Claire L. Shovlin

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.

Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms

Hereditary haemorrhagic telangiectasia (HHT, Rendu-Osler-Weber syndrome) exemplifies an important group of diseases which have catalysed advances in the understanding of fundamental pathophysiological mechanisms. In this paper areas of clinical management of HHT are discussed and the molecular pathogenesis is reviewed. The first section is aimed at all clinicians and concentrates on the recognition of a disorder in which silent cerebral and pulmonary involvement may be life threatening if left untreated. Recent data concerning the diagnostic and treatment modalities for pulmonary arteriovenous malformations (PAVMs) are also reviewed, and the growing concern that many patients with HHT may have small or residual PAVMs is highlighted. The paucity of good longitudinal data on these patients and others with different forms of HHT highlights the need for further clinical studies. In the second section the results of molecular research which suggests a role for receptors and ligands of the transforming growth factor (TGF)-β superfamily in the pathogenesis of this vascular disease are discussed. The means by which such information may relate to the clinical heterogeneity observed in HHT are specifically addressed, and more fundamental questions such as how reduced cell surface expression of endoglin predisposes a patient to develop PAVMs are also discussed. The classical patient with the vascular disorder hereditary haemorrhagic telangiectasia (HHT) has nose bleeds, dilated blood vessels over the lips and finger tips, and gastrointestinal bleeding in later life. However, this clinical scenario represents only one of the presentation patterns of HHT.1 2 It is now recognised that, in addition to microscopic mucocutaneous telangiectases derived from post capillary venules (fig 1A),3 HHT leads to the development of larger abnormal vascular structures at other sites. Arteriovenous malformations in the pulmonary, cerebral, and hepatic circulations account for some of the most devastating clinical complications of the disease. Figure 1 Hereditary haemorrhagic telangiectasia …

Hereditary haemorrhagic telangiectasia: a clinical and scientific review.

The autosomal-dominant trait hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5–8000 people. Genes mutated in HHT (most commonly for endoglin or activin receptor-like kinase (ALK1)) encode proteins that modulate transforming growth factor (TGF)-β superfamily signalling in vascular endothelial cells; mutations lead to the development of fragile telangiectatic vessels and arteriovenous malformations. In this article, we review the underlying molecular, cellular and circulatory pathobiology; explore HHT clinical and genetic diagnostic strategies; present detailed considerations regarding screening for asymptomatic visceral involvement; and provide overviews of management strategies.

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings.

A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5

Patients with hereditary haemorrhagic telangiectasia (HHT, or Osler-Weber-Rendu syndrome) have variable presentation patterns and a high risk of preventable complications. Diagnostic tests for mutations in endoglin (HHT type 1) and ALK-1 (HHT type 2) are available. Some HHT patients are now known to have HHT-juvenile polyposis overlap syndrome due to Smad4 mutations. Families were ascertained following the presentation of probands for embolization of pulmonary arteriovenous malformations. Genome-wide linkage studies using over 700 polymorphic markers, and sequencing of candidate genes, were performed. In a previously described HHT family unlinked to endoglin or ALK-1, linkage to Smad4 was excluded, and no mutations were identified in the endoglin, ALK-1, or Smad4 genes. Two point LOD scores and recombination mapping identified a 5.4 cM HHT3 disease gene interval on chromosome 5 in which a single haplotype was inherited by all affected members of the pedigree. The remainder of the genome was excluded to a 2–5 cM resolution. We are currently studying a further family potentially linked to HHT3. We conclude that classical HHT with pulmonary involvement can result from mutations in an unidentified gene on chromosome 5. Identification of HHT3 should further illuminate HHT pathogenic mechanisms in which aberrant transforming growth factor (TGF)-β signalling is implicated.

Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia

Background: Brain abscesses and ischaemic strokes complicate pulmonary arteriovenous malformations (PAVMs). At risk individuals are poorly recognised. Stroke/abscess risk factors have not been defined. Methods: A cohort study of 323 consecutive individuals with PAVMs (n = 219) and/or the commonly associated condition hereditary haemorrhagic telangiectasia (HHT, n = 305) was performed. Most of the 201 individuals with PAVMs and HHT had no respiratory symptoms, and were unaware they had HHT. Anderson–Gill models assessed constant and time dependent potential predictive variables for stroke/abscess, and rate reduction by PAVM embolisation. Results: 57 individuals with PAVMs and HHT experienced brain abscess or ischaemic stroke, usually prior to the diagnosis of underlying PAVMs/HHT. The primary determinants of stroke and abscess risks were unrelated to severity of PAVMs. Males had higher brain abscess rates (hazard ratio 3.61 (95% CI 1.58, 8.25), p = 0.0024); interventional histories and bacteriological isolates suggested dental sources. Once adjusted for gender, there was a marginal association between brain abscess and low oxygen saturation. For ischaemic stroke, there was no association with any marker of PAVM severity, or with conventional neurovascular risk factors. Surprisingly, low mean pulmonary artery pressure was strongly associated with ischaemic stroke (hazard ratio 0.89 (95% CI 0.83, 0.95) per mm Hg increase; p = 6.2×10−5). PAVM embolisation significantly reduced ischaemic stroke rate (p = 0.028); no strokes/abscesses occurred following obliteration of all angiographically visible PAVMs. The mean PAVM diagnosis–treatment interval was longer, however, when neurological risks were unrecognised. Conclusions: Ischaemic strokes and brain abscesses occur commonly in undiagnosed HHT patients with PAVMs. Risk reduction could be improved.

