What is HHT?
Can HHT be Treated?
Is There a Test for HHT?
What Should I Do?
What Causes HHT?
What Research Is Being Done on HHT?

What is HHT?
HHT is a genetic disorder that causes abnormalities of blood vessels. Most blood vessels in the body of someone with HHT are normal. However, a small percentage of the blood vessels in a person with HHT have a specific type of abnormality.

Blood vessels are the tubes that carry blood around our bodies. There are two types of blood vessels: arteries and veins. Arteries carry blood under high pressure out to all areas of the body after being pumped by the heart. Veins carry blood that should be under low pressure, back to the heart. An artery does not usually connect directly to a vein. Usually there are very small blood vessels called capillaries that connect an artery to a vein.

A person with HHT has a tendency to form blood vessels that lack the capillaries between an artery and vein. This means that arterial blood under high pressure flows directly into a vein without first having to squeeze through the very small capillaries. This place where an artery is connected directly to a vein tends to be a fragile site that can rupture and result in bleeding. We usually call a blood vessel that is abnormal in this way a telangiectasia (tel-AN-jee-eck-TAZE-ee-ya), if it involves small blood vessels. We tend to call it an arteriovenous malformation (AVM) if involves larger blood vessels. So, an AVM might be thought of as a big telangiectasia. The basic abnormality in the blood vessel is the same.

Telangiectases tend to occur at the surface of the body such as the skin and the mucous membrane that lines the nose. AVMs tend to occur in the internal organs of the body. The telangiectases (plural for telangiectasia) and AVMs of HHT occur primarily in the nose, skin of the face, hands, and mouth and the lining of the stomach and intestines (GI tract), lungs, liver and brain. It is not currently known why these abnormal blood vessels tend to occur in certain parts of the body and not others.
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Can HHT be Treated?

Yes. Although there is not yet a way to prevent the telangiectases or AVMs from occurring, most can be treated once they occur. They should be treated if they are either causing a significant problem (as in the case of frequent nosebleeds) or if they are at high risk of causing a serious problem (such as a stroke from a lung AVM.) The recommended treatment for a telangiectasia or AVM depends on both its size and location in the body.

Bleeding from telangiectases in the nose sometimes responds satisfactorily to some everyday practical treatments implemented at home. Humidification of the air and use of an ointment on the lining of the nose help keep the mucous membrane of the nose moist and can reduce nosebleeds. There are products sold over-the-counter in pharmacies or pharmacy sections of big stores that can be used to help control nosebleeds when simple pressure applied to the outside of the nose isn�t enough. Click on the following link for more information on Nosebleed Self-Help: Nosebleeds Self Help

More information on home remedies for epistaxis and which herbs and drugs are associated with nosebleeds, please click on the following link to uspharmacist.com.

If these home management techniques do not result in a satisfactory control or reduction in nosebleeds, the first medical treatment that should usually be considered is laser therapy. Laser coagulation therapy is preferable to electric and chemical cautery primarily because- if done carefully by an ENT physician with specific expertise in both laser therapy and HHT- it has less risk to damage the inside of the nose. A small beam is directed around the margins of each telangiectasia and photocoagulation occurs. Most patients who undergo laser therapy see significant improvement for a period of time, but it usually needs to be repeated periodically. Because the procedure has little risk of harming the nose if done by an experienced physician, it can be repeated as needed.

Septal dermoplasty is another treatment option for severe nosebleeds, and is usually considered when laser therapy has repeatedly failed to help. Septal dermoplasty replaces the thin lining of the nose (called the mucous membrane) with a thicker graft of skin. When performed by an ENT (Ears, Nose, and Throat) physician knowledgeable and experienced with the Saunder’s method, it can significantly reduce the frequency and severity of nosebleeds. It is a more drastic treatment than laser in that it permanently removes the natural lining of nose and replaces it with skin. Daily care and attention to the nose is required after septal dermoplasty to keep the nose moist and clean. Some studies have shown hormonal therapy to be helpful in some patients for whom the local therapies (i.e. home moisturizing care and laser therapy) have not been successful.

Embolization (blocking off an artery) can be used to halt severe nose bleeding that has been unresponsive to other treatments, but is usually only effective for 6-8 weeks. Other arteries enlarge and cause recurrence of the bleeding. This therapy for the nose is generally used only on an emergency basis and is generally only a temporary measure.

Telangiectases of the skin can also be treated with laser therapy if they bleed to an extent that is bothersome or if the telangiectases are a cosmetic concern. Lesions of the skin are usually best treated by a dermatologist who has particular expertise in the use of lasers.

