Hereditary Hemorrhagic Telangiectasia

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Hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia also known as HHT or Osler-Weber-Rendu syndrome, is a rare autosomal dominant inherited disorder that affects blood vessels throughout the body causing malformations of various blood vessels (vascular dysplasia), potentially resulting in a tendency for bleeding (hemorrhaging) and shunting of blood 1. People with HHT can develop abnormal blood vessels called arteriovenous malformations (AVMs) in several areas of the body 2. Arteriovenous malformations (AVMs) on the skin are called skin telangiectasia (skin lesions resulting from dilation of blood vessels). Arteriovenous malformations (AVMs) can also develop in other parts of the body, including the central nervous system (brain & spinal cord), lungs, liver, and spleen, as well as the urinary tract, gastrointestinal (GI) tract, conjunctiva, trunk, arms, and fingers 3, 4. Up to 10% of HHT patients have brain arteriovenous malformations, 15 to 45% develop lung arteriovenous malformations, and 75% have liver arteriovenous malformations 5. Rupture of these arteriovenous malformations can result in severe complications, including internal hemorrhage, embolic or hemorrhagic stroke, seizures, migraines, or brain abscesses 5. Untreated pulmonary and hepatic arteriovenous malformations can lead to arteriovenous shunting and pulmonary hypertension 6.

Recurrent and severe nosebleeds (epistaxis) is the most common presentation, frequently leading to severe anemia that necessitates transfusion 7. Gastrointestinal (GI) bleeding is also common 8. HHT symptoms can occur at any age, but symptom onset may be delayed until the fourth decade of life (~90% of patients manifest by age 40 years) or later 9.

Hereditary hemorrhagic telangiectasia is caused by changes (mutations) in 5 different genes. It is likely that more genes are yet to be discovered. This genetic mutation causes blood vessels to form abnormally, which can lead to the symptoms of HHT. Mutations in the endoglin (ENG) and ACVRL-1 (or ALK-1) genes account for 80% of all cases of HHT. 3-5% of cases of HHT are caused by a mutation in the SMAD4 (MADH4) gene. A mutation in SMAD4 (MADH4) causes a combined syndrome of juvenile polyps of the gastrointestinal (GI) tract and HHT, also known as JP-HHT. The distribution in gene mutations among HHT patients is predominantly ENG (61%), followed by ACVRL1 (37%), and then MADH4 (2%). Additionally, more than 600 mutations, including deletions, missense, nonsense, and insertions, have been identified in either ENG or ACVRL-1 (ALK-1) genes. A defect in just one of these genes causes an abnormality in the formation of blood vessels, which may easily rupture and bleed 10. The abnormal blood vessels are known as telangiectases (telangiectasia), or arteriovenous malformations (AVM) if larger blood vessels are involved. Normally, arteries and veins are connected by an intermediary capillary system. Arteriovenous malformations (AVMs) and telangiectasias lack this intermediary, with a direct connection between the artery and the vein. Telangiectasias occur on mucocutaneous surfaces, while AVMs are found within internal organs. Histological evaluation of arteriovenous malformations (AVMs) shows irregular endothelium, increased collagen and actin deposition in the basement membrane, and a disorganized basement membrane 11.

Hereditary hemorrhagic telangiectasia affects males and females of all ages in equal numbers and from all ethnic and racial backgrounds.

Hereditary hemorrhagic telangiectasia is estimated to occur in approximately 1 per 5,000 to 1 in 10,000 people worldwide 12. However, because some affected individuals develop few obvious symptoms and findings, the disorder often remains unrecognized. HHT is known to be underdiagnosed. This makes it difficult to determine the true frequency of HHT in the general population.

The diagnostic criteria (Curacao diagnostic criteria) for HHT are 10:

  1. Spontaneous recurrent nosebleeds (90% of people with HHT live with recurring nosebleeds). Nosebleeds in people with HHT can vary in severity from a simple nuisance to bleeds that require blood transfusion.
  2. Multiple telangiectasia on skin and mucous membranes
  3. Involvement of internal organs (gastrointestinal bleeding, pulmonary, hepatic, cerebral, or spinal arteriovenous malformations)
  4. Family history with one affected first-degree relative (parent, sibling or child)

The presence of three of the four criteria indicates a definite diagnosis.

People with a family history of HHT, even those without symptoms, are potentially at-risk for having the condition and associated internal arteriovenous malformations (AVMs). Anyone with a parent, sibling or child with HHT is considered at-risk. Features leading to a suspicion of HHT, like nosebleeds and telangiectasia, often do not appear until adolescence or later, and sometimes never appear. Approximately 10% of adults with HHT do not have nosebleeds and skin telangiectasia can be subtle, so the absence of these signs does not exclude the condition. Lung and brain arteriovenous malformations often don’t cause symptoms, but if it is of a significant size, it can increase the risk for stroke, brain abscess and hemorrhage. Indeed, these serious complications can be the first evidence of the presence of arteriovenous malformations, for which preventive therapy is available.

The most accurate way to determine who in a family has HHT is through genetic testing. A family member with definite HHT, based on clinical findings, is first tested to determine the family’s mutation, which is possible in 85% to 90% of families with HHT. Testing for this known mutation can then be done on at-risk family members with no or minimal symptoms. Only those with the family’s mutation would need HHT evaluation and arteriovenous malformation screening. Since the potentially life-threatening complications associated with HHT are preventable with appropriate treatment and follow-up, we recommend genetic testing and/or screening at-risk family members, even in the absence of symptoms.

HHT cannot be prevented but most cases can be treated symptomatically. Hereditary hemorrhagic telangiectasia treatment is directed at controlling the specific complications and identifying and treating arteriovenous malformations (AVMs). Recently, intranasal topical timolol and 0.1% sirolimus in petrolatum have both been reported to reduce nosebleeds and requirement for blood transfusion 13. Estrogen and/or tamoxifen therapy may decrease the incidence of nose bleeds. Nasal septum skin transplants (septal dermoplasty) may be helpful for long term treatment of nose bleeds. Laser treatment of involved mucosal regions is helpful. Telangiectases or lesions of the skin can be treated with cautery or dye laser surgery, best performed by a dermatologist. Interventional radiology with selective embolization may be useful in treating pulmonary and intracranial AVMs. Gastrointestinal bleeding causing anemia is treated with iron replacement therapy. If this is ineffective, blood transfusion and endoscopic treatments may be performed. Thalidommide can reduce gastrointestinal bleeding and transfusion dependence. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VGEF) delivered intravenously, has dramatically improved some severely ill patients.

Figure 1. Skin telangiectasia in hereditary hemorrhagic telangiectasia

osler weber rendu syndrome
[Source 14 ]

Figure 2. Hereditary hemorrhagic telangiectasia patient with multiple telangiectasias on his lips, neck, tongue, hard palate, finger tips, nail folds and nail beds.

Osler-Weber-Rendu syndrome

Footnote: 22-year-old man with hereditary hemorrhagic telangiectasia presented with multiple bright red punctate macules and papules on his (A) Lips, (B) Neck, (C) Tongue, (D) Hard palate, (E) Finger tips, (F) Nail folds and nail beds. He first noticed them 5 years earlier, and when they did not improve after consultation with a general practitioner, he remained concerned about his appearance. Similar punctate lesions, as well as linear, arciform, and corkscrew-shaped erythematous marks, gradually developed over the buccal mucosae, hard palate, fingertips and nail folds, and sides of the neck. Erythematous linear streaks also were present on the nailbeds of many fingers.

[Source 15 ]

Figure 3. Mouth telangiectasia

hereditary hemorrhagic telangiectasia

Footnote: This is the lower lip of a man in his 50s with hereditary haemorrhagic telangiectasia (HHT), or Osler-Weber-Rendu disease

[Source 16 ]

Is hereditary hemorrhagic telangiectasia considered a “blood disorder” or a “bleeding disorder”?

HHT is a blood vessel disorder that leads to bleeding. People with HHT can develop abnormal blood vessels called arteriovenous malformations (AVMs) in several areas of the body 2. Arteriovenous malformations (AVMs) on the skin are called skin telangiectasia (skin lesions resulting from dilation of blood vessels). Arteriovenous malformations (AVMs) can also develop in other parts of the body, including the central nervous system (brain & spinal cord), lungs, liver, and spleen, as well as the urinary tract, gastrointestinal (GI) tract, conjunctiva, trunk, arms, and fingers 3, 4. Up to 10% of HHT patients have brain arteriovenous malformations, 15 to 45% develop lung arteriovenous malformations, and 75% have liver arteriovenous malformations 5. Rupture of these arteriovenous malformations can result in severe complications, including internal hemorrhage, embolic or hemorrhagic stroke, seizures, migraines, or brain abscesses 5. Untreated pulmonary and hepatic arteriovenous malformations can lead to arteriovenous shunting and pulmonary hypertension 6.

