Cardiopulmonary aspects of hereditary haemorrhagic telangiectasia

Abstract

This thesis addresses several clinical aspects of pulmonary arteriovenous malformations (PAVMs) in patients with hereditary haemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease. HHT is characterized by arteriovenous malformations (AVMs) in multiple organs and inherited as an autosomal dominant trait. PAVMs result in a right-to-left shunt which bypasses the pulmonary capillary filter, and are responsible for a high prevalence of brain abscess and ischemic stroke in HHT patients. Therefore, all HHT patients are routinely screened for PAVMs. Results In the first part we compared TTCE as a screening technique for PAVM with chest computed tomography (CT) as the gold standard, in a prospective study of almost 300 patients. The sensitivity of TTCE was 97% and negative predictive value 99%. However, no treatable PAVMs were missed. TTCE was also positive in 59% of patients without a PAVM on chest CT. Therefore, it appears that TTCE detects even small intrapulmonary shunts below the detection limit of CT. In a second study, the use of semi-quantitative grading (minimal, moderate, and large) of pulmonary shunt size was investigated. We showed that in patients with small shunts, no treatable PAVMs were found. This implies that a chest CT can be withheld in this group of patients. In the second part we show that a pulmonary shunt on TTCE is more prevalent and larger in HHT1 relatives (positive TTCE in 85%, of which 54% large shunts), as compared with HHT2 related mutation carriers (positive TTCE in 35%, of which 59% small shunts). Shunt grading is particularly helpful in HHT2 patients, as most patients in this group have small shunts. TTCE appeared to be also positive in 6.3% of persons without HHT. The clinical diagnosis of HHT is based on the presence of at least three of four criteria, of which one is the presence of visceral AVMs. We studied the use of TTCE to assess this criterium. The use of TTCE slightly improved clinical diagnosis in patients with genetically confirmed HHT, but also raised false positive clinical diagnosis from 0 to 6.5% in persons without HHT. In the third part we show that a PAVM on chest CT is independently associated with MA (OR 3.0, 95% CI 1.00–9.20; p=0.05). Using echocardiographic shunt grading, a large shunt increased the risk for MA more than seven-fold after multivariate analysis (OR 7.61; 95% 3.11-18.61; p<0.001). Small and moderate shunts were not associated with MA. Conclusion TTCE can be used as a first-line screening test for PAVM, only followed by chest CT to detect treatable PAVMs when positive for a pulmonary shunt. A graded approach of intrapulmonary shunting should be employed to identify patients with small pulmonary shunts in whom unnecessary additional testing can be prevented. A pulmonary shunt on TTCE should not automatically be regarded as a clinical criterium for HHT because it raises false-positive diagnosis. This relates to the presence of a small intrapulmonary shunts in a part of the general population. A large intrapulmonary shunt, but not shunts of lesser degree, is a strong independent predictor for MA+