Hematology

Hereditary haemorrhagic telangiectasia

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Hereditary haemorrhagic telangiectasia

What every physician needs to know:

Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia which affects approximately 1 in 5,000 individuals and is inherited as an autosomal dominant trait. Affected individuals may experience substantial morbidity, and there are premature deaths, but for most HHT-affected individuals, life expectancy will be normal. Causative mutations have been identified in the endoglin, activin receptor-like kinase 1 (ACVRL1/ALK1), and SMAD family member 4 (SMAD4)genes which influence transforming growth factor beta (TGF-beta) signalling in vascular endothelial cells.

Classically, the condition was recognised as a triad of familial nose bleeds, mucocutaneous telangiectasia, and iron deficiency anemia due to chronic bleeding from nasal and/or gastrointestinal telangiectasia. The spectrum of HHT encompasses multiple organ systems, and within these, numerous forms of disease.

The majority of HHT patients are affected by arteriovenous malformations (AVMs) in the pulmonary (approximately 50%), hepatic (more than 30%), and cerebral (5 to 10%) circulations. AVMs are usually clinically silent, but can cause major complications including stroke, massive hemoptysis, high output cardiac failure, and maternal death in pregnancy. Compared to the general population, HHT patients are also at higher risk of venous thromboemboli, two forms of pulmonary hypertension (predominantly ALK1 patients), and juvenile polyposis (SMAD4 mutations only).

Currently, HHT-specific treatments focus on removal/obliteration of abnormal vessels by laser therapy, embolization and surgery, and management of acute bleeding and complications such as iron deficiency anemia, by regimens used in the general population.

There is great interest in the development of medical therapies for HHT. Hormonal manipulation has been shown to be effective in reducing nasal and/or gastrointestinal bleeding in small randomised controlled trials; tamoxifen is better tolerated than the earlier high dose oestrogen-progesterone regime. Other hormonal and antiangiogenesis agents are currently undergoing clinical trials.

Since many preventable complications occur in undiagnosed or previously asymptomatic individuals, HHT family screening and education programs accompany the management of clinical problems caused by HHT. Management of the diverse clinical presentations of HHT often differs from standard practice guidelines. This is particularly the case for acute stroke presentations and pregnancy.

Although international management guidelines were published in 2011, these were based on evidence published by October 2006, and do not include evaluation of more recent data.

Are you sure your patient has hereditary haemorrhagic telangiectasia? What should you expect to find?

Only a small subgroup of HHT patients will present in the classical manner with a triad of nose bleeds, mucocutaneous telangiectasia, and iron deficiency anemia, due to chronic bleeding from nasal and/or gastrointestinal telangiectasia.

Many HHT patients present due to AVM complications; hemorrhage is not common, but when it does occur, particularly from cerebral AVMs, it is acute and life-threatening. Other complications arise as a result of blood bypassing specific capillary beds, and the attendant compensatory mechanisms. Pulmonary AVMs cause: hypoxemia, paradoxical embolic stroke and brain abscess in relatively high proportions of patients, and are associated with a higher prevalence of migraine. Hepatic AVMs, while usually well tolerated, may lead to high output cardiac failure and other complications.

Nosebleeds affect the majority of individuals at some point in their life. They may be sufficiently frequent to require otorhinolaryngologic attention and long term maintenance iron or transfusions, but for many individuals they may be considered trivial.

Most HHT patients will provide a family history of known HHT/ AVMs, nosebleeds, telangiectasia, or a major AVM complication (ask about nosebleeds, "red spots" on lips or finger tips, brain abscess, early onset strokes or brain hemorrhage).

Telangiectasia (visible dilated vessels) are often evident on the lips, oral mucosa, tongue, palmar aspect of finger tips, and ears. These develop with age, are rarely apparent in childhood, rarely florid under 40, and may remain subtle in old age. Telangiectasia in non sun-exposed areas are more diagnostic. Truncal and limb lesions are not considered to be related to HHT.

Other anticipated abnormal findings include: anemia, clubbing, cyanosis, elevated jugular venous pressure; bruits over liver or lung fields, and neurological sequelae of prior stroke.

A diagnosis of HHT is commonly made as a result of family screening protocols. In this setting, expect to find a healthy, spotty, normal individual despite low hemoglobin and/or low oxygen saturations (particularly on standing).

