Overview of Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia, or HHT, is a genetic disorder that affects the blood vessels. Also called Osler–Weber–Rendu syndrome, HHT results in symptoms and manifestations that can vary a lot from person to person.

It is also possible to have HHT and not know you have it, and some people are first diagnosed after they develop serious complications due to HHT. Nearly 90% of those with HHT will have recurrent nosebleeds, but more severe complications are also relatively common. The serious complications depend in part on where the abnormal blood vessels are located and include internal bleeding and stroke, but HHT can also be silent for years.

What Is HHT?

HHT is an inherited condition that affects your blood vessels in ways that can result in abnormalities that can range from very innocent to potentially life-threatening when you take a whole life-span view. Though signs and symptoms may be present early, it is often the case that more serious complications may not develop until after the age of 30.

There are two main types of disorders of the blood vessels that can affect people with HHT:

• Telangiectasias
• Arteriovenous malformations, or AVMs.

Telangiectasia

The term telangiectasia refers to a group of small blood vessels (capillaries and small venules) that have become abnormally dilated. Although they can form in all different parts of the body, telangiectasias are most easily seen, and most commonly thought of as appearing near the surface of the skin, often on the face or on the thighs, sometimes referred to as “spider veins,” or “broken veins.”

They also can be seen on moist mucous membranes or linings, such as inside the mouth on the cheeks, gums, and lips. They are red or purplish in hue, and they look like winding, wiry threads, or spidery networks.

Impact and Management of Telangiectasia

Telangiectasia of the skin and mucous membranes (the moist lining of the mouth and lips) are common among patients with HHT. The telangiectasias tend to occur while the person is young and progress with age. Bleeding can occur from these sites, but it is usually mild and easily controlled. Laser ablation therapy is sometimes used if needed.

Telangiectasias of the nose—in the lining of the nasal airways—are the reason nosebleeds are so common in people with HHT. Some 90% of people with HHT have recurrent nosebleeds. Nosebleeds can be mild or more severe and recurrent, leading to anemia if not controlled. Most people who have HHT develop nosebleeds before the age of 20, but the age of onset can vary quite a bit, as can the severity of the condition. 

In the gastrointestinal tract, telangiectasias are found in about 15 to 30% of people with HHT. They can be a source of internal bleeding, however, this rarely occurs before the age of 30. The treatment varies depending on the severity of the bleeding and the individual patient. Iron supplementation and transfusions as needed may be part of the plan; estrogen-progesterone therapy and laser therapy can be used to reduce the severity of bleeding and the need for transfusions.

Arteriovenous malformations (AVM)

Arteriovenous malformations, or AVMs, represent another kind of malformation of blood vessels, often occurring in the central nervous system, lungs, or liver. They may be present at birth and/or develop over time.

AVMs are considered malformations because they violate the orderly sequence that blood vessels normally follow to deliver oxygen to the tissues and carry carbon dioxide back to the lungs, to be exhaled: oxygenated blood normally goes from the lungs and heart, out the aorta, to the biggest of arteries, to smaller arteries to arterioles and even smaller arterioles eventually to the smallest of smaller capillaries; then, de-oxygenated blood flows into tiny venules to small veins to larger veins to eventually to the great veins, like the superior vena cava, and back to the heart, etc.

In contrast, when an AVM develops, there is an abnormal “tangle” of blood vessels connecting arteries to veins, in a certain part of the body, and this can disrupt normal blood flow and oxygen circulation. It’s almost as if an interstate highway suddenly empties into a parking lot, whereupon the cars swirl around for a while before getting back onto the interstate, perhaps to be headed in the wrong direction.

Impact and Management of AVMs

In people with HHT, AVMs can occur in the lungs, brain and central nervous system, and liver circulation. AVMs can rupture to cause abnormal bleeding, leading to stroke, internal bleeding, and/or severe anemia (not enough healthy red blood cells, resulting in fatigue, weakness, and other symptoms).

When AVMs form in the lungs in people with HHT, the condition may not get medical attention until the person is 30 years old or older. A person can have an AVM in their lungs and not know it because they don't have any symptoms. Alternatively, people with lung AVMs may suddenly develop massive bleeding, coughing up blood. Lung AVMs may also cause harm more silently, whereby the oxygen delivery to the body is sub-par, and the person feels like they cannot get enough air when lying down to bed at night (this symptom is more commonly due to non-HHT related conditions, such as heart failure, however). Something called paradoxical emboli, or blood clots that originate in the lungs but travel to the brain, can cause stroke in someone with HHT who has AVMs in the lungs.

AVMs in the lungs can be treated with something called embolization, whereby a blockage is purposefully created in the abnormal blood vessels, or surgically, or there may be a combination of both techniques.

Patients with lung AVMs should receive regular chest CT scans to detect growth or re-formation of known areas of malformation and to detect new AVMs. Screening for lung AVMs is also recommended prior to becoming pregnant because changes to the mother’s physiology that are a normal part of pregnancy can affect an AVM.

As many of 70% of people with HHT develop AVMs in the liver. Often these AVMs are silent and will only be noticed incidentally when a scan is done for some other reason. AVMs in the liver also have the potential to be serious in some cases, however, and may lead to circulatory problems and problems with the heart, and very rarely, liver failure requiring a transplant.

AVMs in people with HHT cause problems in the brain and nervous system in only about 10-15% of cases, and these problems tend to arise among older individuals. Again, however, there is the potential for severity, whereby brain and spinal AVMs can cause devastating hemorrhage if they rupture.