Bleeding from the stomach or intestines is generally treated only if it causes anemia (low blood count.) Iron replacement therapy is the first line of defense. Iron is usually first given orally (a tablet by mouth), but can be given intravenously (IV) if a patient does not tolerate the oral iron, or if the oral method is not getting enough iron into the body. If iron therapy cannot control the anemia, transfusion and endoscopic treatments using a heater probe, bicap, argon photocoagulation or laser are options. Hormonal treatment has also been helpful in some people.

Lung and brain AVMs should be treated before they cause symptoms or problems in most cases. This is why testing or screening for them is recommended in all individuals with HHT, regardless of their specific symptoms. Lung AVMs can almost always be treated completely and permanently using an outpatient procedure called embolization. An Interventional Radiologist inserts a small tube (catheter) in a large vein in the groin. The tube is then passed through the blood vessel system to the AVM in the lung. A devise (a coil or occasionally a balloon) is placed in the artery leading to the AVM to stop blood flow through the AVM. The procedure usually takes 1-3 hours and requires only a few hours of recuperation.

Brain AVMs are treated in different ways depending on the size, structure and location in the brain of the abnormal blood vessels. Surgery, embolization and stereotactic radiosurgery can all be used, separately or in combination, to successfully treat brain AVMs.

Liver AVMs are currently treated only if a patient shows signs of liver or heart failure, as a result of their liver AVM. Embolization, which is so successful for the treatment of pulmonary AVMs, can cause severe complications when performed in the liver. Decisions regarding treatment of liver AVM are made on a case-by-case basis and should be managed by a physician very familiar with the liver manifestations of HHT.
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Is There a Test for HHT?

Yes, genetic testing for HHT is available, but it needs to be preceded by a clinical confirmation of HHT in your family. This is because the genetic testing for HHT must first be run on a �clearly affected� person in your family. Results from these genetic tests results HHT will determine whether it is useful to test other family members who want to know whether they have HHT. Genetic testing for HHT is complex, has some significant limitations that a patient should understand, and involves testing more than one member of the same family. It is not widely available- typically done in 1 or 2 laboratories per country.

Many individuals who initially request a genetic test for HHT actually do not need this expensive test to determine whether they have HHT. In many cases a physician familiar with the sometimes-subtle external signs of HHT, and who takes a detailed family history, can make the diagnosis during a clinic visit. The following Diagnostic Criteria for HHT have been published by an international group of HHT experts. The diagnosis of HHT is considered definite if three or more of the following four criteria are present, or suspected if two of the following four criteria are present:

• Nosebleeds- spontaneous and recurrent
• Telangiectases- multiple, at characteristic sites, including lips, oral cavity, fingers and nose Internal telangiectases or AVM- lung, brain, GI, liver or spinal
• Family history-parent, sibling or child with HHT according to these criteria

To establish the diagnosis of HHT in your family, and to proceed with genetic testing as needed it is usually best to be seen at an HHT Center, or a genetics clinic in your area. Physicians or genetic counselors in these clinics will understand the process and particulars of how best to determine whether you and/or members of your family have HHT, including genetic testing. The youngest individuals in an HHT family are typically the most helped by genetic testing, but testing usually must start with a parent or grandparent.

(See Genetic Testing for a detailed explanation of genetic testing for HHT)
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What Should I Do?

There are several tests that everyone who is known or suspected to have HHT should have. Since lung and brain AVMs can cause serious damage without warning, and they can be successfully treated, testing is strongly suggested for these. Testing for brain and lung AVMs is often referred to as “screening”, meaning the AVM is looked for prior to causing a problem.

To screen for brain AVMs an MRI with and without gadolinium is recommended. It is currently recommended that a brain MRI only needs to be done once early in life and once as an adult, if it is normal. Most brain AVMs are thought to be congenital (present at birth).

Screening for lung AVMs is dependent on the age of the individual, and to a lesser degree their symptoms. During childhood, oxygen saturation should be checked every one to two years by finger oximetry done in both lying and sitting positions. Any subnormal result should be followed up with appropriate diagnostic testing. At 10-12 years of age, more sensitive screening should be done to rule out lung AVM(s). Currently in North America, a contrast echocardiogram (echo bubble) is usually recommended to screen for lung AVM in adults. It is a very sensitive test (meaning it will miss very few lung AVM), but everyone with a positive or abnormal echo bubble test does not have a lung AVM large enough to require treatment. To determine who requires treatment by an embolization procedure, a chest CT scan is usually done to follow-up on a positive echo bubble test. If a pregnant woman has not had recent evaluation for lung AVMs, it is imperative to screen for lung AVMs as soon as pregnancy is recognized. Preferably, individuals with HHT will have had screening for lung AVMs before pregnancy.