Beware of other conditions that can mimic hereditary haemorrhagic telangiectasia:

Inherited disorders of coagulation that cause nosebleeds

Von Willebrand Disease (vWD) is the closest mimic of HHT as it can also lead to the development of mucocutaneous and gastrointestinal telangiectasia. In contrast to vWD, it is rare for HHT patients to have excessive bleeding at sites of dental extraction or from the genitourinary tract. Consider vWD in a family where there is no evidence of any visceral AVMs.

Autosomal dominant vascular dysplasias that lead to cutaneous vascular malformations and refractory gastrointestinal bleeding

Bean syndrome (blue rubber bleb nevus syndrome) is the one most likely to cause diagnostic confusion. Inherited TIE2 mutations cause cutaneous, gastrointestinal and visceral venous malformations. These are of a different type and distribution to HHT telangiectasia, and should not cause confusion to the expert eye. Gene testing is available.

Autosomal dominant vascular dysplasias that lead to cutaneous and visceral vascular malformations

RAS p21 protein activator 1 (RASA1) related disorders are the ones most likely to cause diagnostic confusion. Cutaneous lesions are of a different type and distribution to HHT telangiectasia. Gene testing is available.

Sporadic pulmonary arteriovenous malformations

These are unusual - more than 90% of patients with pulmonary arteriovenous malformations (PAVMs) have HHT. Only consider sporadic etiology to be a likely possibility if a single pulmonary AVM is present, and there is no personal or family history of nosebleeds.

Sporadic cerebral arteriovenous malformations

A sporadic etiology is more common than for pulmonary AVMs; less than 10% of cerebral AVM patients have HHT.

Sporadic dilated cutaneous vessels ("red spots")

Cutaneous vascular lesions are very common in the general population, especially in children, or in later life in sun exposed areas. The majority of normal individuals will experience a nose bleed at some time in their life. The combination of skin lesions and nosebleeds is, therefore, very common. In contrast, HHT affects approximately 1 in 5,000. Caution should be employed before over-interpreting normal characteristics in the absence of a family history.

Hepatopulmonary syndrome and chronic liver disease

These individuals have very low blood oxygen levels due to intrapulmonary shunting and may have spider nevi that can cause diagnostic confusion with HHT telangiectasia, if sites and lesion features are not appreciated. In practice, the distinction is easier than on paper.

Which individuals are most at risk for developing hereditary haemorrhagic telangiectasia?

Inheritance of HHT is governed by Mendelian principles for an autosomal dominant trait. Thus, individuals who have a parent with HHT have a 50% chance of inheriting the condition. Features of HHT are not present at birth, but become more apparent with age. For a clinically unaffected child of an HHT patient, the risk that they have HHT is approximately 1 in 5 at the age of 18, and 1 in 20 at age 40 years.

HHT can develop in the absence of a family history due to limited information on key blood relatives, non recognition of HHT symptoms in other family members, or a new mutation.

Environmental factors, nutrition, race, and gender influence the presentation of HHT, but will not affect its inheritance.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

A clinical diagnosis of HHT is made in the setting of at least three of the four Curacao criteria (nosebleeds, characteristic telangiectasia, visceral lesions and a family history). An individual has "definite HHT" if three are present, "suspected or possible HHT" with two, and "unlikely HHT" if only one. Anemia is not a criterion.

Certain clinical criteria are more predictive of HHT. For example, pulmonary AVMs should carry more weight than spontaneous nosebleeds. Most children with HHT will not have three criteria evident, as telangiectasia often develop later. Although technically, it is possible to have definite HHT status with just nosebleeds and telangiectasia in two first degree relatives; where there is no AVM history in any family member, it may be wise to retain the phrase "suspected HHT" for the family while excluding vWD or obtaining a molecular diagnosis.

Gene testing is available for endoglin, ALK1 and SMAD4. Gene testing is most helpful in two settings: to exclude HHT definitively for an apparently unaffected member of an HHT family or to make the diagnosis where there is insufficient clinical evidence. Gene testing is not required to confirm a definite clinical diagnosis in any individual. Since mutations are not found in approximately 15-20% of HHT families, if no mutation is found, this should not affect a clinical diagnosis of HHT for members of that family.

