Reproducibility of right-to-left shunt quantification using transthoracic contrast echocardiography in hereditary haemorrhagic telangiectasia.

AIM: Transthoracic contrast echocardiography (TTCE) is recommended for screening of pulmonary arteriovenous malformations (PAVMs) in hereditary haemorrhagic telangiectasia. Shunt quantification is used to find treatable PAVMs. So far, there has been no study investigating the reproducibility of this diagnostic test. Therefore, this study aimed to describe inter-observer and inter-injection variability of TTCE. METHODS: We conducted a prospective single centre study. We included all consecutive persons screened for presence of PAVMs in association with hereditary haemorrhagic telangiectasia in 2015. The videos of two contrast injections per patient were divided and reviewed by two cardiologists blinded for patient data. Pulmonary right-to-left shunts were graded using a three-grade scale. Inter-observer and inter-injection agreement was calculated with κ statistics for the presence and grade of pulmonary right-to-left shunts. RESULTS: We included 107 persons (accounting for 214 injections) (49.5% male, mean age 45.0 ± 16.6 years). A pulmonary right-to-left shunt was present in 136 (63.6%) and 131 (61.2%) injections for observer 1 and 2, respectively. Inter-injection agreement for the presence of pulmonary right-to-left shunts was 0.96 (95% confidence interval (CI) 0.9-1.0) and 0.98 (95% CI 0.94-1.00) for observer 1 and 2, respectively. Inter-injection agreement for pulmonary right-to-left shunt grade was 0.96 (95% CI 0.93-0.99) and 0.95 (95% CI 0.92-0.98) respectively. There was disagreement in right-to-left shunt grade between the contrast injections in 11 patients (10.3%). Inter-observer variability for presence and grade of the pulmonary right-to-left shunt was 0.95 (95% CI 0.91-0.99) and 0.97 (95% CI 0.95-0.99) respectively. CONCLUSION: TTCE has an excellent inter-injection and inter-observer agreement for both the presence and grade of pulmonary right-to-left shunts.

Follow-up of Thalidomide treatment in patients with Hereditary Haemorrhagic Telangiectasia.

BACKGROUND: Patients with a hereditary vascular disorder called Rendu-Osler-Weber syndrome (Hereditary Haemorrhagic Telangiectasia, HHT) haemorrhage easily due to weak-walled vessels. Haemorrhage in lungs or brain can be fatal but patients suffer most from chronic and prolonged nosebleeds (epistaxis), the frequency and intensity of which increases with age. Several years ago, it was discovered serendipitously that the drug Thalidomide had beneficial effects on the disease symptoms in several of a small group of HHT patients: epistaxis and the incidence of anaemia were reduced and patients required fewer blood transfusions. In addition, they reported a better quality of life. However, Thalidomide has significant negative side effects, including neuropathy and fatigue. METHODS: We followed up all HHT patients in the Netherlands who had been taking Thalidomide at the time the original study was completed to find out (i) how many had continued taking Thalidomide and for how long (ii) the nature and severity of any side-effects and (iii) whether side-effects had influenced their decision to continue taking Thalidomide. RESULTS: Only a minority of patients had continued taking the drug despite its beneficial effects on their symptoms and that the side effects were the primary reason to stop. CONCLUSION: Despite symptom reduction, alternative treatments are still necessary for epistaxis in HHT patients and a large-scale clinical trial is not justified although incidental use in the most severely affected patients can be considered.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Screening for pulmonary arteriovenous malformations using transthoracic contrast echocardiography: a prospective study.