I have hereditary hemorrhagic telangiectasia and want to know if my children have HHT. What do I do?

If you have HHT, there is a 50% chance that your child has inherited the disorder. Establishing a diagnosis at a young age can be crucial to improving their quality of life.

You or another affected family member should seek genetic testing to identify the HHT-associated gene.

  • HHT families will share the same mutation-affected gene, so if one person has been genetically diagnosed, other family members can be diagnosed by comparing DNA.
  • The test ordered to look for a pre-determined, family mutation has several names, including “Site Specific”, “Familial Mutation” and “Targeted Sequencing”.

HHT does not skip generations.

  • If a child tests negative for the family-affected gene, that child does not require any further evaluation and will not pass on HHT to future generations.
  • If you test positive, keep your test results! Your test results can be used to diagnose family members. You should also be screened for manifestations such as arteriovenous malformations (AVMs) in the brain and lungs.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Should children be screened for arteriovenous malformations?

There are currently no standard guidelines for the screening and treatment of lung arteriovenous malformations in children. Based on the fact that some children have had complications from lung arteriovenous malformations, we do advocate screening for all children of a parent with HHT. This screening should start as a baby with pulse oximetry every two or three years. Though oximetry will not detect mildly or moderately decreased oxygen levels, it will detect severely decreased oxygen levels. It seems to be the children who have severely decreased oxygen levels who are at risk for complications. Also, if a child is complaining of shortness of breath when exercising, or is having a hard time keeping up in sports, they should additional testing for lung arteriovenous malformations depending on their age. At the age of 12, all children with HHT should have the same screening for lung arteriovenous malformations recommended for adults. Children can be safely treated with embolization.

Can I play sports with hereditary hemorrhagic telangiectasia?

Regular exercise is important for everybody, and this certainly includes children who have HHT. Most children with HHT can participate in sports at all levels including competitive sports, but there are a few exceptions. Contact sports are not recommended for children with HHT who have brain arteriovenous malformations unless they are completely treated; you should talk to your doctor about that, if you are unsure what the status is. For children with untreated pulmonary arteriovenous malformations, if their oxygen saturation is not normal, strenuous exercise may put them at extra risk and I usually recommend against it until treatment of the arteriovenous malformation has improved the situation. Even if the oxygen saturation is fine at rest, this may change during exercise. In cases where this is not clear, I perform a formal exercise test in the clinic. This also often provides comfort to parents as the test can determine the “safe” level of exercise that their child can participate in. Scuba diving is the one sport that individuals with HHT should avoid because small lung arteriovenous malformations may be present and cause “the bends”.

Is drinking alcohol safe for people with hereditary hemorrhagic telangiectasia?

Alcohol has several effects on the blood which are relevant to HHT patients. First, alcohol acts to inhibit platelet aggregation, meaning the platelets that make your blood clot become less sticky, making your blood thinner. This explains why moderate alcohol consumption (1-2 drinks per day) is thought to be good for heart health, since it may help prevent formation of clots in the heart vessels, which causes a heart attack. However, in an HHT patient, thinning of the blood may cause worsening of nosebleeds or gastrointestinal bleeding.

Alcohol consumption also causes vasodilation, meaning blood vessels can enlarge slightly- this in part can account for the warmth and flushing felt with alcohol. Again, this can be a favorable for narrowed or blocked vessels, in the heart for example, but dilation of the telangiectasias (and the arteries which supply them) in HHT patients could increase bleeding.

Anecdotally, alcohol (particularly red wine) has been one of the most common triggers of nosebleeds in my HHT patients. That being said, a large portion of HHT patients tolerate alcohol without ill effects, which underscores the complexity of the disease and of the blood clotting pathways, which cannot always be predicted in an individual patient. Experts advice HHT patients to enjoy alcohol as they wish, but to pay attention to whether alcohol triggers bleeding – if so, limiting or eliminating alcohol is a reasonable strategy to reduce bleeding.

What are the risks and precautions a hereditary hemorrhagic telangiectasia patient should be aware of when getting a tattoo?

Experts have come to the consensus that it should generally be safe, but you not have a tattoo applied to a visible telangiectasia, as that may bleed quite a bit. Be sure that the skin was carefully cleaned at the site, such as with rubbing alcohol, to avoid any infection, and probably avoid areas that are less sterile such as in the pelvis.

If you have known pulmonary arteriovenous malformations (lung arteriovenous malformations), consider being extra careful by taking a single dose of an antibiotic at the time of the procedure, to avoid any bacteria released from the skin passing through a lung AVM and going to the brain or other places in the body and causing an infection.

As a more general precaution, make sure they use clean needles (to avoid getting infected with HIV or hepatitis) and stick to reputable places, rather than doing it “homemade.”

Is it okay to get my nose pierced if I have HHT?

Experts don’t recommend it as the trauma may result in more telangiectasias on the inside of the nose at the piercing site, and more nosebleeds. But that said, it is ultimately up to the individual.

What are common symptoms of pulmonary arteriovenous malformations and how can they lead to a misdiagnosis?

Pulmonary arteriovenous malformations (lung arteriovenous malformation) are the most common serious problem in patients with HHT and are seen in 30% to 40% of patients. Common symptoms of lung arteriovenous malformation include shortness of breath, low oxygen levels when checked by finger oximetry and hemoptysis (coughing up blood). Shortness of breath and low oxygen levels are often misdiagnosed as other problems such as asthma and heart disease because the standard chest X-ray may be normal, especially if the lung arteriovenous malformation are microscopic. Hemoptysis is less likely to be misdiagnosed because this symptom usually results in checking a CT scan of the chest, which usually finds the lung arteriovenous malformation.

In any case, the best first test for finding lung arteriovenous malformation is a contrast (“bubble”) echocardiogram which shows shunting in the lungs – a characteristic finding of lung arteriovenous malformation. Less common symptoms of lung arteriovenous malformation include stroke and brain abscess (infection on the brain). These may also be misdiagnosed because physicians do not usually look at the lungs in case of these symptoms. Again, a contrast echo should find the lung arteriovenous malformation. Bottom line, if you have any of these symptoms and they are eluding diagnosis or not getting better, please ask your physician to consider lung arteriovenous malformation and ordering a contrast echocardiogram.

What are coils made of and are they safe for an MRI?

  • Stainless steel coils
  • Titanium coils
  • Non-ferromagnetic coils

MRI can be performed at least 6 weeks after coil embolization with stainless steel coils to allow the coils a chance to form scar tissues.

MRI can be performed immediately in patients with titanium and other non-ferromagnetic coils.

It is believed that the benefits of using MRI to rule out brain or spine arteriovenous malformation (10% incidence in HHT) or monitor existing CNS arteriovenous malformation in HHT patients far outweighs the small theoretical risk of complications related to steel coils in the lungs.

Can excessive treatment for nosebleeds permanently harm my nose?

It’s possible to develop a septal perforation, which occurs when cartilage separating the two nostrils (known as the septum) develops a hole or fissure. This can cause a variety of symptoms, most notably nose bleeding. In HHT patients, septal perforation is usually attributed to nasal trauma from aggressive laser or electric coagulation sometimes used in treating epistaxis.

A septal perforation alters the anatomy of the nose, affecting its function. The normal humidity in the nose is decreased by constant airflow across the weak or torn edges of the perforation, causing the site of the perforation to dry out, leading to a crusted or scabbed area likely to bleed. When left untreated, it causes further deterioration of the condition.

The surgical procedure to repair a septal perforation should be performed soon after a diagnosis, and not as a last resort. The goal is to restore normal nasal anatomy and humidification and to reestablish the structural integrity of the nose – it is not a cure for HHT-related epistaxis.

What are the instances when it is permissible for a HHT patient to take a blood thinner?

Many decisions in both life and medicine require that one balances the potential benefits and risks of an action, an intervention or a medication. This is true when one considers the use of blood thinners, especially for a person with HHT.

Blood thinners have been shown to significantly reduce the risk of harm and/or death in a number of conditions, including, but not limited to, heart attacks, atrial fibrillation, stroke and blood clots (both deep venous thrombosis and pulmonary embolism). However, in any patient, blood thinners increase the risk of undesired bleeding. The risk of nosebleeds and gastrointestinal bleeding while taking blood thinner may be higher in some people with HHT compared to those without HHT.

Experience from many HHT Centers of Excellence suggests that at least many HHT patients who take a blood thinner are able to do so without a serious complication and, therefore, are able to benefit from their use 17. At the present time, there is no good way to know who will have a complication from a blood thinner. Based on experience to date, there are no absolute contraindications for the use of a blood thinner in a person with HHT; blood thinners can be used with caution when there is a strong indication and potential benefit for their use.

Is pregnancy safe for someone with HHT?