It is critical that genetic testing only uses definite disease-causing mutations for diagnostic purposes. Unfortunately, some missense polymorphisms that are not disease-causing were entered onto the HHT Mutation Database; thus, a prior report is not always sufficient to assign disease-causing status.

  • Identification of a frameshift, start codon, or stop codon mutation in any of the HHT genes is diagnostic.

  • Splice site mutations also appear to be diagnostic; there has been no evidence for polymorphic inheritance of these in HHT families to date.

  • Missense substitutions are more difficult to interpret, and misassignment as disease-causing has led to misdiagnosis of members of HHT families.

- There are definite disease-causing mutations in ALK1, for example, those affecting the conserved kinase domain. Missense changes are more difficult to explain as being pathogenic in endoglin; one interferes with protein processing. However, in general, missense changes in the endoglin gene should not be interpreted as being disease-causing unless supported by strong laboratory evidence.

Other laboratory tests characterize complications (such as anemia, iron deficiency, hypoxemia, polycythemia), but are not specific to HHT and cannot be used to confirm the diagnosis.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of hereditary haemorrhagic telangiectasia?

Using imaging as a screening tool to identify asymptomatic AVMs in HHT may help in making the diagnosis. The international guidelines published in 2011 recommend clinical screens for pulmonary, cerebral and hepatic AVMs.

For non-specialists, however, there are three potential pitfalls in initiating these screens:

  • The first is the inappropriate assignment of diagnostic criteria (see below).

  • The second is that the identification process for asymptomatic AVMs is primarily governed by screening risk-benefit considerations.

- There are complex issues involved in screening for certain manifestations of HHT, particularly cerebral AVMs in which investigations and treatments carry substantial risks. The evidence base has changed since guideline development; and there are strong differences in clinician and patient opinion regarding interpretation in favor of screening.

  • Finally, receiving a diagnosis of an asymptomatic AVM should be accompanied by appropriate information about prognosis and recommended management.

- This may be challenging outside of specialized centers.

Specific issues:

  • For pulmonary AVMs, positive imaging by thoracic computed tomography (CT) scan can provide an additional HHT diagnostic criterion, and provoke additional management as detailed in the "What if " section below.

  • As part of a pulmonary AVM screen, many patients have a contrast "bubble" echocardiogram. Identifying an intrapulmonary right to left shunt does not contribute to the diagnosis of HHT, as ~8% of the general population have a positive scan, positive rates increase for people with migraines, and repeated injections in the same study can cause false positives.

  • Cerebral vascular abnormalities that are not arteriovenous malformations (AVMs) or arteriovenous fistulae (AVF), such as, aneurysms, cerebral cavernous malformations, Vein of Galen malformations, and other non AVM/AVF malformations, are not currently thought to be HHT-associated.

If you decide the patient has hereditary haemorrhagic telangiectasia, what therapies should you initiate immediately?

The majority of patients will not require immediate treatment, other than initiation of iron replacement therapy.

If the patient is presenting as a medical or surgical emergency, then management should follow standard emergency management protocols - with the following exceptions:

  • For acute stroke presentations, the possibility of hemorrhagic, ischemic and abscess pathologies need to be considered, with an early cerebral magnetic resonance imaging (MRI) scan to rule out abscess pathology that would require neurosurgical intervention.

  • For acute myocardial infarction (rare), or acute ischemic stroke (more common), HHT would be considered a relative contraindication to thrombolysis (see below).

  • For surgical interventions, the possibility of telangiectasia and enhanced bleeding risk should be appreciated.

  • For countries where nasal intubation is common, the endotracheal route would be preferable for HHT patients.

It is important that the diagnosis of HHT does not restrict full investigation of an emergency clinical presentation. For example, collapse and chest pain are rare in HHT patients even with very low hemoglobin or oxygen saturation, unless there is non-HHT related pathology.

It is also important that the diagnosis of AVMs does not hamper normal speciality-specific approaches to emergency management. For example, where massive hemoptysis occurs in a patient with known PAVMs, it is still likely that systemic arterial feeders to PAVM sacs will be responsible.

More definitive therapies?