Pulmonary arteriovenous malformations (PAVMs) are associated with severe neurological complications in patients with hereditary haemorrhagic telangiectasia (HHT). The objective of the present study was to prospectively establish the diagnostic value of transthoracic contrast echocardiography (TTCE) as a screening technique for PAVM using chest high-resolution computed tomography (HRCT) as the gold standard for PAVMs. All consecutive adult patients referred for HHT screening underwent a chest HRCT (n = 299), TTCE (n = 281), arterial blood gas analysis (n = 291), shunt fraction measurement (n = 111) and chest radiography (n = 296). TTCE was positive in 87 (58.8%), 12 (16.7%) and four (6.7%) patients, and chest HRCT was positive in 54 (36.5%), three (4.2%) and zero (0%) patients with a definite, possible and negative clinical diagnosis of HHT, respectively. Two patients with a negative TTCE were diagnosed with PAVMs after computed tomography; in both cases the PAVMs were too small to be treated by embolotherapy. The sensitivity of TTCE was 97% (95% confidence interval (CI) 93.6-98.3) and negative predictive value 99% (95% CI 96.9-99.8). The other diagnostic tests showed a considerable lower diagnostic value. The present prospective study shows that transthoracic contrast echocardiography has an excellent diagnostic value and can be used as an initial screening procedure for pulmonary arteriovenous malformations. The high false-positive rate of transthoracic contrast echocardiography possibly represents microscopic pulmonary arteriovenous malformations.

Pulmonary arteriovenous malformations associated with migraine with aura.

Migraine with aura (MA) is associated with cardiac right-to-left shunt. We prospectively studied the association between pulmonary arteriovenous malformations (PAVMs) and MA in hereditary haemorrhagic telangiectasia (HHT). All 220 consecutive HHT patients who underwent high-resolution chest computed tomography for PAVM screening were included prospectively. Prior to screening, a structured validated headache questionnaire was completed by 196 patients (57% female; mean+/-sd age 44.6+/-15.2 yrs). Two neurologists diagnosed migraine according to the International Headache Society Criteria. A PAVM was present in 70 (36%) patients. The prevalence of MA was 24% in the presence of a PAVM compared with 6% in the absence of a PAVM (OR 4.6, 95% CI 1.84-11.2; p = 0.001), and MA was an independent predictor for the presence of PAVM using multivariate analysis (OR 3.6, 95% CI 1.21-10.5; p = 0.02). A PAVM was present in 68% of the patients with MA compared with 32% in the non-migraine controls (OR 4.6, 95% CI 1.84-11.2; p = 0.001), and a PAVM was an independent predictor for MA using multivariate analysis (OR 3.0, 95% CI 1.00-9.20; p = 0.05). In conclusion, PAVMs are associated with MA in HHT patients.

The effect of N-acetylcysteine on epistaxis and quality of life in patients with HHT: a pilot study.

BACKGROUND: Free O2- radicals may cause precapillary sphincter abnormalities, resulting in epistaxis in hemizygous knockout mice for Endoglin. The objective of this study was to test if antioxidants, like N-acetylcysteine (NAC), are have a role in the treatment of epistaxis in hereditary hemorrhagic telangiectasia (HHT). METHODS: Forty-three patients participated in this study taking NAC 600 mg t.i.d for 12 weeks. Patients registered frequency, severity and duration of epistaxis and private and work-related quality of life (QOL), using a diary for two 6 weeks periods. The first period was prior to starting treatment and the second started after 6 weeks using NAC. RESULTS: There was a decrease infrequency (p < 0.01) and severity (p < 0.01) of epistaxis during the day. The improvement was most remarkable in male patients and patients with an ENDOGLIN mutation. In women and patients with an ALK-1 mutation, only a trend for improvement was found. Nocturnal epistaxis did not improve. The effect of epistaxis on the ability to work (p = 0.02) was reduced. CONCLUSION: This pilot study was conducted to investigate whether animal experiments can be translated to humans with HHT regarding epistaxis. The positive results with NAC are promising and justify a randomised clinical trial.

Pulmonary arteriovenous malformations and migraine: a new vision.

Migraine is a common neurological disorder with a great impact on the quality of life and social activities. Pulmonary arteriovenous malformations (PAVMs) are mostly congenital, with a prevalence of 5-50% in patients with hereditary hemorrhagic telangiectasia (HHT). A high prevalence of PAVMs is found in patients with HHT and migraine. Embolization of PAVMs seems to decrease the prevalence of migraine. Different pathophysiological hypotheses have been proposed to explain the association between migraine and the different right-to-left shunts. This review article describes the association between a pulmonary right-to-left shunt and the occurrence of migraine.

Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by vascular malformations in multiple organ systems, resulting in mucocutaneous telangiectases and arteriovenous malformations predominantly in the lungs (pulmonary arteriovenous malformation; PAVM), brain (cerebral arteriovenous malformation; CAVM), and liver (hepatic arteriovenous malformation; HAVM). Mutations in the ENG and ALK-1 genes lead to HHT1 and HHT2 respectively. In this study, a genotype-phenotype analysis was performed. A uniform and well classified large group of HHT patients and their family members were screened for HHT manifestations. Groups of patients with a clinically confirmed diagnosis and/or genetically established diagnosis (HHT1 or HHT2) were compared. The frequency of PAVM, CAVM, HAVM, and gastrointestinal telangiectases were determined to establish the genotype-phenotype relationship. The analysis revealed differences between HHT1 and HHT2 and within HHT1 and HHT2 between men and women. PAVMs and CAVMs occur more often in HHT1, whereas HAVMs are more frequent in HHT2. Furthermore, there is a higher prevalence of PAVM in women compared with men in HHT1. In HHT1 and HHT2, there is a higher frequency of HAVM in women. HHT1 has a distinct, more severe phenotype than HHT2. There is a difference in the presence of symptoms between men and women. With these data, genetic counselling can be given more accurately when the family mutation is known.

SMAD4 mutations found in unselected HHT patients.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease exhibiting multifocal vascular telangiectases and arteriovenous malformations. The majority of cases are caused by mutations in either the endoglin (ENG) or activin receptor-like kinase 1 (ALK1, ACVRL1) genes; both members of the transforming growth factor (TGF)-beta pathway. Mutations in SMAD4, another TGF-beta pathway member, are seen in patients with the combined syndrome of juvenile polyposis (JP) and HHT (JP-HHT). METHODS: We sought to determine if HHT patients without any apparent history of JP, who were undergoing routine diagnostic testing, would have mutations in SMAD4. We tested 30 unrelated HHT patients, all of whom had been referred for DNA based testing for HHT and were found to be negative for mutations in ENG and ALK1. RESULTS: Three of these people harboured mutations in SMAD4, a rate of 10% (3/30). The SMAD4 mutations were similar to those found in other patients with the JP-HHT syndrome. CONCLUSIONS: The identification of SMAD4 mutations in HHT patients without prior diagnosis of JP has significant and immediate clinical implications, as these people are likely to be at risk of having JP-HHT with the associated increased risk of gastrointestinal cancer. We propose that routine DNA based testing for HHT should include SMAD4 for samples in which mutations in neither ENG nor ALK1 are identified. HHT patients with SMAD4 mutations should be screened for colonic and gastric polyps associated with JP.

SMAD4 gene mutation increases the risk of aortic dilation in patients with hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations in the genes ENG, ACVRL1 and SMAD4 that are part of the transforming growth factor-beta signalling pathway cause hereditary haemorrhagic telangiectasia (HHT). Mutations in non-HHT genes within this same pathway have been found to associate with aortic dilation. Therefore, we investigated the presence of aortic dilation in a large cohort of HHT patients as compared to non-HHT controls. METHODS: Chest computed tomography of consecutive HHT patients (ENG, ACVRL1 and SMAD4 mutation carriers) and non-HHT controls were reviewed. Aortic root dilation was defined as a z-score>1.96. Ascending and descending aorta dimensions were corrected for age, gender and body surface area. RESULTS: In total 178 subjects (57.3% female, mean age 43.9±14.9years) were included (32 SMAD4, 47 ENG, 50 ACVRL1 mutation carriers and 49 non-HHT controls). Aortopathy was present in a total of 42 subjects (24% of total). Aortic root dilatation was found in 31% of SMAD4, 2% of ENG, 6% of ACVRL1 mutation carriers, and 4% in non-HHT controls (p<0.001). The aortic root diameter was 36.3±5.2mm in SMAD4 versus 32.7±3.9mm in the non-SMAD4 group (p=0.001). SMAD4 was an independent predictor for increased aortic root (ß-coefficient 3.5, p<0.001) and ascending aorta diameter (ß-coefficient 1.6, p=0.04). CONCLUSIONS: SMAD4 gene mutation in HHT patients is independently associated with a higher risk of aortic root and ascending aortic dilation as compared to other HHT patients and non-HHT controls.

Life expextancy of parents with Hereditary Haemorrhagic Telangiectasia.

