[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
Journal of Medical Genetics 07/2009; 48(2):73-87. · 5.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Skeletal muscle atrophy in individuals with advanced chronic obstructive pulmonary disease (COPD) is associated with diminished quality of life, increased health resource use, and worsened survival. Muscle wasting results from an imbalance between protein degradation and synthesis, and is enhanced by decreased regenerative repair. We investigated the activation of cellular signaling networks known to mediate muscle atrophy and regulate muscle regenerative capacity in rodent models, in individuals with COPD (FEV(1) < 50% predicted). Nine patients with COPD and nine control individuals were studied. Quadriceps femoris muscle isometric contractile force and cross-sectional area were confirmed to be significantly smaller in the patients with COPD compared with control subjects. The vastus lateralis muscle was biopsied and muscle transcript and/or protein levels of key components of ubiquitin-mediated proteolytic systems (MuRF1, atrogin-1, Nedd4), inflammatory mediators (IkappaBalpha, NF-kappaBp65/p50), AKT network (AKT, GSK3beta, p70S6 kinase), mediators of autophagy (beclin-1, LC3), and myogenesis (myogenin, MyoD, Myf5, myostatin) were determined. Atrogin-1 and Nedd4, two ligases regulating ubiquitin-mediated protein degradation and myostatin, a negative regulator of muscle growth, were significantly increased in the muscle of patients with COPD. MuRF1, Myf5, myogenin, and MyoD were not differentially expressed. There were no differences in the level of phosphorylation of AKT, GSK3beta, p70S6kinase, or IkappaBalpha, activation of NF-kappaBp65 or NF-kappaBp50, or level of expression of beclin-1 or LC3, suggesting that AKT signaling was not down-regulated and the NF-kappaB inflammatory pathway and autophagy were not activated in the COPD muscle. We conclude that muscle atrophy associated with COPD results from the recruitment of specific regulators of ubiquitin-mediated proteolytic pathways and inhibition of muscle growth.
American Journal of Respiratory Cell and Molecular Biology 06/2009; 42(4):461-71. · 4.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder, characterised by the presence of vascular malformations. The pulmonary vascular complications of HHT include pulmonary arteriovenous malformations, pulmonary hypertension associated with high-output heart failure and liver vascular malformations and, finally, pulmonary arterial hypertension secondary to HHT. In the present review, the authors describe the clinical presentation, diagnosis and management of all three pulmonary vascular presentations of HHT, as well as the underlying genetics and pathophysiology.
European Respiratory Journal 06/2009; 33(5):1186-94. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterised by vascular dysplasia complicated by visceral arteriovenous malformations (AVMs). To date, the diagnostic yield of screening procedures for pulmonary and cerebral AVMs in children with definite or potential HHT is not well defined. The aim of the present study was to prospectively evaluate the diagnostic yield of a screening protocol for pulmonary and cerebral AVMs in children with either a definite or potential HHT diagnosis. All children referred for evaluation for HHT between 1996 and 2008 were included in the present analysis. Screening tests for AVMs included chest computed tomography and brain magnetic resonance imaging. 61 children with a definite clinical and/or genetic diagnosis of HHT were asymptomatic for visceral AVMs at their first baseline assessment (mean+/-SD age 8.7+/-4.7 yrs; range 0-17.0 yrs). Of these, 15 (25%) had pulmonary and/or cerebral AVMs diagnosed on initial screening tests. Pulmonary AVMs predominated in paediatric HHT patients (14 out of 15 patients) and were found in eight children aged <10 yrs. 55 children had a potential HHT diagnosis as they fulfilled only one or two HHT clinical diagnostic criteria and did not have a confirmatory genetic diagnosis (age 10.9+/-4.8 yrs; range 0-17.9 yrs). None of these children had pulmonary or cerebral AVMs on initial screening tests. The present data suggest that children with a definite HHT diagnosis have a high frequency of pulmonary AVMs even when clinically asymptomatic. In contrast, no AVMs were observed in children not fulfilling HHT diagnostic criteria. Genetic testing appears to be useful in defining an at-risk group for pulmonary AVMs in childhood.
European Respiratory Journal 05/2009; 34(4):875-81. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although experts recommend presymptomatic coil embolotherapy for patients with hereditary hemorrhagic telangiectasia (HHT) who have pulmonary arteriovenous malformations (PAVMs), this approach has not been studied prospectively and is not applied universally. We used decision analysis to evaluate the optimal treatment strategy for HHT patients with asymptomatic PAVMs.
