with pressure 2
• Telangiectasias have age-related expression and may not be present in younger patients despite having the genetic mutation 1
• Look for signs of anemia (pallor, conjunctival pallor) even without reported epistaxis, as GI bleeding may be occult 1

Genetic Testing Strategy

Perform simultaneous genetic testing for ENG, ACVRL1, and SMAD4 mutations, which identifies causative mutations in 97% of patients with definite clinical HHT. 1

• Genetic testing is particularly critical for asymptomatic individuals from families with known HHT, allowing early screening and preventive treatment 1
• SMAD4 testing must be included in the initial panel, as these patients develop juvenile polyposis-HHT overlap syndrome requiring different surveillance protocols 1
• A negative genetic test does NOT exclude HHT - clinical Curaçao criteria remain the diagnostic foundation 1

Mandatory Screening Protocol for All HHT Patients

Even without epistaxis, all patients with confirmed or suspected HHT require comprehensive organ screening because asymptomatic arteriovenous malformations can cause life-threatening complications including stroke, cerebral abscess, or hemorrhage. 1

Pulmonary AVM Screening

• Perform contrast echocardiography or chest CT immediately upon diagnosis to detect pulmonary AVMs, which create right-to-left shunts causing risk of paradoxical emboli leading to stroke or brain abscess 1
• Pulmonary AVMs can be treated presymptomatically to prevent these life-threatening complications 1
• This is particularly critical in HHT type 1 (ENG mutations), where pulmonary AVMs are more frequent and larger 1

Cerebral AVM Screening

• Perform brain MRI to detect cerebral vascular malformations, as cerebral AVMs occur more commonly in HHT1 and nearly one in five HHT patients develop stroke or cerebral abscess 1

Hepatic Screening

• Perform Doppler ultrasonography as first-line imaging for liver involvement in all HHT patients 1
• Key diagnostic findings include enlarged hepatic artery (>6 mm), intrahepatic hypervascularization, peak flow velocity >80 cm/sec, and resistivity index <0.55 1
• NEVER perform liver biopsy in any patient with proven or suspected HHT due to catastrophic hemorrhage risk 1
• Hepatic involvement is substantially more common and symptomatic in HHT type 2 (ACVRL1 mutations) with marked female predominance 1, 3

Gastrointestinal Evaluation

• Perform upper endoscopy to evaluate for gastrointestinal telangiectasias, especially if unexplained anemia is present disproportionate to any epistaxis severity 1
• GI bleeding may be the primary bleeding manifestation in patients without significant epistaxis 1

SMAD4-Specific Surveillance

If SMAD4 mutation is identified, initiate upper GI tract surveillance every 1-3 years starting at age 18 years due to 73% prevalence of gastric polyposis and high risk of gastric cancer 1

• All gastric cancers in one cohort occurred exclusively in SMAD4 carriers, making this surveillance life-saving 1
• SMAD4 carriers require management at a specialized HHT center with experience in both HHT and juvenile polyposis complications 1

Management Approach

Anemia and Iron Deficiency Management

Test all HHT patients for iron deficiency and anemia regardless of epistaxis symptoms, as GI bleeding may be occult 1

• Assess complete iron studies including hemoglobin, ferritin, and transferrin saturation - not just hemoglobin alone 1
• Start with oral iron (35-65 mg elemental iron daily), escalating dose if inadequate response 1
• Switch to intravenous iron for patients with inadequate absorption, intolerance, or severe anemia 1
• Reassess at 1 month for adequate response (hemoglobin rise ≥1.0 g/dL, normalization of ferritin and transferrin saturation) 1

GI Bleeding Management

For GI bleeding, follow the same stepwise approach: tranexamic acid first, then bevacizumab for refractory cases. 1

• Oral tranexamic acid reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54% 1
• Systemic bevacizumab (5 mg/kg IV every 2 weeks for 4-6 doses, then maintenance every 1-3 months) produces a 50% reduction in bleeding severity score and mean hemoglobin improvement of 3.2 g/dL 1

Multidisciplinary Referral

Refer all patients diagnosed with HHT to a multidisciplinary team with expertise in HHT management or to an HHT Center of Excellence. 2, 1

• HHT-related complications pose unique challenges requiring specialized management strategies 2
• Treatment decisions should prioritize quality of life, not just hemoglobin levels, as chronic bleeding causes significant psychosocial morbidity, social isolation, and employment difficulties 1

Critical Pitfalls to Avoid

• Do not dismiss HHT diagnosis based solely on absence of epistaxis - while epistaxis occurs in >90% of HHT patients, it is not required for diagnosis and may develop later or be absent entirely 2, 1
• Do not rely on genetic testing alone for diagnosis - clinical Curaçao criteria remain the diagnostic foundation, and negative genetic testing does not exclude HHT 1
• Do not perform liver biopsy in any patient with proven or suspected HHT due to high hemorrhage risk from vascular malformations 1
• Do not skip pulmonary and cerebral AVM screening even in asymptomatic patients, as these can cause stroke, cerebral abscess, or hemorrhage without warning 1
• Do not forget SMAD4 testing in the initial genetic panel, as these patients require earlier and more intensive GI surveillance starting at age 18 rather than age 25 1