BACKGROUND: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disease associated with epistaxis, arteriovenous malformations and telangiectasias. Disease complications may result in premature death. METHOD: We investigated life-expectancies of parents of HHT patients compared with their non-HHT partners using self- or telephone-administered questionnaires sent to their children. Patients were extracted from the databases of 2 participating HHT Centres: the Toronto HHT Database (Toronto, Canada) and the St. Antonius Hospital HHT Database (Nieuwegein, The Netherlands). RESULTS: Two hundred twenty five/407 (55%) of respondents were included creating HHT- (n = 225) and control groups (n = 225) of equal size. Two hundred thirteen/225 (95%) of the HHT group had not been screened for organ involvement of the disease prior to death. The life expectancy in parents with HHT was slightly lower compared to parents without (median age at death 73.3 years in patients versus 76.6 years in controls, p0.018). Parents with ACVRL 1 mutations had normal life expectancies, whereas parents with Endoglin mutations died 7.1 years earlier than controls (p = 0.024). Women with Endoglin mutations lived a median of 9.3 years shorter than those without (p = 0.04). Seven/123 (5%) of deaths were HHT related with a median age at death of 61.5 years (IQ range 54.4-67.7 years). CONCLUSION: Our study showed that the life expectancy of largely unscreened HHT patients was lower than people without HHT. Female patients with Endoglin mutations were most strikingly at risk of premature death from complications. These results emphasize the importance of referring patients with HHT for screening of organ involvement and timely intervention to prevent complications.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease): new insights in pathogenesis, complications, and treatment.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is a hereditary disorder leading to easily bleeding telangiectases on skin and mucosal surfaces, and it is associated with the presence of arteriovenous malformations (AVMs) in multiple organ systems. These AVMs may cause serious complications when they are located in the lungs, liver, or brain. The prevalence of AVMs in patients with HHT might be higher than previously estimated. Nowadays, treatment is often possible. In some families, mutations have been shown in the gene encoding for a transforming growth factor receptor, endoglin. Genetic heterogeneity has been demonstrated, suggesting involvement of other transforming growth factor receptors. This might explain the variable clinical expression of the disease. In view of the high prevalence of pulmonary and cerebral AVMs, all patients with HHT should be screened for their presence, and relatives of patients with HHT should be investigated for presence of the disease.

Screening family members of patients with hereditary hemorrhagic telangiectasia.

PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder which may give rise to arteriovenous malformations in lungs and brain. When left untreated, these may cause serious complications. We screened family members of HHT patients for presence of the disease and associated pulmonary or cerebral arteriovenous malformations. PATIENTS AND METHODS: We investigated 98 family members of HHT patients on an outpatient basis. A stepped screening protocol was used based on prevalence of different manifestations of HHT. RESULTS: Thirty-six cases of HHT were found in the 98 persons screened. Pulmonary arteriovenous malformations were found in 12 of the 36 patients (33%), and cerebral arteriovenous malformations in 4 (11%). Therapy was recommended in 9 patients with pulmonary arteriovenous malformations and in 2 with cerebral arteriovenous malformations. CONCLUSIONS: Family members of known HHT patients should be encouraged to engage in a screening program, since the prevalence of potentially serious localizations is higher than previously thought.

Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).

Hereditary Hemorrhagic Telangiectasia (HHT) is easily recognized in individuals displaying the classical triad of epistaxis, telangiectasia, and a suitable family history, but the disease is more difficult to diagnosis in many patients. Serious consequences may result if visceral arteriovenous malformations, particularly in the pulmonary circulation, are unrecognized and left untreated. In spite of the identification of two of the disease-causing genes (endoglin and ALK-1), only a clinical diagnosis of HHT can be provided for the majority of individuals. On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., we present consensus clinical diagnostic criteria. The four criteria (epistaxes, telangiectasia, visceral lesions and an appropriate family history) are carefully delineated. The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot be established in patients with only two criteria, but should be recorded as possible or suspected to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetration in this disorder. These criteria may be refined as molecular diagnostic tests become available in the next few years.

Dilatation, compensatory growth, or both after pneumonectomy during childhood and adolescence. A thirty-year follow-up study.

