Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)

What is Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)?

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a genetic disease where the blood vessels form incorrectly. The disease, named after the doctors who first discovered it, mainly shows up as telangiectasias (small, widened blood vessels on the skin or mucous membranes) and arteriovenous malformations (abnormal connection between arteries and veins). These issues with the blood vessels often result in bleeding ranging from occasional nosebleeds to serious bleeding in the brain.

Some people with HHT may also develop high blood pressure in the lungs, an increased likelihood of blood clots, or problems with their immune system. The first sign of HHT often appears by young adulthood, typically starting with frequent nosebleeds. Telangiectasias, usually on the skin or inside the mouth, commonly appear by late adulthood. As a person gets older, these symptoms can become more frequent, leading to more nosebleeds or gastrointestinal bleeds, which can cause anemia (low red blood cell count), worsened quality of life, and increase the need for healthcare resources, like iron or blood transfusions and hospital stays.

What Causes Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)?

Genes are part of our DNA, and they carry instructions for making proteins that our bodies need to function. This process works by turning the gene’s DNA instruction into a molecule called messenger RNA (mRNA), which then gets turned into a protein. HHT, or Hereditary Hemorrhagic Telangiectasia, is a condition that affects the blood vessels in various parts of the body. This condition happens when one copy of a specific gene isn’t able to make enough of a needed protein.

Investigators have found that nearly all people with a confirmed diagnosis of HHT have mutations or changes in one of three specific genes. These mutations disturb the function of a molecule called transforming growth factor-beta (TGF-B), which is important for keeping blood vessels healthy.

HHT Type 1, or HHT1, is caused by mutations in a gene called ENG, located on chromosome 9. This gene normally provides instructions for making a protein called endoglin, which works with TGF-B in the body and is important for the health and stability of our blood vessels.

HHT Type 2, or HHT2, is due to mutations in a gene called Activin A Receptor-Like Type I (ACVRL1). This gene provides instructions for making a protein, called ALK1, and is located on chromosome 12. ALK1 is found on the surface of cells and works with TGF-B especially in developing arteries.

Another type of HHT, known as HHT associated with Juvenile Polyposis or JPHT, happens due to mutations in a gene called MADH4. This gene helps encode for a protein named SMAD4, which is important for TGF-B’s function. Specific changes in this gene can cause JPHT.

The distribution of these gene mutations among HHT patients is mostly ENG (61%), followed by ACVRL1 (37%), and then MADH4 (2%). More than 600 different mutations, including deletions, substitutions, and insertions, have been identified in the ENG or ACVRL1 genes.

Risk Factors and Frequency for Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)

HHT, or Hereditary Hemorrhagic Telangiectasia, is a disease that impacts between 1 in 5,000 to 8,000 people. It does not discriminate based on gender or race, affecting all people equally. Some research suggests it might be more common in women, but this could be due to differences in healthcare access.

Signs and Symptoms of Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)

Hereditary Hemorrhagic Telangiectasia (HHT) is an inherited condition that can show up differently in different people, even within the same family. It’s typically identified by a set of three signs: frequent nosebleeds, reddish spot on skin or mucous membranes, and a family history of these symptoms.

The main symptom in up to 96% of patients is recurrent nosebleeds, which can start in childhood. The nosebleeds become more common as the person gets older and may result in anemia, leading to the need for blood or iron transfusions. The average age that nosebleeds start is 12 and almost all HHT patients experience this by the age of 40. Nosebleeds should be evaluated using a procedure called a rhinoscopy, which involves examining the nasal cavity.

Reddish spots on the skin and mucous membrane usually start appearing in people’s 30s and become more numerous as they age. Some HHT patients, about 15-20%, also have recurring gastrointestinal bleeds. Patients should be checked for the frequency and severity of bleeds, and physically examined for reddish spots in various areas, such as the nasal mucosa, oral cavity, and skin on the fingers and nose.

• Recurrent nosebleeds
• Reddish spots (telangiectasias) on skin and mucous membranes
• Recurring gastrointestinal bleeds (in some patients)

Moreover, patients may also develop Arteriovenous Malformations (AVMs), which are abnormal connections between arteries and veins, in the lungs, gastrointestinal tract, brain, liver, or spine. Symptoms and complications related to these AVMs should be evaluated. These might include stroke, heart failure, blood clot, iron deficiency, brain abscess, liver disease, migraines, and high blood pressure in the lungs. Additionally, patients with a certain form of HHT are at higher risk of developing colon cancer.