We developed a Markov model to evaluate the following three strategies: no embolotherapy; embolotherapy only in the event of a PAVM complication; and immediate embolotherapy. Our model incorporated PAVM complications, embolotherapy effectiveness and complications, and the possibility of PAVM growth or reperfusion of successfully embolized PAVMs. The base case was a 40-year-old man with HHT and an asymptomatic PAVM with a 3-mm feeding artery. We modeled the natural history of HHT and the clinical course of embolotherapy based on review of the medical literature. We incorporated quality-of-life weights derived from the direct assessment of patient preferences (n = 45) and a literature review.
No embolotherapy, embolotherapy only in the event of a PAVM complication, and immediate embolotherapy were associated with expected survival times of 37.2, 37.6, and 39.0 years, respectively. After adjusting for quality of life, the corresponding estimates were 32.6, 34.1, and 37.2 quality-adjusted life-years. The outcome of the model was robust to changing model parameters within plausible ranges.
Patients with HHT and a PAVM with a feeding artery of >or= 3 mm have improved life expectancy and quality-adjusted survival with immediate embolotherapy. Embolotherapy should be the standard of care in such circumstances.
[show abstract][hide abstract] ABSTRACT: Patients with intrapulmonary shunt due to hepatopulmonary syndrome have diffuse pulmonary microvascular dilatation. Studies have shown that these patients have increased exhaled nitric oxide (NO) levels, suggesting that alveolar capillary NO production is increased. We speculated that alveolar capillary NO overproduction might have a similar mechanistic role in the development of shunting vessels, arteriovenous malformations, in hereditary hemorrhagic telangiectasia (HHT), in which 30-45% of patients have pulmonary arteriovenous malformations (PAVMs). Our objective was to determine if alveolar exhaled NO is elevated in patients with HHT compared to controls. We measured the alveolar fraction of exhaled NO (200 ml/s expiratory flow rate) in HHT subjects with and without a history of PAVMs and in healthy, nonsmoking controls with no known lung disease. We compared 58 HHT subjects to 49 healthy controls. Exhaled NO was significantly greater in HHT subjects (mean = 12.0 ppb, SD = 3.5) than in controls (mean = 10.5 ppb, SD = 3.2) (p = 0.02). We detected a significantly higher level of alveolar exhaled NO in subjects with HHT compared to healthy controls, suggesting that alveolar capillary NO production may be increased in HHT and may have a mechanistic role in PAVM formation.
Beiträge zur Klinik der Tuberkulose 11/2008; 187(1):43-9. · 2.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sarcoidosis is a multisystem disorder commonly affecting the lungs, but also the liver, with cirrhosis and portal hypertension occurring in fewer than 1% of cases. Although hepatopulmonary syndrome (HPS) is seen in 15% to 20% of patients with cirrhosis of varying causes, it has rarely been associated with sarcoidosis. Also, although a brain abscess is not uncommon in patients with discrete pulmonary arteriovenous malformations, it is rarely seen in patients with the much smaller intrapulmonary vascular dilations that characterize HPS. A patient with an unusual series of uncommon sarcoidosis complications, including cirrhosis with HPS, brain abscess and finally Nocardia meningitis, is reported. The possibility of HPS should be considered in sarcoidosis patients with liver involvement, if gas-exchange abnormalities are out of proportion to the degree of lung involvement. These patients may also be susceptible to a cerebral abscess by paradoxical embolization, and to opportunistic infections due to cirrhosis.
Canadian respiratory journal: journal of the Canadian Thoracic Society 05/2008; 15(3):124-6. · 1.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess whether pulmonary arteriovenous malformation (PAVM) is associated with hereditary hemorrhagic telangiectasia (HHT).
This study was a review of 12 children (sex ratio = 1) including family history, mutation analysis, and long-term follow-up.
Five children were under age 3 years when PAVM was diagnosed. Presentations included pulmonary symptoms (n = 8), cerebral abscess (n = 2), and transient ischemic attack (TIA) (n = 1); 1 patient was asymptomatic. Nine of the 12 children (75%) had a family history of PAVM. The diagnosis of HHT was confirmed in all cases. A mutation in ENG was found in 9 of the 10 children available for testing. No mutation in ACVRL1 was found. During long-term follow-up (mean, 16 years), the following complications occurred: TIA (n = 2), hemoptysis (n = 2), and cerebral abscess (n = 2). Nine children experienced recurrence of PAVM. The children with no recurrence were those without a family history of PAVM.