Yes, as long as the pregnant woman has no untreated lung arteriovenous malformations. Experts strongly recommend that all women known or suspected to have HHT be screened for lung and brain arteriovenous malformation prior to becoming pregnant, or during the early second trimester of pregnancy if a pregnancy is already in process. Serious complications, such as life-threatening bleeding and strokes, have occurred in pregnant women with HHT who had undetected and thus untreated lung arteriovenous malformations. Otherwise, serious HHT-related complications for the mother or baby are rare. Some women report that new skin telangiectases developed during their pregnancy and that their nosebleeds worsen. However, some women actually report an improvement in nosebleeds while pregnant.

Is it safe to take oral contraceptive pills (OCPs) with HHT? What effect do OCPs that contain estrogen have on bleeding?

HHT is not thought to be a contraindication for estrogen or estrogen containing oral contraception pills (OCPs). However, individuals with increased risk of thrombosis or untreated lung arteriovenous malformations should consult with an HHT specialist.

It is recognized in the hematology/bleeding disorders community that estrogen containing oral contraception pills can help in patients with inherited bleeding disorders. Some patients report that being on oral contraception pills actually helps decrease their epistaxis.

When do I need to take prophylactic antibiotics?

Antibiotic prophylaxis is recommend before dental procedures that involve manipulation of the gingival tissues (such as cleaning and extractions) and certain other potentially non-sterile procedures such as surgery on respiratory mucosa. It is not recommended for typically sterile procedures like heart catheterization, gall bladder surgery and gastrointestinal endoscopy. A colonoscopy is a low risk procedure so no antibiotics are recommended.

What should I take for aches and pains or a headache?

Acetaminophen, such as Tylenol, is recommended for HHT patients to treat minor aches, pains and reduce fever.

NSAIDS (nonsteroidal anti-inflammatory drugs) such as aspirin, ibuprofen (Motrin, Advil), celecoxib (Celebrex) and others are not recommended for HHT patients. NSAIDS are a drug class that reduce pain, decrease fever, prevent blood clots and decrease inflammation. Increased bleeding can occur in HHT patients with these medications.

There are circumstances when HHT patients need to take NSAIDS but this should be under the direction of your doctor.

Can an HHT patient have total hip replacement? Is it safe to use blood thinners?

There is really no reason why an HHT patient can’t have hip replacement, though the blood thinners are a potential issue. Blood thinners are important to reduce the risk of blood clots during and after the surgery, but are not mandatory. About half of patients with HHT have increased bleeding while on blood thinners, but half don’t. One option would be a trial of blood thinners before the surgery to see how you do. If bleeding gets a lot worse, you could work on fixing that problem before the surgery.

Hereditary hemorrhagic telangiectasia types

HHT type 1

Hereditary hemorrhagic telangiectasia type 1 or HHT type 1 is caused by a mutation (change in the DNA sequence) in the ENG gene. Lung and brain arteriovenous malformations (AVMs) are more common in patients with HHT type 1.

HHT type 2

Hereditary hemorrhagic telangiectasia type 2 or HHT type 2 is caused by a mutation in the activin receptor-like kinase 1 (ACVRL1) gene and abnormalities of the protein in encodes (ALK1). Liver arteriovenous malformations (AVMs) are more common in people with HHT type 2.

HHT Associated with Juvenile Polyposis (JPHT or JP-HHT)

HHT associated with Juvenile Polyposis (JPHT or JP-HHT) is due to a mutation in the gene Mothers Against Decapentaplegic homolog 4 (MADH4) that codes for the transcription factor SMAD4, a critical downstream effector of TGF-B signaling 18. The mutations in JPHT are located on the last four exons of SMAD4 (MADH4) gene and include several mutation types, including nonsense, missense, frameshift, and de novo 6.

Hereditary hemorrhagic telangiectasia cause

Hereditary hemorrhagic telangiectasia (HHT) is caused by changes (mutations) in 5 different genes. It is likely that more genes are yet to be discovered.

Mutations of the ENG gene on chromosome 9 and abnormalities of the protein it produces (endoglin) result in HHT type 1 19. Endoglin is found on the surface of the cells that line the inside of the blood vessels. Scientists believe that endoglin binds to transforming growth factor-beta (TGF-ß). In mice that are deficient in endoglin, the blood vessels do not mature and there is a failure in vascular smooth muscle development 20. The loss of vascular integrity, combined with constant pressure, results in the formation of telangiectasias (dilated microvessels) and large arteriovenous malformations (AVMs) 21. Due to the decreased elasticity of the blood vessel walls and dilation of the vascular lumen, telangiectasias are fragile and more prone to hemorrhage. Arteriovenous malformations (AVMs) can form in the brain, lungs, gastrointestinal tract, spine, or liver 21.

Mutations of the activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 and abnormalities of the protein in encodes (ALK1), result in HHT type 2 22. People with mutations in this gene are more prone to complications from liver arteriovenous malformations such as liver failure and elevated pressure on the right side of the heart (pulmonary hypertension).

Approximately 1-2% of individuals with HHT have a combination of HHT and juvenile polyposis known as JPHT (or JPHHT) overlap syndrome, a disorder involving polyps in the gastrointestinal tract. This type of HHT is caused by mutations in the SMAD4 gene.

Mutations in the BMPR9 and RASA1 genes produce syndromes that share phenotypic overlap with HHT including atypical telangiectases (similar to cutaneous capillary malformations), mild nosebleeds and arteriovenous malformations typically in the brain and soft tissue. Whether these syndromes are truly HHT or merely HHT look-alikes remains controversial.

With the exception of RASA1, the genes that cause HHT encode for proteins involved in the TGF-ß/BMP (for bone morphogenic protein) superfamily of signaling. This group of proteins helps regulate many cellular functions such as cell survival, proliferation and differentiation. With malfunctioning signaling, the cells formation of blood vessels (angiogenesis) is defective, causing the clinical features of HHT.

Hereditary hemorrhagic telangiectasia inheritance pattern

HHT is inherited in an autosomal dominant pattern, which means that only one abnormal gene needs to be inherited from one affected parent to express the disease. In autosomal dominant disorders, only a single copy of the disease gene (received from either the mother or father) is required to cause the disease. The risk of transmitting HHT from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females. However, the signs and symptoms of HHT within a single family can vary considerably. One family member may suffer from severe recurrent nosebleeds whilst another with HHT may have minimal symptoms.

Each child born to an HHT parent has a 50% chance of inheriting the HHT gene mutation. One copy of each gene is inherited from the father and the other copy from the mother. People with HHT have one normal copy of the HHT gene and one mutated copy. When a person with HHT has a child, he or she will either pass on the normal copy of the gene or the copy with the mutation. A child who inherits the gene with the mutation will have HHT. A child who inherits the normal copy of the gene will not have inherited HHT. Therefore, each time a person with HHT has a child, there is a 50% chance that the child will have HHT.

In rare cases, hereditary hemorrhagic telangiectasia occurs randomly as the result of a spontaneous genetic change (i.e., new mutation). All relatives affected in a family with HHT will have the same mutation. However, in different families the causative mutation is usually different, with over 900 different mutations found within the five genes known to cause HHT.

Figure 4. Hereditary hemorrhagic telangiectasia inheritance pattern

Hereditary hemorrhagic telangiectasia autosomal dominant inheritance pattern

Can HHT skip generations?

No. Each child born to an HHT parent has a 50% chance of inheriting the HHT gene mutation. One copy of each gene is inherited from the father and the other copy from the mother. People with HHT have one normal copy of the HHT gene and one mutated copy. When a person with HHT has a child, he or she will either pass on the normal copy of the gene or the copy with the mutation. A child who inherits the gene with the mutation will have HHT. A child who inherits the normal copy of the gene will not have inherited HHT. Therefore, each time a person with HHT has a child, there is a 50% chance that the child will have HHT.

At the genetic level, you either have HHT or you don’t. There is no such thing as being a carrier of HHT (that term is reserved for genetic disorders that are recessive, not dominant like HHT). If a grandparent and grandchild both have HHT, it can safely be assumed that the “parent” in between the two also has HHT. However, since symptoms of HHT can be EXTREMELY variable even within the same family, it is possible that the “parent” shows such mild symptoms that are not obvious, it could make it seem like HHT skipped a generation. For example, some people with HHT get multiple nosebleeds per day, while some people only get a couple per year.

Hereditary hemorrhagic telangiectasia signs and symptoms

The symptoms associated with HHT vary from person to person. Differences in disease expression (phenotype) partially reflect the specific gene that is mutated in HHT. Phenotypic penetrance is age dependent with approximately 90% showing signs or symptoms by age 40-45 years. Some individuals may experience symptoms during infancy or early childhood; others may show few signs or symptoms until the thirties, forties or later in life.