The ventilatory function of 230 patients with pneumonectomy, performed at ages ranging from 2 to 40 years, has been followed for more than 30 years (mean 33 years). We have tried to analyze whether the available data gave information about the nature and the mechanisms adapting the remaining lung to the larger than normal pleural space and about the persistence of this adaptation in the longer term. There were 32 patients with a persistent, disturbed forced expiration (mean 50% of vital capacity). This group of patients was excluded from the study to answer the above questions, because the subdivisions of the total lung capacity in this group differed significantly from those in the group of 98 patients with a normal forced expiratory volume of 72% (mean) of vital capacity. The data of the 98 patients, who were subdivided into seven age groups at the time of pneumonectomy, permitted the following conclusions: In the youngest age group (0 to 5 years), the ventilatory capacity is hardly smaller than the predicted capacity for two lungs; this suggests that compensatory growth by way of hyperplasia might have been the most important adaptive mechanism in this group. In the age group 6 to 20 years, a significant difference is still found as compared to the group of patients operated on at an older age; this difference indicates that in this period compensatory growth, possibly mainly simple hypertrophy, still played an important but gradually decreasing role. The fact that the effect of the adaptational mechanisms could be observed more than 30 years after ablation of one lung, without loss in quality of function (i.e., forced expiratory volume constituting a normal percentage of the vital capacity), indicates that the adaptive mechanisms also compensate for the loss in lung tissue in the longer term. A striking finding was the stability of the tidal volume/functional residual capacity ratio, which, especially in the younger age groups, was very close to the predicted value for two lungs. This finding is in agreement with the fact that most persons with a healthy remaining lung lead a normal family and social life after pneumonectomy.

A comparative study of intravenous digital subtraction angiography and ventilation-perfusion scans in suspected pulmonary embolism.

We observed 102 patients suspected of having pulmonary emboli (PE) who underwent ventilation-perfusion (V/Q) lung scintigraphy and IV digital subtraction angiography (DSA). Only five DSA studies were inadequate for interpretation. In 81 of the remaining 97 patients (83.5 percent) the results of both studies correlated regarding the probability of PE. In 50 patients the results of both studies were highly suggestive of PE; in 31 patients DSA and V/Q were normal or classified as low probability of PE. There was disagreement in 3/97; in 13/97 one or both studies were nondiagnostic. The clinical data of these 16 patients are given. Conventional catheter pulmonary angiography was indicated in 11/102 patients to establish a firm diagnosis of PE. The results of V/Q and DSA correlated in 83 percent (49/59) of patients without chronic obstructive pulmonary disease (COPD) and in 84 percent (32/38) of the patients with COPD.

Unusual complications after embolization of a pulmonary arteriovenous malformation.

A pulmonary arteriovenous malformation was embolized in a patient with hereditary hemorrhagic telangiectasia. Several unusual complications, including early deflation of a detachable balloon, migration of a coil, and development of severe pulmonary hypertension, occurred. Pulmonary hypertension was attributed to a coexistent left-to-right shunt caused by a large hepatic arteriovenous malformation.

Is resection of bronchiectasis beneficial in patients with primary ciliary dyskinesia?

A retrospective study of 21 patients with primary ciliary dyskinesia (PCD) was done. Thirteen had prior resection of bronchiectasis and eight had not. Information about present complaints was obtained by a questionnaire. The prevalence of present respiratory symptoms was the same in both groups. The surgical patients had more severe disease and 85% of them considered the operation beneficial. Selected patients with PCD may have improved conditions with resection of bronchiectasis.

Pulmonary resection after pneumonectomy in patients with bronchogenic carcinoma.

Eight patients with a previous pneumonectomy for bronchogenic carcinoma underwent an additional resection because of a second primary carcinoma in the remaining lung. One patient died of pulmonary embolism in the postoperative period. The postoperative course was otherwise uneventful except for prolonged air leak. Two patients died after 3 months (bone metastasis) and 5 months (recurrent small-cell carcinoma). Two patients were alive at the time this article was written but had evidence of recurrence after 18 months (distant metastasis) and 21 months (local recurrence at the site of positive resection margins). Three patients were alive and doing well without evidence of disease after 16, 17, and 40 months. After careful selection, even patients with a previous pneumonectomy may be good candidates for additional resection of a second primary bronchogenic carcinoma.