The diagnosis of HHT should be considered in a child with an apparently isolated PAVM. Because serious complications may occur at any age, we recommend screening for PAVM and long-term follow-up in children from families with HHT, especially those with an ENG mutation.
The Journal of pediatrics 10/2007; 151(3):299-306. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Untreated pulmonary arteriovenous malformations (PAVMs) can present with life-threatening complications. Agitated saline solution transthoracic contrast echocardiography (TTCE) has been recommended as the screening test of choice for PAVMs in hereditary hemorrhagic telangiectasia (HHT). A TTCE grading system has been proposed but not validated. The aim of this study was to determine the positive predictive value (PPV) of TTCE grades for the presence of PAVMs on CT.
A blinded retrospective review was conducted. All patients screened at the Toronto HHT Center (June 2002 to September 2004) with positive TTCE results were included. TTCE results were scored for delay (number of cardiac cycles) before appearance of microcavitations in the left atrium and graded for intensity of opacification. Grade 1 indicates minimal left ventricular opacification, grade 2 indicates moderate opacification, grade 3 indicates extensive opacification without outlining the endocardium, and grade 4 indicates extensive opacification with endocardial definition. Thoracic CT was performed in all patients, and results were scored as positive, negative, or indeterminate for PAVMs.
Of 155 patients screened for PAVMs, 104 had positive TTCE results. Complete data were available for 90 patients (87%). Mean age was 45 years; 62% were female. Seventeen percent of patients screened and 27% of patients with positive TTCE results had CT detectable PAVMs. There was a significant association between TTCE grade and presence of PAVMs on CT (p < 0.0001). The PPV of grades 1, 2, 3, and 4 were 0.02 (95% confidence interval, 0.00 to 0.06), 0.25 (95% confidence interval, 0.06 to 0.44), 0.56 (95% confidence interval, 0.23 to 0.88), and 1.0 (95% confidence interval, 1.0 to 1.0), respectively.
Increased shunt grade predicts increased probability of PAVMs and may be used to guide decisions in the screening algorithm for PAVMs.
[show abstract][hide abstract] ABSTRACT: STUDY PURPOSE: To formulate recommendations about clinical management of liver involvement in hereditary hemorrhagic telangiectasia (HHT), using a formal consensus development process. CONSENSUS PROCESS: A nominal group technique was used. A list of main clinical, diagnostic and therapeutic issues about liver involvement in HHT was generated by the organizing committee. Panel members then scored their agreement with each statement; the median score, and standard deviation for each statement were determined for each of the three successive panel rounds. These consensus statements formed the basis for recommendations graded with the strength and quality of supporting evidence. RECOMMENDATION STATEMENTS: Doppler US is sufficiently accurate and suitable for first-line imaging of the liver in the general HHT population. Liver biopsy in any patient with proven or suspected HHT should be avoided. Liver involvement in HHT is generally asymptomatic; in the minority of patients where it is symptomatic, morbidity and mortality can be substantial. The prevalence of focal nodular hyperplasia is much higher in patients with liver involvement by HHT than in the general population. Invasive therapies for liver involvement by HHT (namely liver transplantation) should be considered only in patients who have failed to respond to intensive medical therapy.
Liver international: official journal of the International Association for the Study of the Liver 12/2006; 26(9):1040-6. · 3.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the clinical and genetic characteristics of symptomatic children with hereditary hemorrhagic telangiectasia (HHT).
The HHT clinics in Toronto.
All children with symptomatic HHT treated from April 1, 1996, through December 31, 2002.
Participants were screened for visceral arteriovenous malformations (AVMs). Molecular testing was performed in the children or their affected family members.
Prevalence of epistaxis, telangiectases, pulmonary and cerebral AVMs, and genetic characteristics.
Fourteen children presented with manifestations of HHT. Seven had cardiorespiratory symptoms related to pulmonary AVMs. Three had neurological symptoms secondary to bleeding from spinal or cerebral AVMs. Two were referred because of skin telangiectases and 2, because of multiple episodes of epistaxis. Screening results revealed a cerebral AVM in 1 of 11 neurologically asymptomatic children. Of the children without respiratory symptoms, 1 was diagnosed as having definite and 1, suspected pulmonary AVMs. Four children with pulmonary AVMs carried an endoglin gene mutation (HHT type 1), and 1 carried an activin receptor-like kinase 1 gene mutation (HHT type 2). The 2 children with spinal AVMs belong to the same HHT type 2 family. No mutation was found in 1 child with pulmonary and 1 with cerebral AVMs.