Lung and brain AVMs are the only problems associated with HHT for which pre-symptomatic screening is routinely recommended. Most insurance companies will pay for these recommended screening tests if a brief explanation of the association between HHT and AVMs in these internal organs is provided. Until lung AVMs are excluded by this testing, a person known or suspected to have HHT should follow the American Heart Association guidelines (see Dental Care-Important Precaution) for taking antibiotics before all dental cleaning or work. This is to prevent brain abscess, which can occur when bacteria in the mouth enter the bloodstream during dental work or cleaning and passes through a lung AVM to the brain.

Other than in the brain and lungs, HHT can be treated as symptoms warrant. With this in mind, a yearly evaluation by a physician familiar with the wide spectrum of symptoms associated with HHT is recommended, along with an annual check of hematocrit/hemoglobin.
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What Causes HHT?

An abnormal gene on either chromosome 9 or 12 causes most HHT. The gene on chromosome 9 is called endoglin and the gene on chromosome 12 is called activin-like kinase 1 (ALK-1). Any particular individual or family will have only one of these two genes appear abnormal. Normally, these genes produce a substance that is involved in the formation of blood vessels. Because of an abnormality in one of these genes, individuals with HHT make less of one of these substances. This, in turn, can interfere with the normal formation of a blood vessel.

The abnormal HHT gene is usually inherited from one parent who has HHT. HHT is a “dominant” disorder, meaning it only takes one abnormal copy of the gene, from only one parent, to cause the disorder. Each child of a parent with an HHT gene has a 50% chance of inheriting this abnormal gene. If a particular child does not inherit the HHT gene from his or her parent, he/she has no chance to pass the HHT gene to a child or grandchild. The gene does not skip generations! However, sometimes it can appear to skip because an individual with an HHT gene has symptoms that are so mild that they aren�t recognized, or if recognized are not correctly attributed to HHT. Very rarely in HHT, a genetic accident (new mutation) occurs in a sperm or egg cell of an unaffected parent and causes HHT in the child. But in most cases, the abnormal HHT gene has been in the family for generations.

Almost 10 years after the genes which cause the most common forms of HHT (HHT1 and HHT2) were discovered, a new gene was identified that causes a combined syndrome of HHT and juvenile polyposis. Juvenile polyposis is characterized by multiple polyps in the intestinal tract, usually noticed clinically at a young age. Patients with juvenile polyps are at risk for gastrointestinal cancer at much younger ages than GI cancer typically occurs. Mutations in a gene called MADH4 (or sometimes referred to as SMAD4) cause this combined syndrome.

It is important to understand that most patients or families with HHT do not have polyposis. This is a distinct and separate medical condition that combines the clinical features of both disorders in the same family. Like HHT, it affects both males and females and can be passed from either a father or mother to their child.

The fact that these two disorders (HHT and juvenile polyposis) occasionally go together as a “package” has implications for how physicians should manage patients with either one. First, anyone in an HHT family with gastrointestinal bleeding at an early age should be screened for mutations in the MADH4 gene. If a mutation in MADH4 is found, genetic testing should be offered to other family members at risk and screening for juvenile polyps should be performed on those people who have the mutation. Screening for juvenile polyps should also be performed in any individual with a history of gastrointestinal bleeding. Second, patients with juvenile polyposis and mutations in the MADH4 gene, or juvenile polyposis and a family history consistent with HHT, should be screened for the internal AVMs of HHT that can present unexpectedly and cause serious complications.

1. Paper published by a group lead by Douglas Marchuk, PhD
The Lancet, vol 363, March 13, 2004
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What Research Is Being Done on HHT?

In the mid-1990s scientists discovered the two genes are responsible for most HHT. There seem to be one or more additional, much rarer genes that can also cause HHT. Currently, scientists are trying to understand exactly how it is that these abnormal genes interfere with normal blood vessel formation. Research is also being done that may eventually lead to the ability to truly “cure” genetic disorders by either fixing the abnormal gene or by replacing the substance in the body that the abnormal gene is not producing. In the meantime, physicians at universities around the world are working to develop better treatments and therapies for the manifestations and symptoms of HHT. Great advancements have been made in the last two decades in the treatment and management of HHT. Advancement in treatment will continue to be made as long as there are symptoms to treat.
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How Can I Get More Information and Help?

The HHT Foundation International, with its mission of patient/doctor education and support for research, provides multiple sources of information about HHT. Each year a patient/family conference is held at which medical and scientific experts on HHT come to talk and participate. A newsletter is published quarterly, providing the most current information about HHT. Membership entitles you to receive information about meetings as well as a subscription to the newsletter. By becoming a member of the Foundation, you also support the important work to improve care and eventually find a cure for HHT. The HHT Foundation International can also refer you to a clinic or center that specializes in the diagnosis, management and treatment of HHT. There are currently 8 centers in the U.S., two in Canada, and others around the world.