Novel diagnostics and therapeutics in hereditary hemorrhagic telangiectasia

Despite the increase in awareness and knowledge, hereditary hemorrhagic telangiectasia (HHT) remains a disease in which long diagnostic delay resulting in severe but preventable morbidity is not uncommon. Even after a correct diagnosis, the existing treatment options are not always sufficient to decrease the disease burden enough and to treat the recurrent epistaxis and gastrointestinal blood loss. In this thesis we have tried to address both challenges in HHT care. We have investigated clinical characteristics and novel diagnostics to aid in a correct diagnosis of HHT, and evaluated three novel treatment options for severe bleeding in HHT. The use of capillary microscopy has proven to be an useful diagnostic tool for a correct HHT diagnosis in certain cases. A novel quantification method of transthoracic contrast echocardiography for the detection of treatable pulmonary arteriovenous malformations (PAVMs) using a change in gray density following contrast injection has led to an increase in diagnostic yield and a substantial decrease in needed thoracic CT-scans and thus avoidance of harmful Rontgen radiation. The clinical and radiographical features of patients with PAVMs without identifiable cause were largely like HHT associated PAVMs suggesting similar treatment and follow-up methods. In the search for affordable and well tolerated drugs to treat HHT related bleeding and subsequent anemia, we repurposed three existing drugs: octreotide, itraconazole and tacrolimus. Octreotide, a somatostatin analogue, decreases splanchnic blood flow and has antiangiogenic properties. In our clinical trial, octreotide treatment significantly decreased the required number of red blood cell transfusions of HHT patients by decreasing gastrointestinal blood loss. Itraconazole, a widely used antifungal drug, has strong anti-angiogenic properties by inhibiting vascular endothelial growth factor (VEGF). In HHT, VEGF is overexpressed and decreasing VEGF has shown to decrease bleeding in HHT. As result, treatment with oral itraconazole significantly decreased epistaxis severity in HHT. Haploinsufficiency of several receptors expressed in the Transforming Growth Factor beta (TGF-β) pathway are believed to be an important part of the pathophysiology of HHT. Tacrolimus, a calcineurin inhibitor, has shown to increase one of the receptors in the TGF-β pathway directly linked to HHT: ALK1. In HHT, oral tacrolimus treatment significantly decreased epistaxis, gastrointestinal bleeding and blood transfusion needs and significantly increased hemoglobin levels in HHT patients. These three drugs should be considered as viable treatment options for severe HHT-related bleeding. We observed that systematic screening and treatment if needed, in a HHT center according to a standardized protocol has resulted in the normalization of the life-expectancy of HHT patients compared to the life-expectancy of their relatives. While life-expectancy has normalized, the quality of life is still negatively affected, especially by epistaxis and gastrointestinal bleeding. Therefore, the ongoing research to find affordable, well-tolerated drugs to decrease the bleeding severity in HHT remains of paramount importance.