HHT-specific treatments focus on removal/obliteration of abnormal vessels by laser therapy, embolization, and surgery. Hormonal manipulation (estrogen/progesterone, tamoxifen), has been proven to be effective to treat nasal and/or gastrointestinal bleeding in small randomised control trials. Tamoxifen is better tolerated than the earlier high dose estrogen-progesterone regimen.

For many years, there has also been widespread use of other agents based on anecdotal responses, case reports, small series, and standard practice in non HHT populations. These include the use of antifibrinolytics such as tranexamic acid and aminocaproic acid, and thalidomide. There is great interest in the development of new medical therapies for HHT, including antioxidants, the selective estrogen receptor antagonist raloxifene, and anti-angiogenesis therapies such as bevacizumab (Avastin) - which has shown promise in early reports. Randomised control trials are currently underway in specialised HHT centres and it is likely that the landscape of HHT treatments will evolve in the next few years.

Nosebleeds

First line: Based on reported benefits and the absence of side effects, nasal humidification using topical creams and sprays have been recommended, although there is no specific evidence base in HHT. Note that many patients also use topical and emergency treatments that they consider to be of benefit. Thus use of tranexamic acid acutely in oral or topical form is common in certain countries, and many patients have their favorite emergency packing device.

Second line treatment has traditionally been dedicated laser therapy: Coagulating lasers (argon or KTP laser) may be preferable to carbon dioxide (CO2) lasers, but the expertise of the operator appears to be more important than the type of laser. Alternatively or in addition, there is randomised control trial evidence of benefit from tamoxifen (20mg/qd) in HHT, but this is not suitable for patients with previous thrombosis, and other standard contraindications apply. It is likely that other second line medical therapies will emerge from current ongoing randomised trials.

Third line (if persisting intolerable bleeds or transfusional requirements): Conventionally, dedicated surgical approaches have been used (septal dermoplasty, Young's procedure [nostril closure]), with long term beneficial reports stated by many patients, though there are no randomised control trials. Newer medical therapies that have significant side effects may be added to these approaches in the future.

Gastrointestinal telangiectasia

In HHT, gastrointestinal tract endoscopic treatments are less successful than in the general population, due to the multiplicity and recurrence of lesions. High dose estrogen-progesterone therapy (including 50ug ethinylestradiol) is of proven benefit for patients with high transfusion requirements. However, side effects made this regimen intolerable for most men, and concern about thrombotic complications has limited its use in women. It is unclear, but likely, that the beneficial effects of tamoxifen will not be limited to nosebleeds.

Mucocutaneous telangiectasia

These can be treated cosmetically, but will recur and generally are left untreated. Specialist attention is required for the occasional lesions that cause problematic oral hemorrhage.

Iron deficiency anemia

The standard approaches for iron replacement and transfusions should be employed as for other chronic anemic states, including improved dietary iron intake, oral iron supplements, parenteral iron preparations and transfusions. It is important to ensure that the frequency and severity of nosebleeds is identified, as this is more commonly the cause of HHT iron deficiency anemia than gastrointestinal bleeding, and nosebleeds are more amenable to therapy (see above).

Pulmonary arteriovenous malformations, cerebral arteriovenous malformations, hepatic arteriovenous malformations and other pathologies

See "What if" scenarios.

What other therapies are helpful for reducing complications?

General:

  • Iron rich diet

  • Optimal dental hygiene

  • Pregnancy advice

  • HHT diagnostic label

Pulmonary AVMs:

  • Antibiotic prophylaxis for dental and surgical treatments (post dates American Heart Association (AHA)/National Institute for Health and Clinical Excellence(NICE)

  • Avoid scuba diving or, if cannot avoid, ensure has received training in safe dive profiles to reduce the liberation of venous bubbles

Hepatic AVMs:

  • Avoid liver biopsy

Cerebral AVMs:

  • None known for HHT. Standard advice for cerebral arteriovenous malformations (CAVMs) in general population varies from no recommendations to avoidance of high g-forces

What should you tell the patient and the family about prognosis?

HHT is an inherited lifelong disorder that can cause some individuals substantial problems and even early death, but overall, for most people, it will be managed successfully and life expectancy is usually normal. Better diagnosis and treatments are preventing many complications and there is active research to improve treatments further. There is also evidence that the more information the individual has about HHT, the better their health will be. This is particularly true for women during pregnancy. For any individual with HHT, each of their children will have a 1 in 2 chance of having HHT.