Visceral AVMs and mucosal telangiectases are present in children with HHT and can lead to life-threatening events. Failure to identify a disease-associated mutation for each child suggests complex mutations or novel HHT genes.
Archives of Pediatrics and Adolescent Medicine 07/2006; 160(6):596-601. · 4.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine if there is an association between migraines and intrapulmonary right-to-left shunt.
Several studies have described an association between migraines and intracardiac right-to-left shunt.
Patients with hereditary hemorrhagic telangiectasia (HHT) were retrospectively recruited from the Toronto Hereditary Hemorrhagic Telangiectasia Center Clinical Database. All patients had been prospectively, systematically asked about a history of migraines and systematically screened for pulmonary and cerebral arteriovenous malformations (AVMs). All patients with a definite diagnosis of HHT, assessed during a 2-year period (February 1997 to April 1999), were included. Univariate analyses and logistic regression were performed, for migraine as the dependent variable and the following independent variables: age, sex, pulmonary AVMs, and cerebral AVMs.
Of the 200 patients assessed during the 2-year period, 124 (62%) had a definite diagnosis of HHT and were included in the analysis. Eighty (65%) were females. Forty-seven (38%) of the HHT patients had a history of migraine, of whom 38 (81%) had migraine with aura. The prevalence of migraine was greater in patients with pulmonary AVMs (46%) compared to patients without pulmonary AVMs (33%), OR = 1.7 (0.8 to 3.6), though this did not reach statistical significance (P = .14). Pulmonary AVMs were significantly associated with migraine (OR = 2.4, 95% CI = 1.1 to 5.5, P = .04), after adjustment for age and sex, using logistic regression.
There is a significant association between intrapulmonary right-to-left shunt and migraine.
Headache The Journal of Head and Face Pain 04/2006; 46(3):439-43. · 2.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: The objective was to determine the repeatability and stability of capnography interfaced with human exposure facility.
Capnographic wave signals were obtained from five healthy volunteers exposed to particle-free, filtered air during two consecutive 5 min intervals, 10 min apart, within the open and then the sealed and operational human exposure facility (HEF). Using a customized setup comprised of the Oridion Microcap portable capnograph, DA converter and AD card, the signal was acquired and saved as an ASCII file for subsequent processing. The minute ventilation (VE), respiratory rate (RR) and expiratory tidal volume (VTE) were recorded before and after capnographic recording and then averaged. Each capnographic tracing was analyzed for acceptable waves. From each recorded interval, 8 to 19 acceptable waves were selected and measured. The following wave parameters were obtained: total length and length of phase II and III, slope of phase II and III, area under the curve and area under phase III. In addition, we recorded signal measures including the mean, standard deviation, mode, minimum, maximum--which equals end-tidal CO2 (EtCO2), zero-corrected maximum and true RMS.
Statistical analysis using a paired t-test for means showed no statistically significant changes of any wave parameters and wave signal measures, corrected for RR and VTE, comparing the measures when the HEF was open vs. sealed and operational. The coefficients of variation of the zero-corrected and uncorrected EtCO2, phase II absolute difference, signal mean, standard deviation and RMS were less than 10% despite a sub-atmospheric barometric pressure, and slightly higher temperature and relative humidity within the HEF when operational.
We showed that a customized setup for the acquisition and processing of the capnographic wave signal, interfaced with HEF was stable and repeatable. Thus, we expect that analysis of capnographic waves in controlled human air pollution exposure studies is a feasible tool for characterization of cardio-pulmonary effects of such exposures.
[show abstract][hide abstract] ABSTRACT: To describe the mechanisms and risk factors associated with reperfusion of successfully treated pulmonary arteriovenous malformations (PAVMs) after embolotherapy.
Among 112 consecutive patients with PAVMs treated by embolotherapy, 19 patients were identified who had 33 angiographically confirmed reperfused PAVMs. A retrospective analysis of computed tomography (CT) and angiography was performed in patients with documented reperfused PAVMs in which reperfused PAVMs were compared with nonreperfused PAVMs. CT images were examined for persistence of the aneurysm and/or draining vein after initial embolotherapy and correlated with angiography to determine the mechanism of reperfusion. PAVM and embolic agent characteristics (eg, feeding artery size and number; PAVM location; coil size, number, and location) were evaluated for association with reperfusion. The outcomes of repeat embolotherapy for reperfused PAVMs were evaluated.