A double-blind, placebo controlled study of Ginkgo biloba extract ('tanakan') in elderly outpatients with mild to moderate memory impairment.

Thirty-one patients over the age of 50 years and showing a mild to moderate degree of memory impairment entered a 6-month double-blind, placebo controlled, parallel group design study to assess the effects of a standardized Ginkgo biloba extract (containing 24% flavonoid glycosides and 6% terpenes) on cognitive function. Patients were allocated at random to receive oral doses of 40 mg Ginkgo biloba extract or identical placebo 3-times daily. Assessments were made at baseline and after 12 and 24 weeks of treatment using a range of psychometric tests. Efficacy data were available for 27 patients (15 in the placebo group and 12 in the active treatment group). Statistical analysis of the data as compared to baseline suggests that Ginkgo biloba extract had a beneficial effect on cognitive function in this group of patients. Performance on the Digit Copying sub-test of the Kendrick battery was significantly improved at both 12 and 24 weeks, while the median speed of response on a computerized version of a classification task also showed a significant superiority over placebo at 24 weeks.

Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu syndrome): suggested approach for obstetric services

Objectives  Hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5–8000 individuals. Pregnancy outcomes are rarely reported. The major reason is that most women do not have their HHT diagnosed prior to pregnancy. Using a large well‐characterised series, we studied all pregnancies known to have occurred in HHT‐affected women, whether or not their diagnosis was known at the time of pregnancy. Our aim was to estimate rates and types of major complications of HHT in pregnancy, to guide management decisions.

Embolization of pulmonary arteriovenous malformations using the Amplatzer vascular plug: successful treatment of 69 consecutive patients.

ObjectiveThe technique of embolization of pulmonary arteriovenous malformations (PAVMs) with the Amplatzer vascular plug (AVP) has been reported, but no large series has evaluated the effectiveness of this relatively new embolic device. The purpose of this study is to assess the role of AVPs in the treatment of PAVMs.Materials and methodsSixty-nine consecutive patients underwent embolization of pulmonary arteriovenous malformations between September 2006 and December 2008. Clinical, procedural, and physiological data were reviewed retrospectively.ResultsOf 161 PAVMs, 120 (75%) were successfully embolized with Amplatzer vascular plugs alone. Complete and rapid occlusion of feeding vessels was easily achieved at the site of arteriovenous communication without complication. Particularly small or tortuous feeding arteries supplying 27 complex and 14 simple PAVMs were occluded with coils. There have been no documented instances of recanalization on follow-up.ConclusionAmplatzer vascular plugs allow the rapid and safe distal occlusion of the majority of PAVMs.

Pulmonary Arteriovenous Malformations

Within the past decade, pulmonary arteriovenous malformations (PAVMs) have evolved from rare curiosities to not uncommon clinical states, with the latest estimates suggesting a prevalence of ~1 in 2,600. PAVMs provide anatomic right-to-left shunts, allowing systemic venous blood to bypass gas exchange and pulmonary capillary bed processing. Hypoxemia and enhanced ventilatory demands result, although both are usually asymptomatic. Paradoxical emboli lead to strokes and cerebral abscesses, and these commonly occur in individuals with previously undiagnosed PAVMs. PAVM hemorrhage is rare but is the main cause of maternal death in pregnancy. PAVM occlusion by embolization is the standard of care to reduce these risks. However, recent data demonstrate that currently recommended management protocols can result in levels of radiation exposure that would be classified as harmful. Recent publications also provide a better appreciation of the hematologic and cardiovascular demands required to maintain arterial oxygen content and oxygen consumption in hypoxemic patients, identify patient subgroups at higher risk of complications, and emphasize the proportion of radiologically visible PAVMs too small to treat by embolization. This review, therefore, outlines medical states that exacerbate the consequences of PAVMs. Chief among these is iron deficiency, which is commonly present due to concurrent hereditary hemorrhagic telangiectasia: iron deficiency impairs hypoxemia compensations by restricting erythropoiesis and increases the risk of ischemic strokes. Management of periodontal disease, dental interventions, pulmonary hypertension, and pregnancy also requires specific consideration in the setting of PAVMs. The review concludes by discussing to what extent previously recommended protocols may benefit from modification or revision.