Clinical features of Hereditary Haemorrhagic Telangiectasia

Abstract

Hereditary Haemorrhagic Telangiectasia (HHT), also known as Rendu-Osler-Weber disease (ROW), is an autosomal dominant disease with multi-systemic vascular dysplasia characterized by mucocutaneous telangiectasia, arteriovenous malformations and recurrent spontaneous epistaxis (nosebleeds). Most cases of HHT result from mutations in the ENG, ACVLR1 or SMAD4 genes. Affected individuals suffer from multi-systemic vascular lesions, known as telangiectases, characterized by focal dilation of post-capillary veins, that are susceptible to rupture and haemorrhage because of weak vessel walls and high perfusion pressures, leading to major morbidity and mortality. Telangiectasia in the nasal mucosa and gastro-intestinal tract frequently haemorrhage, leading to chronic iron deficiency anaemia which may even be transfusion-dependent. This thesis focuses on several aspects that characterizing the HHT patient to enable more research into diagnostic and treatments modalities. Life expectancy of patients is evaluated, differentiating in the underlying genetic mutation. Data show a normal life expectancy of unscreened patients with a ACVRL1 mutation and a lower life expectancy in unscreened and untreated patients with an ENG mutation. The prevalence of malignancies is analysed in an international patient cohort showing a higher prevalence of breast cancer but far lower prevalence of lung cancer, despite more severe smoking habits. The relationship between pulmonary arterial hypertension and HHT is described. This is a rare but severe complication that can arise, especially in patients with an ACVRL1 mutation. The question on how to screen children is addressed and the methodology of screening in the St. Antonius Hospital is evaluated. The use of antiplatelet and anticoagulant therapy is discussed, which is particularly relevant considering the dilemma between protection for other comorbidities, like stroke due to cardiac arrhythmias, and the amount of blood loss patients already suffer without blood thinners. The use of Thalidomide (or Softenon) is evaluated, not only in its effectivity to treat epistaxis but also the side effects patients suffer. The final chapter identifies factors influencing the severity of epistaxis in HHT patient. Numerous dietary items, including alcohol, spices and foods high in salicylates, were identified as being detrimental to the epistaxis severity. This thesis concludes that ongoing advances in medical and scientific understanding of this hereditary disease help to continuously improve patient care. Future challenges lie in several areas including genetics and their relation to the widely variable HHT phenotype, optimisation of screening, diagnostics and treatment, and improving life expectancy and quality of life of the current and future generations affected by HHT.