Who Is Affected?

HHT is a genetic disorder that is transferred from parents to children in a dominant fashion, so anyone may inherit the disorder, but it’s relatively rare. The frequency is similar in both males and females.

Overall, it’s estimated to occur in about 1 in 8,000 people, but depending on your ethnicity and genetic makeup, your rates could be much higher or much lower. For instance, published prevalence rates for individuals of Afro-Caribbean ancestry in the Netherlands Antilles (islands of Aruba, Bonaire, and Curaçao) have some of the higher rates, with estimates at 1 in 1,331 people, while in the northernmost reaches of England the rates are estimated at 1 in 39,216.

Diagnosis

The Curaçao diagnostic criteria, named after the Caribbean island, refer to a schematic that can be used to determine the likelihood of having HHT. According to the criteria, the diagnosis of HHT is definite if three of the following criteria are present, possible or suspected if two are present, and unlikely if fewer than two are present:

• Spontaneous, recurrent nose bleeds
• Telangiectasias: multiple, spidery vein patches at characteristic sites—the lips, inside the mouth, on fingers and on the nose
• Internal telangiectasias and malformations: gastrointestinal telangiectasias (with or without bleeding) and arteriovenous malformations (lungs, liver, brain and spinal cord)
• Family history: a first-degree relative with hereditary hemorrhagic telangiectasia

Types

According to the 2018 review on this subject by Kroon and colleagues, five genetic types of HHT and one combined juvenile polyposis syndrome and HHT are known.

Traditionally, two major types have been described: Type I is associated with mutations in a gene called the endoglin gene. This type of HHT also tends to have high rates of AVMs in the lungs or pulmonary AVMs. Type 2 is associated with mutations in a gene called the activin receptor‐like kinase‐1 gene (ACVRL1). This type has lower rates of pulmonary and brain AVMs than HHT1, but a higher rate of AVMs in the liver.

Mutations in the endoglin gene on chromosome 9 (HHT type 1) and in the ACVRL1 gene on chromosome 12 (HHT type 2) are both associated with HHT. These genes are believed to be important in how the body develops and repairs its blood vessels. It’s not as simple as two genes, however, in that not all cases of HHT arise from the same mutations. Most families with HHT have a unique mutation. According to the study by Prigoda and colleagues, now potentially dated, 168 different mutations in the endoglin gene and 138 different ACVRL1 mutations had been reported.

In addition to endoglin and ACVRL1, several other genes have been associated with HHT. Mutations in the SMAD4/MADH4 gene have been associated with a combined syndrome of something called juvenile polyposis and HHT. Juvenile polyposis syndrome, or JPS, is a hereditary condition identified by the presence of noncancerous growths, or polyps, in the gastrointestinal tract, most commonly in the colon. The growths can also occur in the stomach, small intestine and rectum. So, in some cases, people have both the HHT and the polyposis syndrome, and this seems to be associated with the SMAD4/MADH4 gene mutations.

Monitoring and Prevention

Aside from the treatment of telangiectasias and AVMs as needed, it is important for people with HHT to be monitored, some more closely than others. Doctor Grand’Maison completed a thorough review of HHT in 2009 and proposed a general framework for monitoring:

Annually, there should be checks for new telangiectasias, nosebleeds, gastrointestinal bleeding, chest symptoms such as shortness of breath or coughing up blood, and neurologic symptoms. Checking for blood in the stool should also be done annually, as should a complete blood count to detect anemia.

It has been recommended that every couple of years during childhood a pulse oximetry be done to screen for lung AVMs, followed up with imaging if the oxygen levels in the blood are low. At the age of 10, a workup of the cardiovascular system is recommended to check for serious AVMs that could affect the ability of the heart and lungs to do their jobs.

For those with established AVMs in the lungs, the recommended monitoring is done even more frequently. Liver screening for AVMs is not prioritized as highly but can be done, whereas a brain MRI to exclude serious AVMs is recommended on at least one occasion after the diagnosis of HHT has been made.

Investigational Treatments

Bevacizumab has been used as a cancer therapy because it is a tumor starving, or anti-angiogenic, therapy; it prevents the growth of new blood vessels, and this includes normal blood vessels and blood vessels that feed tumors.

In a recent study by Steineger and colleagues, 33 patients with HHT were included to investigate the effects of bevacizumab on people with nose telangiectasia. On average, each patient had about 6 intranasal injections of bevacizumab (range, 1-16), and they were watched for an average of about 3 years in this study. Four patients showed no improvement after treatment. Eleven patients showed initial improvement (lower symptom scores and less need for blood transfusions), but the treatment was discontinued before the end of the study because the effect became gradually shorter-lasting despite repeated injections. Twelve patients continued to have a positive response to the treatment at the end of the study.

No local adverse effects were observed, but one patient developed osteonecrosis (a bone disease that can limit physical activity) in both knees during the treatment period. The authors concluded that intranasal bevacizumab injection is an effective treatment for most of the moderate and severe grades of HHT-associated nosebleeds. The duration of the effect of the treatment varied from patient to patient, though, and the development of resistance to the treatment seemed to be quite common.

Screening

Screening for the disease is an evolving area. Recently Kroon and colleagues proposed that systematic screening be performed in patients with suspected HHT. They recommend both clinical and genetic screening of patients suspected with HHT to confirm the diagnosis and to prevent complications associated with HHT.