Pulmonary hypertension associated with hereditary haemorrhagic telangiectasia: from genetics to clinical management

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with an estimated prevalence of one in 5000 to one in 7000. Pathogenic variants in three genes, endoglin (ENG), activin receptor-like kinase 1 (ACVRL1) and mothers against decapentaplegic homolog 4 (SMAD4), all part of the transforming growth factor-β signalling pathway, account for over 90% of HHT cases. Clinically, HHT is characterised by recurrent epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and visceral arteriovenous malformations (AVMs), most commonly affecting the lungs, liver and brain. Pulmonary hypertension (PH) is a recognised but heterogeneous complication of HHT, with reported prevalence ranging widely from 1.5% to 45%, depending on diagnostic methods and study populations. PH associated with HHT can result from distinct, and sometimes overlapping, pathophysiological mechanisms, including high cardiac output resulting from AVMs, either isolated or associated with left heart disease and precapillary PH, usually consistent with pulmonary arterial hypertension (PAH). Accurate haemodynamic classification by right heart catheterisation is essential to determine the predominant mechanism and guide appropriate therapeutic strategies. These may include embolisation or other management of AVMs, assessment for hepatic transplantation, administration of anti-angiogenic therapies such as anti-vascular endothelial growth factor agents or the use of PAH-approved drugs in selected patients with precapillary involvement. Given the complexity of PH associated with HHT, optimal management requires a multidisciplinary approach within specialised centres experienced in both diseases. This review aims to provide a comprehensive overview of genetics, clinical phenotypes and the diagnostic and therapeutic challenges in PH associated with HHT.