Even within a family, the pattern of HHT differs completely. Just because one individual has followed a particular course, this does not mean that others in the family will also.

As people get older, the number of blood spots on the skin and in the gut increases, but we do not think that new lung or brain AVMs will develop after puberty for someone who does not have them already. Nosebleeds sometimes get worse with age, sometimes improve, and it is not easy to predict what will happen to any one individual. About 1 in 5 people will also bleed from the gut, and this is more common in older people.

The most important change as people get older, however, is their ability to compensate for changes caused by HHT. The same low oxygen level that was tolerated unknowingly for many years can suddenly appear to have developed in later life, because that was when other aspects of health and cardiovascular fitness worsened.

Just because an abnormal vessel is present, it does not mean that it will cause the individual any problems. For HHT, it is important to be able to live with AVMs; having the best treatments, but accepting when no treatment is the best option at that time.

"What if" scenarios.

Hematological issues arising from nasal and/or gastrointestinal bleeding

Discussed above.

Pulmonary arteriovenous malformations are present

First line treatment is: embolization for all PAVMs of a suitable size, advice for optimal dental hygiene, antibiotic prophylaxis for dental and surgical treatments, and lifestyle advice (scuba diving, pregnancy). Pulmonary hypertension and/or hepatic AVMs with high output cardiac states are relative contraindications to embolization in the non-emergency setting. It is very rare that surgical therapies will be required, even if embolization is not able to occlude all PAVMs.

The 3mm rule is no longer applied, but even so, approximately 70% of treated patients have residual PAVMs that are too small for further embolization. Surgery should generally be avoided because of the likelihood of extensive or recurrent disease. Lung transplantation is not appropriate, due to the longevity of severely hypoxemic patients over many decades, in contrast to 6-7 year 50% survival, post-lung transplant. There are no currently available medical treatments; anecdotal evidence suggests that anti-angiogenic therapies will not have a role, and may be detrimental.

Cerebral arteriovenous malformations are present

The treatment options will depend upon the specific lesion and site, and patient preference. The four options are: embolization, neurosurgery, stereotactic radiotherapy (each of which carries its own risks), and no treatment. The management of unruptured CAVMs in the general population is highly controversial because the limited data available suggest, contrary to expectations, that the long term outcome may be better for untreated patients. The National Institutes for Health (NIH) sponsored Aruba trial is currently recruiting to address this.

It has generally been considered that in HHT, due to the lower rates of AVM-associated aneurysms, AVMs may bleed less frequently than the 2% per annum per year quoted for the general population; however, this would not apply to a rarer, but particularly high risk, HHT lesion in children (arteriovenous fistula). Management in a specialised neurological unit with access to all treatment modalities is strongly recommended.

Hepatic arteriovenous malformations are present

Liver biopsy should be avoided, but otherwise there are no medical recommendations for the asymptomatic patient. Symptoms, if they develop, relate to the type of shunt present: high output cardiac failure +/- post-capillary pulmonary hypertension for hepatic artery-hepatic vein shunts, portal hypertension for hepato-portal shunts, and bile duct necrosis for portal vein-hepatic vein shunts. These should be managed using standard hepatology guidelines.

If medical treatment fails, the treatment of choice is liver transplantation; with greater than 80% 10 year survival reported for HHT patients. If patients are not suitable for transplantation, there may be a role for bevacizumab (Avastin), but there are no randomised control trials or long term outcomes reported. Embolization is not recommended, unless supported by a transplantation program. There is no role for hepatic artery ligation, as used in earlier years.

Prophylactic anticoagulants are required as part of venous thromboemboli prevention

HHT patients are not protected from venous thromboemboli (VTE), and even therapeutic anticoagulation is surprisingly well tolerated. Prophylaxis should be provided according to general population guidelines, including prophylactic heparin.

Antiplatelet therapy is required for cerebral or coronary artery disease

The benefits of antiplatelet therapy will usually outweigh the short term risks of antiplatelet therapy. There is no evidence that antiplatelet agents have precipitated bleeds from arteriovenous malformations. Patients should be warned that their nosebleeds may get worse, and that they may require (further) ear, nose and throat (ENT) intervention, but also informed that many HHT patients experience no increase in nosebleed frequency or iron requirements.