In many patients, the most common sign of HHT is telangiectases in the nose and the most common symptom is recurring nosebleeds (epistaxis). While recurrent nosebleeds may develop as early as infancy they most often begin around puberty or adulthood with the average age of the first nosebleed occurring at 12 years. Recurrent nosebleeds are seen in 50-90% of patients with HHT. Bleeding may occur as often as everyday or as infrequently as once a month. Nosebleeds occur because of the formation of small, fragile vascular malformations (telangiectases) in the mucous membranes lining the inside of the nose. Telangiectases occur when capillaries fail to develop between arterioles and venules and most often affect the skin and the mucous membranes. The tongue, lips, face, ears, and fingers are the areas most often affected. Telangiectases may develop at any age including during infancy, but usually become apparent during adolescence and later.

Telangiectases in other parts of the body is not usually seen until after puberty and is most apparent in people aged between 20 and 40 years. It occurs in about 95% of patients with HHT. Telangiectasia of the skin and mucous membranes has the following characteristics.

  • Appearance of small red to purplish spots or dark red lacy lines on the skin and mucous membranes
  • Lesions may occur anywhere but especially on the upper half of the body including the face, inside the mouth and nostrils, lips, ears, conjunctiva of the eyes, forearms, hands and fingers.
  • They are often conspicuous in the nail beds.
  • Lesions may initially appear subtle but become quite prominent by late adulthood
  • Telangiectases on the skin and mouth can bleed but are less likely to than those in the nose

In addition to visible telangiectases, abnormal blood vessel formation may occur in many other organs. Telangiectases can also be found anywhere in the gastrointestinal (GI) system, including the esophagus, stomach, and small and large intestines. Gastrointestinal bleeding (hemorrhaging) occurs in about 25-30% of patients with HHT and the risk is increased in patients older than 50 years. Affected individuals with gastrointestinal bleeding may note dark stools – sometimes black and tarry (melena) – but only rarely do they have red blood in their stools (hematochezia) or vomit (hematemesis). Commonly, blood loss is not detected by the patient, even when it leads to anemia (low red blood cell count). Because bleeding episodes become more severe with age, they often lead to chronically low levels of iron in the blood and eventually to anemia. Anemia may result in chest pain, shortness of breath, and/or fatigue. Gastrointestinal bleeding can often be slow, chronic and intermittent, with few noticeable symptoms until the onset of anemia.

Many individuals with HHT develop arteriovenous malformations (AVMs). Arteriovenous malformations (AVMs), which are direct connections between blood vessels of larger caliber than in telangiectases, most commonly affect the lungs (in about 50% of patients with HHT), central nervous system (brain and spinal arteriovenous malformation), and liver. In recent years arteriovenous malformation have been noted in the pancreas, kidneys, and other organs, though they rarely cause complications in these locations.

Pulmonary arteriovenous malformations are seen in about 50% of individuals with HHT and are often asymptomatic. However, they may result in fatigue, difficulty breathing (dyspnea), episodes of coughing up of blood (hemoptysis), headaches, abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis) and/or abnormally increased levels of red cells in the blood (polycythemia). Serious neurological complications, including brain abscess and stroke, may occur due to passage of blood clots or bacteria through a pulmonary arteriovenous malformations.

Arteriovenous malformations of the brain occur in about 10% of individuals with HHT and may result in headache, dizziness (vertigo), and seizures. In rare cases, individuals with arteriovenous malformations of the brain may experience vision and hearing problems such as double vision (diplopia). However, usually they are asymptomatic prior to a hemorrhagic event. arteriovenous malformations affecting the spinal cord (approximately 1% of those with HHT) are less common and may result in pain in the back and/or loss of feeling or functions of the arms and legs.

Liver vascular malformations are seen in up to 75% of individuals with HHT. In most cases they remain asymptomatic, though over time 10-20% may develop liver or heart failure. Individuals may experience high blood pressure in the veins carrying blood from the gastrointestinal tract back to the heart through the liver (portal hypertension) and abnormalities of the bile ducts (biliary disease). The bile ducts are narrow tubes through which bile passes from the liver to the first section of the small intestine. Pressure on bile ducts from enlarged blood vessels may result in failure of bile to flow to the small intestine, instead becoming trapped in the liver, resulting in yellowing of the skin and the whites of the eyes (jaundice).

Shunting of blood through liver arteriovenous malformation may result in excessive blood flow through the liver. Over time, high output heart failure may occur because the heart is forced to work harder to compensate for the extra blood flow through the liver, in addition to the normal blood flow to the rest of the body.

Hereditary hemorrhagic telangiectasia complications

Patients with hereditary hemorrhagic telangiectasia (HHT) are at substantially increased risk of serious bleeding and neurologic complications, including anemia, cerebral abscess, stroke, venous thrombosis, and heart failure 5.

Table 1. Hereditary hemorrhagic telangiectasia complications

Complication Treatment/Prevention
Iron DeficiencyAnnual screen with complete blood count, ferritin, total iron-binding capacity [TIBC], and reticulocyte count
Replete iron either via oral or IV when ferritin is less than 50
Cerebral AbscessScreen and embolization of pulmonary AVMs
Infection prophylaxis with antibiotics before procedures
Paradoxical StrokeScreen and embolization of pulmonary AVMs
Replete iron either via oral or IV when ferritin is less than 50
Iron deficiency seems to increase the risk of thrombotic events
Venous ThrombosisReplete iron either via oral or IV when ferritin is less than 50
Iron deficiency seems to increase the risk of thrombotic events
Anticoagulation is not contraindicated but has been discussed with specialists
Heart FailureCheck for annual brain natriuretic peptide (BNP) in the presence of
Hepatic AVMs
[Source 23 ]

HHT Screening Guidelines

There are several tests that everyone who is known or suspected to have HHT should have done. These are called screening tests since the abnormality is looked for prior to causing a problem. Lung arteriovenous malformations and brain arteriovenous malformations are the only problems associated with HHT for which experts recommend pre-symptomatic, preventive screening.

A screening test will 24:

  • Confirm you meet the criteria for a diagnosis of HHT
  • Look for pulmonary (lung) arteriovenous malformations and cerebral (brain) arteriovenous malformations since these can cause serious life-threatening events without warning
  • Identify additional areas of impact from HHT

Pediatric screening

Pediatric care recommendations:

  • Diagnostic genetic testing should be offered for asymptomatic children of a parent with HHT.
  • Screening for pulmonary arteriovenous malformations in asymptomatic children with HHT or at risk for HHT at the time of presentation / diagnosis.
  • Large pulmonary arteriovenous malformations and pulmonary arteriovenous malformations associated with reduced oxygen saturation should be treated in children to avoid serious complications.
  • Repeating pulmonary arteriovenous malformation screening in asymptomatic children with HHT or at risk for HHT; typically, at 5-year intervals
  • And screening for brain VMs in asymptomatic children with HHT, or at risk for HHT, at the time of presentation / diagnosis is recommended. Brain arteriovenous malformations with high risk features should be treated.

According to the Clinical Guidelines 25, there is no consensus on the recurring tests of children with HHT. However, it is recommended by most HHT Centers that:

  1. Children with possible or confirmed HHT should be screened for brain arteriovenous malformations in the first year of life (or at the time of diagnosis) and at least one follow-up MRI at puberty since brain arteriovenous malformations development appears to correlate with times of growth.
  2. Lung arteriovenous malformation screening is recommended every 3-5 years, if a pulse oximetry test result is 97% or higher. If a pulse oximetry result is lower than 97%, or a child is short of breath, additional tests or treatment may be required.

Pulmonary arteriovenous malformation screening

Based on the fact that some children do have complications from Parteriovenous malformations, HHT medical professionals currently advocate screening for Parteriovenous malformation in all children of a parent who has HHT 25.

  1. Pulse oximetry PLUS chest X-ray.
  2. Transthoracic contrast echocardiography (TTCE; also called bubble echo) has a higher sensitivity as a screening test for pulmonary arteriovenous malformations. TTCE has the advantage of being a non-radiating test and is the recommended screening test for symptomatic children who have low oxygen levels, complain of shortness of breath, have a hard time keeping up in sports, or have had prior neurologic complications.

When screening tests for Parteriovenous malformations are positive, CT is the next step to determine where the Parteriovenous malformations are located and if they are large enough to treat.

Adult screening

Pulmonary arteriovenous malformations (lung arteriovenous malformations)

Clinicians should screen all patients with possible or confirmed HHT for pulmonary arteriovenous malformations (lung arteriovenous malformations).

At least 40% of people with HHT have pulmonary (lung) arteriovenous malformations. They are often unaware of their lung arteriovenous malformations until they develop a life-threatening complication. Screening and treatment can prevent life-threatening complications. Pulmonary (lung) arteriovenous malformations have been shown to be associated with disabling and life-threatening complications, such as stroke, transient ischaemic attack (TIA), cerebral abscess, massive haemoptysis and spontaneous haemothorax in retrospective series 26, 27. The neurological complications are presumed to occur via paradoxical embolisation through pulmonary (lung) arteriovenous malformations, whereas the hemorrhagic complications occur due to spontaneous pulmonary (lung) arteriovenous malformations rupture. These complications have been demonstrated in largely adult series of HHT patients, although they have also been demonstrated in a paediatric HHT series 28, albeit smaller in size. There have also been small series reporting these same complications during pregnancy 29 and the expert panel agreed that the complication risk appears to be greater during pregnancy.

