What is Hereditary Hemorrhagic Telangiectasia (HHT) type 2?

HHT Type 2: Definition and Clinical Characteristics

HHT type 2 is a subtype of hereditary hemorrhagic telangiectasia caused by mutations in the ACVRL1/ALK1 gene located on chromosome 12q13, distinguished from HHT type 1 by a significantly lower incidence of pulmonary arteriovenous malformations (14% vs 40%) but a higher frequency of hepatic vascular malformations, particularly in females. 1, 2

Genetic Basis

• HHT type 2 results from mutations in the activin receptor-like kinase-1 (ACVRL1/ALK1) gene, which encodes a protein involved in the transforming growth factor-β (TGF-β) signaling pathway on vascular endothelium 1, 2
• Genetic testing identifies ACVRL1 mutations in approximately 43% of HHT families, and should include simultaneous sequencing and deletion/duplication analysis alongside ENG testing 1
• In 97% of patients with a definite clinical diagnosis of HHT, a causative mutation is identified in one of three genes: ENG (HHT type 1), ACVRL1 (HHT type 2), or SMAD4 (juvenile polyposis-HHT overlap) 3

Clinical Phenotype Distinguishing HHT2 from HHT1

Organ-Specific Manifestations

• Hepatic involvement is substantially more common and symptomatic in HHT type 2, with a marked female predominance 1, 4
• Pulmonary arteriovenous malformations occur in only 14% of HHT type 2 patients compared to 40% in HHT type 1, making pulmonary complications significantly less frequent 2
• Cerebral arteriovenous malformations are less common in HHT type 2 compared to HHT type 1 1
• When pulmonary AVMs do occur in HHT type 2, they tend to be smaller in size than those in HHT type 1 1

Hemodynamic Complications

• HHT type 2 patients are at higher risk for high-output cardiac failure due to hepatic arteriovenous malformations creating left-to-right shunts, with symptoms typically appearing around age 30, predominantly in females with ALK-1 mutations 4
• Portal hypertension develops through two mechanisms: hepatic artery-to-portal vein shunting and nodular regenerative hyperplasia, leading to variceal hemorrhage and ascites 4
• The prevalence of focal nodular hyperplasia is substantially higher in HHT patients with liver involvement than in the general population 5

Diagnostic Approach

• Clinical diagnosis uses the Curaçao criteria requiring 3 of 4 features: spontaneous/recurrent epistaxis, multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose), visceral lesions (pulmonary AVMs, cerebral AVMs, hepatic AVMs, GI telangiectasias), and first-degree relative with HHT 5, 3
• Genetic testing for ACVRL1 mutations should be performed, particularly for asymptomatic persons from families with known HHT, to allow early screening and preventive measures 3

Screening Requirements for HHT Type 2

Liver Screening (Priority for HHT2)

• Doppler ultrasonography is the first-line imaging for liver involvement in all HHT type 2 patients, given the higher frequency of hepatic manifestations 5, 3
• Liver involvement should be graded (0-4) based on hepatic artery diameter, peak flow velocity, resistivity index, and presence of peripheral hepatic hypervascularization 3
• Liver biopsy must be strictly avoided in any patient with proven or suspected HHT due to catastrophic hemorrhage risk from hepatic vascular malformations 5, 3, 4

Pulmonary Screening

• Despite the lower incidence of pulmonary AVMs in HHT type 2 (14%), all patients still require screening using contrast echocardiography or chest CT, as these can be treated presymptomatically to prevent stroke and cerebral abscess 5, 1

Cerebral and GI Screening

• MRI of the brain is recommended to detect cerebral vascular malformations, though these are less frequent in HHT type 2 than HHT type 1 3, 1
• Upper endoscopy should be performed to evaluate for gastrointestinal telangiectasias, especially in patients with unexplained anemia disproportionate to epistaxis severity 3

Management Implications

• Cardiovascular monitoring should focus on detecting high-output heart failure rather than systemic hypertension, as HHT does not cause systemic hypertension but creates complex hemodynamic effects through vascular shunting 4
• Liver involvement is generally asymptomatic, but when symptomatic can cause substantial morbidity and mortality; invasive therapies including liver transplantation should only be considered after failure of intensive medical therapy 5, 3
• Treatment of epistaxis and GI bleeding follows the same stepwise approach as HHT type 1: nasal moisturization, oral tranexamic acid (17.3% reduction in epistaxis duration), local ablative therapies, and systemic bevacizumab for refractory cases (50% reduction in epistaxis severity score) 5, 3

Critical Clinical Caveat

• Pregnancy poses particular risk in HHT type 2 due to hormonal and hemodynamic changes causing rapid growth of hepatic vascular malformations, with higher risk of high-output cardiac failure 1, 4