In the author's service, aspirin, clopidogrel (and dipyridamole) have all been used successfully by HHT patients, sometimes in combination and for more than 10 years. However, all have also been associated in some patients with increased nosebleed severity and the need for alternate daily dosing, or even cessation of therapy. Cessation of HHT therapies with procoagulant effects (such as hormones, tamoxifen, tranexamic acid, aminocaproic acid) should be considered.

Anticoagulation is required for venous thromboemboli or other indications

The benefits of anticoagulant therapy are likely to outweigh the short term risks of therapeutic anticoagulation. Despite obvious concern, there is no evidence that anticoagulants have precipitated bleeds from arteriovenous malformations. Patients should be warned that their nosebleeds may get worse, and that they may require (further) ENT intervention, but also informed that many HHT patients experience no increase in nosebleed frequency or iron requirements. In the author's service, heparin, low molecular weight heparin, and warfarin have all been used successfully by HHT patients, some for more than 10 years; however, all have also been associated with reported increases in nosebleed severity in some patients. Cessation of HHT therapies with procoagulant effects (such as hormones, tamoxifen, tranexamic acid, aminocaproic acid) should be considered.

Thrombolysis would be recommended for an individual without hereditary haemorrhagic telangiectasia

Here, HHT is likely to modify risk benefits. While the author is aware of cases where thrombolysis was tolerated (prescribed before the diagnosis of HHT was appreciated), she is also aware of a case where thrombolysis precipitated a terminal PAVM bleed in an emergency situation. HHT would, therefore, appear to be a relative (if not absolute) contraindication to thrombolysis, and the author advises patients in her service to avoid it. Fortunately, HHT patients are relatively protected from ischemic heart disease (for reasons that are not known). Therefore, the question is most likely to arise in the setting of acute ischemic stroke, or acute pulmonary emboli, when benefits of thrombolysis are less well established than for myocardial infarction.

Chest pain is present

HHT generally does not cause chest pain, even when pulmonary AVMs are present. Reports that pleuritic chest pain is present in 10% of PAVM patients most likely reflect ascertainment bias following incidental detection of pulmonary AVMs during imaging investigations performed for suspected pulmonary emboli. Acute chest pain should be investigated and managed as in the general population, with the caution regarding thrombolysis.

An hereditary haemorrhagic telangiectasia patient is experiencing major hemoptysis

Small volume hemoptyses are usually due to nasopharyngeal or posterior nosebleeds. Pulmonary hemorrhage leading to hemoptysis or hemothorax is a relatively rare feature of PAVMs and/or endobronchial telangiectasia. PAVM bleeds are more common in pregnancy, in association with pulmonary hypertension, and in the presence of spontaneous or post-embolization systemic arterial supply to PAVM sacs. In all three settings, hemorrhage may be life-threatening.

Pulmonary hypertension is present

Pulmonary hypertension modifies risk-benefit considerations for PAVM embolization and is a relative, if not absolute, contraindication in the non-emergency setting. It is essential to identify the patient with post-capillary pulmonary hypertension due to hepatic AVMs, when liver transplantation may be the treatment of choice. Otherwise, standard management within specialist pulmonary hypertension services can be followed. Data suggest that patients with pulmonary arterial hypertension due to HHT have a worse prognosis than non-HHT patients with bone morphogenetic protein receptor type II (BMPR2) mutations, but the reason for this is unclear.

The patient is, or wants to become pregnant

There are old literature reports suggesting pregnancy is very hazardous and should not be undertaken. The absolute risk of maternal death is now known to be in the order of 1%, with all maternal deaths occurring in women previously considered well. The risk of death was significantly lower if the diagnosis of HHT or AVMs was already known, but it is not possible to identify women at higher risk of complications. European management recommendations include designation of pregnancies as "high risk"; maternal education to report to hospital if there is haemoptysis or sudden severe dyspnoea and specific obstetric and obstetric anaesthetic considerations based on the assumption that pulmonary and cerebral AVMs are present.