Screening for lung arteriovenous malformations (lung arteriovenous malformation) is dependent on the age of the individual, and to a lesser degree, their symptoms. Preferably, individuals with HHT will have had screening for Parteriovenous malformations by the time of their early teens. If a pregnant woman with HHT has not had a recent evaluation for pulmonary (lung) arteriovenous malformations, it is imperative for her to do so as soon as pregnancy is recognized. In many cases, an HHT Treatment Center will be able to use tests performed by another facility unless the original tests are too old, the old test is not of high enough quality, or the old test was performed a little differently.

Pulmonary (lung) arteriovenous malformations larger than a certain size should be embolized to prevent complications like brain abscesses and strokes. For smaller pulmonary (lung) arteriovenous malformations, antibiotics prior to most dental work and certain other non-sterile invasive procedures, like colonoscopy, are recommended. Until pulmonary (lung) arteriovenous malformations are excluded by testing, a person over the age of 10 with known or suspected HHT should take antibiotics before all dental cleanings, work and other medical procedures which have a risk of introducing bacteria into the bloodstream.

  • Contrast Echocardiogram (bubble echo). This is the recommended test of choice for pulmonary (lung) arteriovenous malformations screening in adults and also used in older children and adolescents. This test uses sound waves (ultrasound) to determine if injected saline bubbles can get through the lung circulation and be seen back in the heart, on the left side. This would be called a shunt. It is a very sensitive test but not everyone with a “positive” or “abnormal” bubble echo test has a pulmonary (lung) arteriovenous malformation large enough to require treatment by embolization. To determine if treatment is necessary, a chest CT scan should be done if the bubble echo is more than minimally abnormal.
  • Chest X-ray. A standard X-ray of the lungs will let doctors look at the size of your heart and the condition of your lungs.
  • Shunt test. During this test you breathe pure oxygen for 15 minutes with a nose clip on, then a small sample of arterial blood is collected from an artery in your wrist. This is not a routine screening test, but rather is used to assess a patient before and after treatment for pulmonary (lung) arteriovenous malformations.
  • CT Scan of the Lungs. This is like a 3-dimensional high-resolution X-ray of your lungs. If “X-ray dye” is used, an IV will need to be started.
  • Pulmonary Angiogram. A catheter is inserted through a large vein in either your leg or neck, and is passed up into the arteries of the lungs. This involves one or more injections of “X-ray dye” into the arteries to expose the arteriovenous malformation.

Brain (cerebral) arteriovenous malformation

The rationale for screening for brain arteriovenous malformations in HHT is that screening will detect a treatable brain arteriovenous malformation before the development of a life threatening or debilitating complication.

To screen for brain arteriovenous malformation, an MRI with and without gadolinium dye is recommended. Since brain arteriovenous malformations can cause brain hemorrhage in infants, a brain MRI early in life is recommended.

No evidence exists at this time to recommend follow-up screening after an initial negative study during childhood, but consideration should be given to one adulthood MRI following initial negative childhood MRI 24.

Gastrointestinal bleeding

  • Mild HHT-related gastrointestinal bleeding: Patient who meets their hemoglobin goals* with oral iron replacement.
  • Moderate HHT-related gastrointestinal bleeding: Patient who meets their hemoglobin goals* with IV iron treatment.
  • Severe HHT-related gastrointestinal bleeding: Patient who does not meet their hemoglobin goals* despite adequate iron replacement or requires blood transfusions.

* Hemoglobin goals should reflect age, gender, symptoms and comorbidities.

An upper endoscopy is the first line diagnostic test for suspected HHT-related bleeding. Patients who meet colorectal cancer screening criteria and patients with a SMAD4 genetic variation (genetically proven or suspected) should also have regular colonoscopies.

Capsule endoscopy is recommended for suspected HHT-related bleeding when upper endoscopy does not reveal significant HHT-related telangiectasia.

Approximately 3% of HHT patients have the SMAD4 mutation and overlap with juvenile polyposis syndrome. These patients are at high risk of colorectal cancer and should be screened frequently starting at age 15. HHT patients without Juvenile Polyposis have colorectal cancer risks like the general population. Patients with the SMAD4 mutation are also at risk for heart and joint problems and require appropriate screening 24.

Liver arteriovenous malformation

Diagnostic testing is recommended for liver arteriovenous malformations in HHT patients with symptoms and/or signs suggestive of complicated liver arteriovenous malformations such as heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension or encephalopathy.

Doppler ultrasound, CT scan or contrast abdominal MRI are used to diagnose liver arteriovenous malformations.

  • Doppler ultrasound has been proposed as the preferred first-line investigation for the assessment of liver arteriovenous malformations due to its safety, tolerability, low costs and accuracy for the detection of liver arteriovenous malformations
  • CT has been recommended previously when expertise in Doppler US is lacking for diagnosing liver arteriovenous malformations
  • Magnetic resonance imaging (MRI) of the liver provides excellent accuracy with both multiphase anatomic assessment and hemodynamic characterization of liver arteriovenous malformations

If a liver arteriovenous malformation has been detected, echocardiographic evaluation is recommended to see how liver arteriovenous malformations impact heart function.

In those with signs or symptoms of heart failure and an intermediate or high probability of pulmonary hypertension, right-heart catheterization should be performed to accurately assess cardiac and pulmonary hemodynamics 24.

Referral is needed for liver transplant in patients with symptomatic complications of liver arteriovenous malformations.

Liver biopsy should be avoided in any patient with proven or suspected HHT.

Hepatic artery embolization should be avoided in patients with liver arteriovenous malformations as it is associated with significant morbidity and mortality.

Anemia

HHT patients who are adults (regardless of symptoms) and all children with recurrent bleeding and/or symptoms of anemia should be screened annually.

Screening for anemia typically involves: complete blood count (CBC), iron panel (serum iron, total iron binding capacity, transferrin saturation), and ferritin. A CBC alone could miss underlying iron deficiency without anemia.

Pregnant women screening

Pregnant HHT patients should consult an HHT expert to make the best decisions for their specific pregnancy. Each pregnant person with HHT has different symptoms and they will need personalized advice. With the right screening, most women with HHT can have a normal pregnancy and delivery with no more risk than a woman without HHT.

Brain arteriovenous malformations screening

0.5% of unscreened women will present with a brain bleed during pregnancy or after they give birth. In cases of prior bleeding of brain arteriovenous malformations, the risk of re-bleeding is increased. This risk is up to 30%, mainly in the 2nd/3rd trimester and after birth.

Screening recommendations:

  • Asymptomatic patients do not require routine brain arteriovenous malformations screening during pregnancy. Around 10% of women with HHT will present with asymptomatic brain arteriovenous malformations. If a woman has no symptoms, in most cases, treatment of brain arteriovenous malformations will be deferred until after pregnancy due to the low risk of bleeding.
  • Pregnant women with HHT who have symptoms suggestive of brain arteriovenous malformations, including those with previous brain bleed, should be screened for brain arteriovenous malformationss using unenhanced (without gadolinium) MRI in the second trimester

Pulmonary arteriovenous malformations screening

During pregnancy there is an increase in cardiac output, an increase in blood volume, and high progesterone levels. This combination can result in enlargement and/or rupture of pulmonary (lung) arteriovenous malformationss during pregnancy.

Pulmonary (lung) arteriovenous malformationss can occur at any time during pregnancy. 85-90% of complications occur in the second or third trimesters. For previously treated pulmonary (lung) arteriovenous malformationss, the risk of complications during pregnancy is not precisely known, but may be about ~5%.

Pulmonary (lung) arteriovenous malformations screening recommendations for pregnant women:

  • In asymptomatic patients, initial pulmonary arteriovenous malformations screening should be performed using either agitated saline transthoracic contrast echocardiography (TTCE) or low-dose non-contrast chest CT, depending on local expertise. Chest CT, when performed, should be done early in the second trimester.
  • In patients with symptoms suggestive of pulmonary arteriovenous malformations, diagnostic testing should be performed using low-dose non-contrast chest CT. This testing can be performed at any gestational age, as clinically indicated.
  • Pulmonary arteriovenous malformationss should be treated starting in the second trimester unless otherwise clinically indicated.

Screening frequency recommendations:

  • Screening and treatment of pulmonary (lung) arteriovenous malformationss should occur as early as possible at ~12-20 weeks.
  • For patients who have had prior negative pulmonary (lung) arteriovenous malformations screening, additional screening during pregnancy is not needed in the absence of symptoms.
  • Pregnant people with HHT who have not been recently screened and/or treated for pulmonary arteriovenous malformations should be screened and treated in pregnancy.

