Pulmonary Hypertension in Osler-Weber-Rendu (HHT)
Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia) can cause multiple types of pulmonary hypertension, most commonly WHO Group 2 PH from high cardiac output due to hepatic arteriovenous malformations and anemia, but also WHO Group 1 heritable pulmonary arterial hypertension (particularly with ACVRL1/ALK1 mutations), and less commonly WHO Group 5 combined post- and pre-capillary PH. 1, 2
Primary PH Mechanisms in HHT
WHO Group 2: High Output Heart Failure (Most Common)
- High cardiac output state develops from two mechanisms: hepatic arteriovenous malformations creating systemic shunting, and chronic anemia from recurrent bleeding (epistaxis and gastrointestinal). 1, 3
- This represents the majority of PH cases in HHT patients and manifests as isolated post-capillary pulmonary hypertension with elevated pulmonary artery wedge pressure. 1
- The hemodynamic profile shows elevated mean pulmonary artery pressure secondary to increased cardiac output rather than primary vascular disease. 2
WHO Group 1: Heritable Pulmonary Arterial Hypertension
- Pre-capillary PAH occurs as a distinct entity in HHT, particularly in patients with ACVRL1 (ALK1) gene mutations (HHT type 2). 4, 3, 5
- This represents a proliferative vasculopathy clinically and histologically indistinguishable from idiopathic PAH, with elevated pulmonary vascular resistance. 6, 3
- The prevalence is rare, affecting less than 1% of the HHT population, but carries significant prognostic implications. 4, 2
- Patients with HHT-associated heritable PAH have worse survival probability compared to controls. 1
WHO Group 5: Combined Post- and Pre-Capillary PH
- A newly recognized hemodynamic profile showing features of both post-capillary and pre-capillary PH, with or without high cardiac output. 1
- This may represent either a continuum between pre- and post-capillary profiles or a different disease course in response to chronic high cardiac output states. 1
- Four cases were identified in a French cohort study, suggesting this is an underrecognized phenotype. 1
Genotype-Phenotype Correlations
ACVRL1 (ALK1) Mutations
- Strongly associated with pulmonary arterial hypertension development, with increased incidence compared to ENG mutations. 4, 3
- Can produce extreme phenotypic variability within the same family, including heritable PAH without hepatic AVMs, portopulmonary hypertension with hepatic AVMs, and hepatopulmonary syndrome. 7
ENG (Endoglin) Mutations
- More commonly associated with pulmonary arteriovenous malformations (15-33% of HHT patients) rather than pulmonary hypertension. 3
- PAVMs themselves do not typically cause PH but can lead to hypoxemia and right-to-left shunting. 3
Clinical Pitfalls and Diagnostic Considerations
Screening Approach
- All adult patients with HHT should undergo systematic echocardiographic screening for PH by examining right cardiac cavities and tricuspid regurgitation flow. 3
- Right heart catheterization is essential to confirm PH diagnosis and classify the hemodynamic subtype, as echocardiography alone cannot distinguish between the various PH mechanisms. 1, 3
- The presence of hepatic AVMs should prompt evaluation for high-output heart failure as the PH etiology. 2
Treatment Challenges
- PAH-specific therapies (phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostacyclins) can worsen HHT bleeding manifestations by increasing epistaxis and gastrointestinal bleeding, leading to worsening anemia. 4, 5
- This creates a therapeutic dilemma requiring careful monitoring and often necessitates increased transfusion support when treating PAH in HHT patients. 4
- Despite these challenges, patients with ALK1-associated HHT and PAH can show objective clinical improvement with parenteral prostacyclins and combination oral agents. 5