What labs and indications are used to assess for hereditary hemorrhagic telangiectasia (HHT)?

Laboratory Testing and Indications for Hereditary Hemorrhagic Telangiectasia

Primary Diagnostic Approach

Genetic testing for mutations in ENG (HHT type 1), ACVRL1 (HHT type 2), and SMAD4 (juvenile polyposis-HHT overlap) is the definitive laboratory assessment for HHT, with these three genes identifying causative mutations in 97% of patients with a definite clinical diagnosis. 1

The diagnosis of HHT is primarily clinical rather than laboratory-based, using the Curaçao criteria as the foundation 1, 2. However, genetic testing plays a crucial complementary role in specific clinical scenarios.

Indications for Genetic Testing

Primary Indications

• Asymptomatic individuals from families with known HHT represent the strongest indication for genetic testing, as this allows for early screening and preventive treatment before clinical manifestations develop 1, 2

• Patients with possible/suspected HHT (meeting only 2 of 4 Curaçao criteria) where genetic confirmation would guide screening for life-threatening visceral arteriovenous malformations 2, 3

• Family members of affected individuals to establish carrier status and enable appropriate surveillance, given the 50% inheritance risk with autosomal dominant transmission 4

Secondary Indications

• Patients with atypical presentations or when genotype-phenotype correlations would influence management decisions, as the frequency and location of arteriovenous malformations vary by specific gene mutation 2, 3

• Young children from affected families where clinical criteria cannot yet be reliably assessed due to age-related expression of telangiectasias and epistaxis 1, 3

Genetic Testing Methodology

• Simultaneous sequencing and deletion/duplication analysis of both ENG and ACVRL1 genes should be performed together rather than sequentially, as this approach identifies approximately 96% of mutations when strict Curaçao criteria are applied 5, 6

• Large deletion/duplication analysis must be included alongside sequencing, as deletions can be missed if only sequencing is performed initially 5

• SMAD4 testing should be included in the initial panel, particularly when juvenile polyposis features coexist 1, 7

Supportive Laboratory Tests

Anemia Assessment

• Complete blood count and iron studies (serum ferritin, transferrin saturation, serum iron) should be obtained in all patients with recurrent epistaxis or gastrointestinal bleeding to assess for iron deficiency anemia 2

• These tests guide iron replacement therapy rather than establish the diagnosis of HHT itself 2

Screening for Visceral Involvement

While not "laboratory" tests in the traditional sense, the following assessments are essential once HHT is suspected or confirmed:

• Doppler ultrasonography as first-line imaging for hepatic vascular malformations in all HHT patients 2

• Contrast echocardiography or chest CT for pulmonary arteriovenous malformations screening 2

• Brain MRI to detect cerebral vascular malformations 2

Clinical Diagnostic Criteria (Curaçao Criteria)

The diagnosis requires assessment of four clinical features rather than laboratory tests 1, 2:

• Spontaneous and recurrent epistaxis
• Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose)
• Visceral lesions (pulmonary, hepatic, cerebral, or spinal arteriovenous malformations; gastrointestinal telangiectasias)
• First-degree relative with HHT

Definite diagnosis requires 3 criteria; possible/suspected diagnosis requires 2 criteria; unlikely diagnosis with fewer than 2 criteria 2

Critical Pitfalls to Avoid

• Never perform liver biopsy in patients with proven or suspected HHT due to extreme hemorrhage risk from hepatic vascular malformations 2

• Do not delay genetic testing in asymptomatic family members waiting for clinical manifestations to develop, as early identification enables presymptomatic screening for life-threatening pulmonary and cerebral arteriovenous malformations 2, 3

• Avoid sequential genetic testing protocols that analyze only one gene at a time, as this delays diagnosis and may miss large deletions if duplication/deletion analysis is reflexed only after negative sequencing 5

• Recognize that approximately 15% of clinically definite HHT cases may have negative genetic testing for the known genes, so negative results do not exclude the diagnosis when clinical criteria are met 7, 3, 6