• Stroke
• Heart failure
• Blood clot
• Iron deficiency
• Brain abscess
• Liver disease
• Migraines
• High blood pressure in the lungs
• Colon cancer (in some patients)

Diagnosis of HHT includes looking for four key features: frequent nosebleeds, family history, reddish spots on skin or mucous membranes, and Arteriovenous Malformations. A confirmed diagnosis is made if patients have at least three of these criteria.

• Frequent nosebleeds
• Family history of HHT
• Reddish spots on skin or mucous membranes
• Arteriovenous Malformations

Testing for Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)

If you or your child have been tested and only meet 1-2 criteria used to diagnose a condition called Hereditary Hemorrhagic Telangiectasia (HHT), your status should ideally be confirmed with genetic mutation testing. The purpose of this is to look for changes in three specific genes, ENG, ACVRL1, and SMAD4, which are commonly associated with HHT. The same tests should also be given to family members of those diagnosed with HHT.

It’s important to know, however, that not all cases of HHT are linked with these known genetic mutations; in fact, in 10 to 15% of HHT families, genetic testing fails to identify these particular mutations. As a result, a negative result on this genetic test doesn’t necessarily mean you don’t have HHT.

If HHT is confirmed, more tests might be necessary to check for any other issues related to the condition. Even if there are no clear symptoms, people with HHT need to be screened for health problems such as silent Arteriovenous Malformations (AVMs), which are abnormal connections between arteries and veins.

Arteriovenous Malformations (AVMs) may occur in various parts of the body, including the lungs, brain, and gastrointestinal tract (stomach and intestines). It is essential to detect these as early as possible due to the potential for serious complications.

For example, lung AVMs can cause severe bleeding in the lungs, strokes, brain abscesses (pus-filled areas), or other serious problems. Two common tests used to screen for these are a chest CT scan and an echocardiogram (ultrasound of the heart), which uses bubbles to enhance the images. A chest X-ray can also be performed, but it’s less effective at detecting lung AVMs.

Brain AVMs are common in HHT and can potentially cause severe damage, although the risk is relatively low. The benefits and risks of treating brain AVMs when no symptoms are present need to be weighed carefully. An MRI scan of the brain may be recommended if there are symptoms that suggest a brain AVM or if there’s a family history of brain hemorrhage (bleeding).

For the gastrointestinal tract, an endoscopy (using a tube with a camera to look inside your body) might be needed if you have anemia or a history of GI bleeding. If the results aren’t clear, a special pill with a tiny camera inside can be used to examine your digestive tract. In some HHT patients who also have a particular form called JPHT, screenings for colon cancer should start at an early age.

For the liver, a Doppler ultrasound (a procedure that uses sound waves to create images of the blood flow) is recommended to check for AVMs. This is important because it can help guide treatment decisions and improve outcomes. If ultrasound isn’t an option, a CT or MRI scan can be used instead.

Before any surgical procedures, your blood will be tested to check for any abnormalities. This includes a complete blood count, which measures the number and types of cells in your blood, and a blood type test if a blood transfusion might be needed. Other tests may be performed annually to screen for anemia caused by a lack of iron (iron deficiency anemia).

For pregnant women with HHT, they should also have tests to check for AVMs in the lungs and possibly the spine. This is ideally done through a team that specializes in high-risk pregnancies. The best time for any interventions is considered to be during the second trimester (months 4 to 6 of pregnancy).

If a pregnant woman has had a brain hemorrhage before or has symptoms of a brain AVM, she may need an MRI scan in the second trimester. The type of delivery (vaginal or cesarean section) will depend on individual medical factors, such as whether or not a woman has had a previous brain hemorrhage or symptoms of a brain AVM.

Treatment Options for Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)

Treatment options for HHT (a genetic disorder that causes blood vessels to form abnormally) are always personalized to each patient and usually focus on relieving symptoms, preventing complications, and optimizing quality of life. There isn’t really a “standard” treatment due to a lack of randomized trials. Below, you’ll find an overview of some of the main aspects of managing HHT.