The patient is a child

Children with symptoms require specialist investigation and treatments, guided by knowledge of HHT pathology. The issues regarding screening of healthy children within HHT families (with or without nosebleeds) are controversial, as evidenced by the low rate of agreement for dedicated pediatric HHT guideline recommendations. Current North American practice includes screening for cerebral AVMs from the age of 6 months, and repeating screens to capture AVMs that develop later in childhood. In other healthcare systems, pediatric screening remains a matter of intense discussion.

The patient is going to the dentist

For pulmonary AVM patients, antibiotic prophylaxis is still required, despite the AHA/NICE guidelines, to reduce the risk of brain abscess.

The patient wants to fly

Flying is well tolerated by HHT patients, even those with low hemoglobin and/or oxygen saturations. The most common problem is nosebleed. There is no relationship between rare in-flight complications (dyspnea, deep venous thrombosis, ischemic stroke) and sea level hemoglobin or oxygen saturation. The best predictor of flight tolerance appears to be prior flight experience.

The patient wants to scuba dive

Pulmonary AVMs should be excluded by thoracic CT scan and detailed contrast echocardiograms. If either is positive, advise the patient against taking up diving. For existing divers who wish to continue, reduce their risks by advising on safe dive profiles to reduce the liberation of venous bubbles.

The patient is, or wants to be, a member of military, government or other service with specific health requirements

Liaison with the relevant medical officer is advised.

Pathophysiology

HHT is inherited as an autosomal dominant trait. More than 600 mutations have been identified in different HHT families in: endoglin (HHT type 1), ACVRL1/ALK1 (HHT type 2), or SMAD4 (HHT in association with juvenile polyposis [JPHT]). Most HHT families have mutations in either endoglin or ALK1. No mutation is particularly common in HHT. A mutation database is publically available on the "HHT Mutation Database. Evidence from phenotypic considerations, cellular, molecular and animal models of HHT indicate that HHT mutations result in a haplo-insufficient state; that is, the mutated allele produces insufficient protein for normal function.

All three proteins encoded by the HHT-mutated genes, encode receptors or regulators of transforming growth factor beta (TGF-beta) superfamily signalling in endothelial cells. Both TGF-beta1 and bone morphogenetic proteins 9 and 10 can bind to ALK1, a transmembrane type I receptor for the superfamily, which signals downstream via SMAD-dependent and independent pathways. Endoglin is a transmembrane glycoprotein that can associate with TGF-beta signalling receptors, including ALK1, and modify signalling. SMAD4 is a downstream signalling molecule that translocates to the nucleus where, in association with coactivators and corepressors, target gene transcription is modified.

HHT gene mutations lead to the development of abnormal vascular structures, which range in size from dilated microvessels to large AVMs, measuring several cms in diameter. Generally, HHT telangiectasia are not evident at birth and increase with age, whereas development of AVMs in the pulmonary and cerebral circulations is thought to be near-complete by the end of puberty. The exact mechanisms by which the HHT mutations lead to the vascular abnormalities, and the reason why specific vascular beds are targeted, have not been established. Current evidence focuses on an aberrant response to particular angiogenic stimuli, when HHT gene mutations appear to result in the inability of a blood vessel to mature or repair appropriately.

HHT telangiectasia, particularly in the nose and gastrointestinal tract, are prone to hemorrhage, due to turbulent high pressure flow (arterial pressure) in vessels with fragile wall structures resembling defective veins. Defective wall structures may also contribute to acute hemorrhage from visceral AVMs, although the triggers for these bleeds are not known.

In addition, in HHT, complex pathophysiology results from defective endothelium and blood bypassing key capillary beds (pulmonary, hepatic), with attendant compensatory changes.

What other clinical manifestations may help me to diagnose hereditary haemorrhagic telangiectasia?

If pulmonary AVMs are present, orthodeoxia is frequently observed (lower oxygen saturations on standing).

What other additional laboratory studies may be ordered?

For a patient with malaise and iron deficiency with an apparently normal hemoglobin, check whether hypoxemia is present, providing a polycythemic stimulus, and whether the hemoglobin was previously high. A fall to the 'normal' range due to blood loss may cause significant symptoms in a patient with pulmonary AVMs.

Screening for pulmonary hypertension is not recommended in HHT, but for HHT patients where impaired exercise tolerance and dyspnea is out of proportion to the level of anemia, contrast echocardiography is an appropriate test.