The PAVM aneurysm and/or draining vein persisted on CT after initial embolotherapy in all reperfused PAVMs and resolved in all nonreperfused PAVMs (in patients with nondiffuse PAVMs). Recanalization was the mechanism of reperfusion in 88%. Reperfusion was associated with the use of a single coil (P < .0001), oversized coils (P < .0001), coil placement more than 1 cm from the aneurysm (P < .0001), and increased feeding artery size (P < .001). Repeat embolotherapy for reperfused PAVMs was technically successful in 94% of cases. In the remaining 6% of cases, insufficient feeding artery length prevented safe repeat treatment. After a mean follow-up of 41 months, 42% of reperfused PAVMs in our series have been successfully treated again and occluded.
Recanalization is the most common mechanism of PAVM reperfusion. Increased feeding artery diameter, low number of coils, use of oversized coils, and proximal coil placement within the feeding artery are associated with reperfusion. Distal coil placement facilitates repeat embolization if reperfusion occurs.
Journal of Vascular and Interventional Radiology 01/2006; 16(12):1675-83. · 2.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Endoglin (ENG) and ALK-1 mutations cause hereditary hemorrhagic telangiecstasia (HHT), an autosomal dominant disorder leading to vascular dysplasia in the form of mucocutaneous telangiectasia and visceral arteriovenous malformations (AVMs). We proposed to compare two alternative strategies for management of HHT: screening HHT families with molecular diagnostic tests followed by targeted clinical screening versus conventional clinical screening. A decision analytic model was constructed to compare screening strategies for a hypothetical HHT family. The family consists of 1 index case and 13 relatives. The clinical screening protocol in use at the Canadian HHT Center in Toronto was assumed to be the standard of care. Unit costs for clinical screening (in Canadian dollars) were obtained from the 2003 Ontario Health Insurance Schedule of Benefits. Genetic screening costs were estimated for quantitative multiplex PCR and sequencing of Endoglin (ENG) and ALK-1 genes, as performed at HHT Solutions, Toronto. The genetic screening strategy resulted in a net cost of $4,060 per individual versus $5,975 for the clinical screening strategy. The genetic screening strategy would save $1,915 per family member or $26,810 saved per family. Sensitivity analyses revealed that the genetic screening strategy was cost saving over all plausible ranges of input variables for all hypothetical families tested. We concluded that a genetic screening strategy with targeted clinical screening is more economically attractive than conventional clinical screening and results in a reduction in the number of clinical tests for family members who do not have HHT.
American Journal of Medical Genetics Part A 09/2005; 137(2):153-60. · 2.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: To describe outcomes of transcatheter embolotherapy (TCE) in children with pulmonary arteriovenous malformations (PAVMs).
Chart and imaging review of all children (age </=18 years) treated for PAVMs by TCE at three hereditary hemorrhagic telangiectasia centers.
All 42 treated patients were included, with a mean age of 12 years (range, 4 to 18). Cyanosis was present in 25 of 42 patients (60%). Hemoptysis had occurred in 3 of 42 patients (7%) and neurologic complications (stroke, cerebral abscess) occurred in 8 patients (19%) before assessment. PAVMs were focal in 30 of 42 (71%) and diffuse in 12 of 42 (29%) patients. TCE was performed for 172 PAVMs and 35 diffuse regions (regional TCE). Follow-up was obtained in 38 of 42 (90%) patients (mean, 7 years). After TCE in patients with focal PAVMs, oxygenation improved significantly, with no further complications from the PAVMs. Reperfusion was noted in 23 of 153 (15%) PAVMs. Eighteen of 23 (78 %) of these were retreated, with documented aneurysmal involution in 10 of 13 (77%) patients. TCE complications included pleuritic chest pain (24% of sessions) and deployment complications (device paradoxical embolization or device misplacement) (3% of sessions, 1% of PAVMs), with no long-term complications.
PAVMs cause life-threatening complications in children; treatment with TCE is safe, with complication rates comparable to adult rates.
Journal of Pediatrics 01/2005; 145(6):826-31. · 4.04 Impact Factor