There is a procedural risk for pulmonary (lung) arteriovenous malformations embolization, which includes bleeding, TIA/stroke, and sedation reaction, but this risk is <1% of cases and are usually minor.

Uterine arteriovenous malformations

  • Uterine arteriovenous malformationss are more likely related to previous uterine procedures
  • Treatment: Uterine artery embolization

Hereditary hemorrhagic telangiectasia diagnosis

A diagnosis of hereditary hemorrhagic telangiectasia is made based upon a detailed patient and family history, a thorough clinical examination, and imaging studies to identify characteristic findings in organs. An international group of experts on HHT established diagnostic criteria for hereditary hemorrhagic telangiectasia. The four criteria (Curacao diagnostic criteria) are:

  1. Spontaneous recurrent nosebleeds (90% of people with HHT live with recurring nosebleeds). Nosebleeds in people with HHT can vary in severity from a simple nuisance to bleeds that require blood transfusion.
  2. Multiple telangiectases on skin and mucous membranes
  3. Involvement of internal organs (gastrointestinal bleeding, pulmonary, hepatic, cerebral, or spinal arteriovenous malformations)
  4. Family history with one affected first-degree relative (parent, sibling or child)

A diagnosis is definite if at least three of the four criteria are present.

Molecular genetic testing is available to determine if a mutation is present in ENG, ACVRL1, SMAD4, RASA1 or BMPR9 genes. This testing is particularly important for children of an affected parent whose mutation is known because each child has a 50% chance to inherit the mutation for HHT but may be too young to show signs. Appropriate screening and treatment, if necessary, can begin earlier for those found to carry an abnormal gene. Genetic testing will detect the mutation in nearly 90% of people who meet clinical criteria for definite HHT.

Genetic Testing for hereditary hemorrhagic telangiectasia

Genetic testing is a type of laboratory test used to diagnose inherited diseases like HHT. In patients with a positive family history of HHT, the presence of a visceral arteriovenous malformation essentially confirms the diagnosis since arteriovenous malformations are rare in the general population. For unaffected patients with a parent with HHT, the disease cannot be ruled out due to variable age-related onset of signs and symptoms. European studies on HHT patients estimate the probability of clinical HHT in patients with an affected family member to range from 0.5, 0.22, and 0.01 at 0-, 16-, and 60 years 30.

HHT-associated genes

  • 80% of people who meet the clinical diagnostic criteria for HHT are found to have a mutation in either the ENG (HHT type 1) or ACVRL1 (HHT type 2) gene
  • 3-5% of clinically diagnosed individuals test positive for a mutation in the SMAD4 gene, which causes a combined syndrome of HHT and Juvenile Polyposis (JP-HHT)
  • About 10-15% of patients will not have a mutation detected in a known HHT gene, and in these cases a diagnosis is made based on clinical evaluation alone*
  • Although a handful of people in the world with HHT have been reported to have a mutation in the BMP9/GDF2 gene, it is so rare (<<1%) that it is not typically a part of routine genetic testing for HHT.

*Because 15% of people diagnosed with HHT do not have a mutation in one of the identified HHT genes, a negative genetic diagnosis does not necessarily mean that a person does not have HHT. There are likely other genes that cause the symptoms of HHT that have not yet been identified.

DNA (genetic material carried in cells) is extracted from a small sample of blood or saliva and analyzed to identify a change (mutation) in one of the HHT genes. Once genetic testing has established the gene mutation which causes HHT within a particular family, this information can be used to help diagnose other members of the family.

Unless HHT is ruled out by genetic testing, all children of a parent with HHT should be screened for brain and lung arteriovenous malformations. For young children, these procedures require sedatives, or general anesthesia, but they are critical to establishing proper diagnosis and care. If an HHT mutation has already been identified in a family, genetic testing of at-risk family members for the known mutation will identify which family members have HHT and therefore need to be screened for internal arteriovenous malformations.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Possible results of a genetic test for HHT

If you are the first member of your family to be genetically tested to identify the gene mutation that causes hereditary hemorrhagic telangiectasia (HHT) in your family, there are three possible results:

  1. Positive for a “pathogenic” (HHT- causing) mutation; the laboratory found a mutation (change in DNA) in one of the HHT-associated genes, and the mutation is thought to cause HHT. This means that you have been genetically diagnosed with HHT and your DNA results can be used to help identify other affected family members.
  2. Negative. In most scenarios, this means a person does not have HHT. In 10-15% of cases, a negative result indicates that a person has HHT, but the affected gene is still unknown.
  3. Variant of Uncertain Significance. This means a genetic variant is detected in one of the HHT genes, but it is not possible to confirm that it is the cause of HHT.

If you are being genetically tested for the specific HHT-causing mutation that was identified in a family member, there are two possible results:

  1. Positive. This result means that the family HHT gene mutation is present, and that you have HHT.
  2. Negative. This result means that the family HHT gene mutation is not present, and that you did not inherit HHT.

Clinical testing and work-up

After a diagnosis of hereditary hemorrhagic telangiectasia has been made from clinical assessment, detailed family history and/or genetic testing, an individual with HHT should have screening for asymptomatic arteriovenous malformations and treatment of existing problems. Current symptoms will be identified and severity assessed for best possible treatment (for example nosebleeds). Standard screening tests for adults in North America include bloodwork to look for iron deficiency anemia, brain MRI with gadolinium to look for brain arteriovenous malformation (AVMs), contrast echocardiography to look for lung arteriovenous malformation and liver imaging (ultrasound, MRI or CT with contrast) to look for liver arteriovenous malformation. Pediatric patients should have a brain MRI with gadolinium and also be screened for lung arteriovenous malformation but the optimal method is controversial; some centers use contrast echocardiography while others use pulse oximetry. If contrast echocardiography shows more than mild right to left shunting, CT of the chest with or without contrast is usually the next step to look for pulmonary arteriovenous malformation. If the child’s brain has no vascular malformations, the imaging should be repeated at least one more time in late adolescence. If the brain is unaffected in late adolescence, then it does not need to be screened again. Finally, patients will be referred to organ specialists for the various systems affected by HHT (lungs, liver, gastrointestinal tract, brain). Those specialists will consult with the patient to determine appropriate treatments or frequency of additional screening for arteriovenous malformations (AVMs).

Hereditary hemorrhagic telangiectasia treatment

The treatment of hereditary hemorrhagic telangiectasia is directed at specific symptoms present in each individual, as well as surveillance for undiagnosed arteriovenous malformations (AVMs). One third of the cases of HHT are mild, one third are moderate, and one third are severe 10. Mild cases usually require no treatment. HHT should be treated if it is causing significant problems, such as severe and/or frequent nosebleeds, or if there is a high risk of causing other problems, such as a stroke from a lung arteriovenous malformation (AVM).

All patients with nosebleeds should use some type of nasal lubrication to prevent nosebleeds such as Vaseline, saline spray, or other products. Nasal trauma such as hard blowing, bumping or picking should be avoided. If conservative measures are insufficient, then oral tranexamic acid or surgical ablation using laser, bipolar cautery, coblation or sclerotherapy should be considered. Tranexamic acid is an antifibrinolytic agent that has been shown to be beneficial in two randomized clinical trials and seems to help about 50% of patients. Surgical ablation is best performed by a specialist (rhinologist) experienced with HHT and is usually >90% effective but the benefit typically lessens after 3-12 months. For patients who fail moisturization, tranexamic acid and ablative measures, systemic antiangiogenic agents should be considered. More aggressive surgical therapies including nasal closure and skin grafts are possible when the patient remains severely anemic from nasal blood loss.

Patients with even small lung arteriovenous malformation should receive antibiotic prophylaxis before dental procedures below the gum line, dental hygiene and potentially non-sterile surgeries such as rectal surgery. Small lung arteriovenous malformation should also be monitored for growth every 5-10 years with either CT scanning or contrast echocardiography, depending on the patient. For patients with lung arteriovenous malformations that have a feeding artery of >2-3 mm in diameter, transcatheter embolization therapy, usually with coils or plugs, is currently recommended.

Brain arteriovenous malformations are usually treated by surgical removal, embolization, or treatment of the affected area with focused radiation (gamma knife). Such treatment should usually be provided at an HHT center or other center with expertise in brain vascular malformations.

Because of the risk of complications, treatment of arteriovenous malformations affecting the liver is usually only undertaken if an individual has symptomatic liver failure or high output heart failure. First line treatment for heart failure includes diuretics and correction of anemia and atrial fibrillation if present. For refractory cases, liver transplantation or intravenous bevacizumab might be considered, though the optimal choice is controversial at this time.