What’s the evidence?

Shovlin, CL, Guttmacher, AE, Buscarini, E. "Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)". Am J Med Genet. 2000. pp. 91;66-67.

[Description of the Curacao Criteria that remain the method by which HHT is clinically diagnosed].

Faughnan, M, Palda, V, Garcia-Tsao, G. "International guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia". J Med Genet. vol. 48. 2011. pp. 73-87.

[Consensus Guidelines generated from the HHT evidence base to October 2006].

Shovlin, CL. "Hereditary hemorrhagic telangiectasia: Pathogenesis, diagnosis and treatment". Blood Reviews. vol. 24. 2010. pp. 203-19 .

[Systematic review article of HHT evidence to late 2010].

Plauchu, H, de Chadarevian Bideau, A, Robert, J-M. "Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population". Am J Med Genet. 1989. pp. 32;291-297.

[The seminal paper describing age-related penetrance in HHT].

Van, Cutsem, Rutgeerts, P, Vantrappen, G. "Treatment of bleeding gastrointestinal malformations with estrogen-progesterone". Lancet. vol. 335. 1990. pp. 953-955.

[Randomised control trial evidence of efficacy for high dose estrogen-progesterone.]

Kjeldsen, AD, Vase, P, Green, A. "Hereditary hemorrhagic telangiectasia: a population based study of prevalence and mortality in Danish patients". J Intern Med. vol. 245. 1999. pp. 31-39.

[Seminal data on prevalence and mortality].

Cottin, V, Plauchu, H, Bayle, J-Y. "Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia". Am J Resp Crit Care Med. vol. 169. 2004. pp. 994-100.

[Evidence for prevalence of CT proven PAVMs and symptoms/complications].

Krings, T, Ozanne, A, Chng, S. "Neurovascular phenotypes in hereditary hemorrhagic telangiectasia patients according to the age. Review of 50 consecutive patients aged 1 day to 60 years". Neuroradiology. vol. 47. 2005. pp. 711-720.

[Illustration of specific subtypes of HHT cerebral vascular malformations with different risk profiles].

Lerut, J, Orlando, G, Adam, R. " Liver transplantation for hereditary hemorrhagic telangiectasia: Report of the European liver transplant registry". Ann Surg. vol. 244. 2006. pp. 854-62.

[Manuscript defining the 82.5% 10 year survival for 48 HHT patients post-liver transplant].

Shovlin, CL, Sodhi, V, McCarthy, A. "Estimates of maternal risk of pregnancy for women with hereditary haemorrhagic telangiectasia: suggested approach for obstetric services". BJOG. vol. 115. 2008. pp. 1108-1115.

[The largest HHT pregnancy series (484 pregnancies) defining a circa 1% maternal death rate, and providing Anglo-French recommendations for pregnancy management].

Shovlin, CL, Jackson, JE, Bamford, K. " Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia". Thorax. vol. 63. 2008. pp. 259-266.

[The evidence that PAVM embolization prevents strokes; stroke/abscess risks with PAVMs less than 3mm in size; and nearly two-thirds of stroke/abscesses occur in patients prior to a diagnosis of PAVMs].

Shovlin, CL, Bamford, KB, Wray, D. " Post NICE 2008: Antibiotic prophylaxis prior to dental procedures for patients with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia". Br Dent J. vol. 205. 2008. pp. 531-3.

[Manuscript co-authored by the chair of the UK Dental NICE Guidelines Committee explaining the differences between PAVM/HHT patients and the cardiac patients for which recommendations changed in 2007/8, and why prophylaxis should still be given].

McDonald, J, Gedge, F, Burdette, A. "Multiple sequence variants in hereditary hemorrhagic telangiectasia cases: illustration of complexity on molecular diagnostic interpretation". J Mol Diagnostics. vol. 11. 2009. pp. 569-575.

[Manuscript highlighting the difficulty in predictive testing with certain HHT genetic lesions].

Yaniv, E, Preis, M, Hadar, T. "Antioestrogen therapy for hereditary hemorrhagic telangiectasia: a double blind placebo controlled trial". Laryngoscope. vol. 119. 2009. pp. 284-8.

[Randomised control trial evidence of efficacy for tamoxifen].
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