For patients with bleeding arteriovenous malformations of the gastrointestinal tract, especially if associated with anemia, endoscopy with cautery is usually the first line treatment, although it should be used sparingly. For persistent bleeding and/or anemia, tranexamic acid or antiangiogenic agents such as intravenous bevacizumab should be considered.

Aggressive iron replacement therapy, either orally or by infusion, should be used to treat anemia secondary to the nose or gastrointestinal bleeding associated with HHT. Blood transfusions are a last resort if frequent iron infusions and other therapies are not successful in reaching the target hemoglobin (usually >7 g/dl for most patients).

Nosebleed treatments

90% of individuals affected by HHT will develop chronic nosebleeds. In some people nosebleeds may be an uncommon occurrence and one that is easily managed, while others may have multiple nosebleeds every day. The Epistaxis Severity Score (ESS) is a useful tool for tracking nosebleeds to help determine whether treatment is necessary. If you do receive treatment you can use the ESS to track the effectiveness of the procedure.

If your HHT physician determines that you need treatment for nosebleeds, there are several options available to you 24:

  • The following therapies should be tried in this order, from least to most invasive:
    1. Moisturizing topical therapies keep the nose from getting too dry to prevent nosebleeds
    2. Oral tranexamic acid
    3. Laser treatment, radiofrequency, electrosurgery, and sclerotherapy
    4. Systemic antiangiogenic agents
    5. Septodermoplasty
    6. Nasal closure surgery: very effective, though patients can no longer breathe through the nose, and senses of taste and smell can be affected.
  • Coagulation therapy changes liquid blood to a congealed form that is less likely to bleed. This is a quick and effective way to stop nosebleeds, although it needs to be repeated periodically.
  • Embolization blocks an artery and typically stops nosebleeds that have been unresponsive to other treatments. Embolization is only effective for 6-8 weeks and is used primarily for emergencies.

Intravenous bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VGEF) that can be given on an intermittent basis to reduce nosebleeds and anemia, and perhaps also gastrointestinal bleeds. Based on several large uncontrolled trials it helps approximately 70-80% of patients and is fairly well tolerated by HHT patients, though serious side effects such as blood clots can occur in a minority of patients.

Other antiangiogenic agents that are under investigation include oral pazopanib, oral thalidomide, oral pomalidomide, oral doxycycline and others. Small uncontrolled trials of the first three suggest benefit to nosebleeds and gastrointestinal bleeds, while doxycycline has shown some benefit for nosebleeds.

Estrogen and progesterone therapy, either alone in combination, have been given in an uncontrolled fashion to prevent recurrent bleeding associated with HHT. Reports of the effectiveness of these treatments have varied in the medical literature and they are also associated with the potential complication of blood clots. Further research is needed to determine the long-term safety and effectiveness of these treatments for HHT.

Arteriovenous malformation treatments

Not all arteriovenous malformations require treatment. Screening by an HHT expert is the best way to determine what course is best for you. The recommended treatment for arteriovenous malformations (AVMs) depends almost entirely on the size of the malformation and its location in the body. Arteriovenous malformations (AVMs) can develop and change over time, so periodic screenings are important to ensure your safety and help.

Cerebral arteriovenous malformations are rare and treatment can have risks. Each HHT patient with cerebral arteriovenous malformations will be treated differently.

Pulmonary arteriovenous malformations require long-term follow-up to ensure treatment remains successful.

If your physician decides that you need to treat your arteriovenous malformations (AVMs), there are several treatment options available 31:

  • Embolization: In this procedure, a catheter is used to place a small medical device or quantity of glue (glue is only used in the case of brain arteriovenous malformation) inside an artery. This device blocks the arteriovenous malformation and reduces or stops the blood flow to an arteriovenous malformation to relieve the pressure on the walls of the blood vessel.
  • Surgical treatment: Surgical procedures remove the part of the tissue that contain the arteriovenous malformation.
  • Radiosurgery (or gamma knife): This procedure uses focused radiation to destroy the arteriovenous malformation tissue.
  • Laser ablation: This procedure focuses a laser to remove material on the surface of the tissue. The amount of material removed depends on the intensity, pulse length, and wavelength of the laser.
  • Drug therapy: There are several types of drugs used to treat HHT that come in different forms (oral, IV, topical) and vary in effectiveness depending on the type and severity of manifestations in an HHT patient. Be sure to consult your HHT physician to understand your options of drug therapies.
    • Antifibrinolytic drugs (e.g. tranexamic acid or aminocaproic acid)
    • Antiangiogenic drugs (e.g. bevacizumab, pomalidomide or pazopanib)
    • Antibiotics (e.g. doxycycline)
    • Immunosuppressants (e.g. sirolimus or tacrolimus)

Lung arteriovenous malformation

Consequences of lung arteriovenous malformations can include stroke, hypoxia, and

  • Adults:
    • Embolization may be used to treat lung arteriovenous malformations to prevent stroke and brain abscess. Embolize lung arteriovenous malformations with FA>2-3mm in adults (many HHT Centers us FA>2mm threshold).
    • The surgical procedure for lung arteriovenous malformations removes the part of the lung containing the arteriovenous malformation.
  • Pregnant patients:
    • Embolize lung arteriovenous malformations in pregnancy starting in second trimester (after organogenesis).
    • Use of abdominal shielding during screening is not helpful and may increase scattered radiation to the fetus.
  • Children:
    • Embolize lung arteriovenous malformations in children that are large (FA>3mm) or associated with hypoxia, and follow long term.

Long-term advice for patients with documented lung arteriovenous malformations (treated or untreated) 31:

  • Use antibiotic prophylaxis for procedures with risk of bacteremia (e.g. dental procedures, colonoscopy, etc)
  • When IV access is in place, take extra care to avoid IV air
  • Avoid SCUBA diving.
  • Follow screening guidelines in order to detect growth of untreated pulmonary arteriovenous malformations and also reperfusion of treated arteriovenous malformations.

Brain arteriovenous malformation

Brain arteriovenous malformations that present a risk of rupture or hemorrhagic stroke should be treated 31.

Brain arteriovenous malformations treatment options 31:

  • Embolization therapy blocks blood flow to the arteriovenous malformation by using an embolizing agent such as coils, plugs, etc. Embolization is a less invasive procedure than traditional surgery.
  • Surgical removal (resection) of brain arteriovenous malformation.
  • Stereotactic radiosurgery (SRS) uses focused radiation to treat abnormalities in the brain and spine. Despite it’s name, stereotactic radiosurgery is not a surgical procedure.

Recommendations for pregnant patients:

Pregnant patients with brain arteriovenous malformation should defer treatment until after delivery. Presence of brain arteriovenous malformation does not change standard delivery procedures.

Recommendations for children:

Brain arteriovenous malformations with high risk features should be treated.

Free second opinion neurological consults are available through Barrow Neurological Institute HHT Center of Excellence (https://www.barrowneuro.org). Patients may contact the Barrow Neurological Institute HHT Center of Excellence directly by calling the toll-free number 1-888-BNI-4HHT or may submit electronic requests for a neurosurgical second opinion at https://www.barrowneuro.org/patient-care/your-journey/im-looking-for-a-second-opinion/

Spinal arteriovenous malformation

Spinal arteriovenous malformations are rare, but if detected embolization and surgical treatments are effective in treating spinal arteriovenous malformations.

Liver arteriovenous malformation

Liver arteriovenous malformations are common but typically do not require treatment. If treatment is required, it is essential that an HHT Center physician is consulted regarding the best option. Procedures to treat Liver arteriovenous malformations can be very invasive and have the potential to worsen the condition of the patient if an HHT specialist is not involved.

Gastrointestinal tract arteriovenous malformation

Arteriovenous malformations are common in the gastrointestinal tract, usually in the stomach and upper portion of the small intestine. When necessary, intestinal arteriovenous malformations can be treated by laser, tranexamic acid, IV Avastin and other angiogenesis inhibitors. The most significant problem with intestinal arteriovenous malformations is anemia caused by chronic bleeding. Anemia can be treated separately from the arteriovenous malformation with oral iron supplements, iron infusions, and/or blood transfusions.

Anemia and iron deficiency

People with HHT who suffer from bleeding should be routinely screened for iron deficiency. It is important that iron deficiency be treated aggressively, by replacing the iron stores in the body. There are multiple methods of replacing iron stores.

Iron replacement typically starts with once daily oral dosing of 35-65 mg of elemental iron, 2 hours before or 1 hour after meals 32. If this is not tolerated, every-other-day dosing of oral iron or an alternate oral iron preparation (such as a heme-iron preparation or a non-heme iron preparation with lower elemental iron content) can be attempted. If initial dosing is inadequate for correction of the iron deficiency, increasing the daily dose or twice daily dosing should be considered. The patient should be counseled about various dietary factors and medications which can affect iron absorption. In general, an interval of 2-12 hours between iron supplements and these medications is preferred. Follow-up complete blood count (CBC), iron panel and/or ferritin 1 month after initiation of iron replacement is recommended to assess response 32. An increase in hemoglobin of at least 1.0 gram/dL is expected and, if not achieved, should be considered an inadequate response 32. When oral iron supplementation is pursued in people with iron deficiency without anemia, improvement in ferritin and transferrin saturation is expected after 1 month. For intravenous iron, routine monitoring of complete blood count (CBC) and ferritin is necessary and helpful in guiding prescription of dose intervals, understanding that ferritin levels may be unreliable for 2 weeks post-infusion. In patients with chronic, recurrent bleeding, regularly scheduled iron infusions, with interval adjusted based on follow-up bloodwork, may be considered to maintain iron stores and prevent the development of severe anemia. The dose of intravenous iron can be guided by the total iron deficit, which can be calculated using the Ganzoni formula 33. Alternatively, a total initial dose of 1 gram of intravenous iron can be provided, as a single infusion or in divided doses based on institutional protocols and preferences. Unless chronic bleeding is successfully halted through systemic therapies and/or procedural interventions, repeated administrations of intravenous iron every few months is expected to prevent recurrence of iron deficiency. A few considerations specific to the type of intravenous iron preparation warrant mention: a significantly higher incidence of hypophosphatemia (>20%) has been reported in patients receiving multiple doses of ferric carboxymaltose 34; ferumoxytol can affect the quality of MRI imaging and therefore MRIs should be avoided for at least 4 weeks following infusion of ferumoxytol 35.

Iron rich food

Iron is an essential component of hemoglobin, a red blood cell (erythrocyte) protein that transfers oxygen from the lungs to the tissues 36. As a component of myoglobin, another protein that provides oxygen, iron supports muscle metabolism and healthy connective tissue 37. Iron is also necessary for physical growth, neurological development, cellular functioning, and synthesis of some hormones 38.

Dietary iron has two main forms: heme and non-heme 36. Plants and iron-fortified foods contain non-heme iron only, whereas meat, seafood, and poultry contain both heme and nonheme iron 37. Heme iron, which is formed when iron combines with protoporphyrin IX, contributes about 10% to 15% of total iron intakes in western diets 39.

Heme iron (from meat) is more easily absorbed by the body, while non-heme iron (from plant sources) is harder to absorb. Because vegetarians only consume non-heme iron, their bodies cannot absorb as much of it, so they are at a higher risk for iron deficiency. If you are deficient in iron, your body will absorb more of it from food than it would if you had good iron stores.

Table 2. Iron content of selected foods

FoodMilligrams per servingPercent DV*
Breakfast cereals, fortified with 100% of the DV for iron, 1 serving18100
Oysters, eastern, cooked with moist heat, 3 ounces844
White beans, canned, 1 cup844
Beef liver, pan fried, 3 ounces528
Lentils, boiled and drained, ½ cup317
Spinach, boiled and drained, ½ cup317
Tofu, firm, ½ cup317
Chocolate, dark, 45%–69% cacao solids, 1 ounce211
Kidney beans, canned, ½ cup211
Sardines, Atlantic, canned in oil, drained solids with bone, 3 ounces211
Chickpeas, boiled and drained, ½ cup211
Tomatoes, canned, stewed, ½ cup211
Beef, braised bottom round, trimmed to 1/8” fat, 3 ounces211
Potato, baked, flesh and skin, 1 medium potato211
Cashew nuts, oil roasted, 1 ounce (18 nuts)211
Green peas, boiled, ½ cup16
Chicken, roasted, meat and skin, 3 ounces16
Rice, white, long grain, enriched, parboiled, drained, ½ cup16
Bread, whole wheat, 1 slice16
Bread, white, 1 slice16
Raisins, seedless, ¼ cup16
Spaghetti, whole wheat, cooked, 1 cup16
Tuna, light, canned in water, 3 ounces16
Turkey, roasted, breast meat and skin, 3 ounces16
Nuts, pistachio, dry roasted, 1 ounce (49 nuts)16
Broccoli, boiled and drained, ½ cup16
Egg, hard boiled, 1 large16
Rice, brown, long or medium grain, cooked, 1 cup16
Cheese, cheddar, 1.5 ounces00
Cantaloupe, diced, ½ cup00
Mushrooms, white, sliced and stir-fried, ½ cup00
Cheese, cottage, 2% milk fat, ½ cup00
Milk, 1 cup00

Footnotes: * DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for iron is 18 mg for adults and children age 4 years and older. FDA requires food labels to list iron content. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Source 40 ]

Here are some easy ways to increase your intake and absorption of iron:

  • Consume iron with a source of vitamin C to increase absorption. Many fruits, vegetables, and juices are good sources of vitamin C, including citrus fruits and juices, cantaloupe, strawberries, broccoli, peppers, and tomatoes (e.g. drink a glass of orange juice with your morning oatmeal)
  • Meat enhances absorption of non-heme iron (e.g. beef in chili will help you absorb the iron in kidney beans)
  • Cooking meals in cast iron pans allows iron from the pan to be absorbed by the food

Iron dietary supplements

Iron is available in many dietary supplements. Multivitamin/multimineral supplements with iron, especially those designed for women, typically provide 18 mg iron (100% of the Daily Value [DV]). Multivitamin/multimineral supplements for men or seniors frequently contain less or no iron. Iron-only supplements usually deliver more than the DV, with many providing 65 mg iron (360% of the DV).

Frequently used forms of iron in supplements include ferrous and ferric iron salts, such as ferrous sulfate, ferrous gluconate, ferric citrate, and ferric sulfate 38. Because of its higher solubility, ferrous iron in dietary supplements is more bioavailable than ferric iron 38. High doses of supplemental iron (45 mg/day or more) may cause gastrointestinal side effects, such as nausea and constipation 41. Other forms of supplemental iron, such as heme iron polypeptides, carbonyl iron, iron amino-acid chelates, and polysaccharide-iron complexes, might have fewer gastrointestinal side effects than ferrous or ferric salts 42.

The different forms of iron in supplements contain varying amounts of elemental iron. For example, ferrous fumarate is 33% elemental iron by weight, whereas ferrous sulfate is 20% and ferrous gluconate is 12% elemental iron 42. Fortunately, elemental iron is listed in the Supplement Facts panel, so consumers do not need to calculate the amount of iron supplied by various forms of iron supplements.

Approximately 14% to 18% of Americans use a supplement containing iron 43. Rates of use of supplements containing iron vary by age and gender, ranging from 6% of children aged 12 to 19 years to 60% of women who are lactating and 72% of pregnant women 44.

Calcium might interfere with the absorption of iron, although this effect has not been definitively established 45. For this reason, some experts suggest that people take individual calcium and iron supplements at different times of the day 46.

Intravenous iron

A hematologist may consider intravenous (IV) iron if a patient is intolerant of oral iron or has ongoing blood loss. There are several IV iron products that can be recommended, consult your HHT physician for dosage amounts and time required to administer the dose.

Advantages of IV iron:

  • Larger amounts of iron can be replaced at a time
  • Reliability and not impacted by dietary issues
  • Little to no gastrointestinal side effects (which are common with oral iron)

Disadvantages of IV iron:

  • Time and cost
  • Side effects, such as weakness, body aches and headaches
  • Risk for serious reaction (anaphylaxis)
  • Possible worsening of nosebleeds

Red blood cell transfusions

A blood transfusion provides the part or parts of blood that you need to replenish due to blood loss. Red blood cells (erythrocyte) are the most commonly used type of blood transfusion in the treatment of HHT patients (as well as in the general population).

Red blood cell transfusions are necessary when the patient has:

  • Hemodynamic instability/shock
  • Comorbidities that require a higher hemoglobin target
  • A need to increase the hemoglobin acutely, such as prior to surgery or during pregnancy
  • An inability to maintain an adequate hemoglobin despite frequent iron infusions 24

HHT disease life expectancy

There are few data on life expectancy in patients with hereditary hemorrhagic telangiectasia (HHT), but people with HHT may have a shorter expected lifespan 23. A retrospective study (also called a historic cohort study that compares two groups of people: those with the disease or condition under study (cases) and a very similar group of people who do not have the disease or condition [controls]) demonstrated lower median age of death in HHT versus non-HHT patients (63.2 vs. 70.0 years) 47.

A more recent prospective study (n=675) found HHT patients to have poorer survival when compared to matched controls with a median age of death at 77 years versus 80 years 5. Furthermore, the study found hazard ratios (a type of relative risk where the ratio of chance of an event occurring in the treatment arm/chance of an event occurring in the control arm) for death were highest within the first three years after HHT diagnosis and subsequently decreased. This decrease in hazard ratio could explain how HHT may be diagnosed after an acute complication such as a stroke. Early detection and screening of HHT and prevention of complications could help increase life expectancy 23.

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