Nosebleeds (Epistaxis)

The goal here is to prevent nosebleeds as much as possible. This includes using moisturizers, maintaining nasal cleanliness, using humidifiers and avoiding triggers or blood thinners. If nosebleeds still occur, things like decongestant sprays, manual pressure, absorbable nasal packing and chemical burning (cauterization) can help. If these still aren’t enough, surgery may be needed. There are also medical treatments that aim to reduce the frequency and severity of nosebleeds, including hormone therapy (estrogen agents), a medication to control bleeding (tranexamic acid), beta-blockers and other drugs.

Procedures like electrosurgical plasma coagulation, laser photocoagulation, and sclerotherapy also exist to help reduce the severity of nosebleeds. The last option is a procedure called Young’s procedure which involves blocking airflow through one or both nostrils, thereby preventing nosebleeds. However, the trade-off is a decrease in sense of smell and taste. This procedure is rarely done unless nosebleeds are very severe.

Anemia and Anticoagulation

Patients suffering from iron deficiency and anemia need iron replacement. This can be done via oral or intravenous (IV) iron infusions. Blood transfusions may also be necessary in some situations. As for blood thinners (anticoagulants), they’re allowed in HHT patients, but the type used depends on the patient’s suitability.

GI Bleeding

Patients with mild to moderate GI bleeding could be managed with iron replacement. For severe cases, iron replacement and transfusions would be necessary. Severe cases might also need certain drugs and endoscopic procedures.

Pulmonary AVMs (PAVMs)

PAVMs are recommended to be detected and treated due to their associated complications. The main treatment is a procedure called transcatheter embolization, which helps block the abnormal bleeding in the lungs. CT scans are recommended after the procedure to confirm it was successful.

Hepatic AVMs (HAVMs)

HAVMs are typically managed according to the symptoms they cause. They could cause problems like cardiac failure, portal hypertension, or cirrhosis, which are all managed medically. However, liver transplantation might be necessary for symptomatic HAVMs that fail to respond to medical treatments.

Cerebral AVMs (CAVMs)

CAVMs are usually small and located superficially. However, they’re usually managed conservatively (without intervention) because intervention has a higher risk of stroke or death. If intervention becomes necessary, options include embolization, microsurgery, stereotactic radiation, or a combination of these procedures. The choice of treatment depends on several factors, such as suitability for surgery and the size of the lesion.

What else can Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu) be?

There are certain conditions where one might bleed a lot after an injury, like von Willebrand disease or hemophilia. Hereditary Hemorrhagic Telangiectasia (HHT), however, tends to cause bleeding more around the areas of faulty blood vessels. Patients can often seem similar to those with other conditions, which is why it’s important to exclude these before landing on a final diagnosis. Sometimes, this might require specialist advice from a hematologist.

Here are some diseases with similar symptoms that have to be eliminated from consideration:

• Limited Systemic Sclerosis (a.k.a. CREST syndrome): This is a condition that causes issues like calcium buildup under the skin, issues with the esophagus, skin of the fingers or toes can tighten up and there can be red spots on the skin. Uncommonly, people will have repeat nose bleeds, unlike with HHT.
• Ataxia-Telangiectasia: This is a condition passed on from parent to child that often leads to loss of coordination, red spots on the skin, immune issues, and a higher risk of cancer. It often develops in early youth.
• Generalized Essential Telangiectasia: This rare condition, often appearing first on the legs before spreading over time, can occur within families or sporadically in individuals.
• Hereditary Benign Telangiectasia: This is, as its name implies, a harmless condition that is inherited and produces red spots on the skin and lips from birth or during childhood. People with this condition don’t often have other problems with their health.
• Rosacea: This is a common condition that causes facial redness and spots. It’s caused by a mixture of genetic and environmental factors.
• Telangiectasia Macularis Eruptiva Perstans: This is a rare type of disease in which there are more mast cells (cells of the immune system) in the skin than there should be. This leads to brownish red spots on the skin.
• Dermatomyositis: This is a condition that affects your muscles and skin, causing inflammation.
• Systemic Lupus Erythematosus (SLE): This is a condition that can have varied presentations and affects multiple body parts. It leads to problems like rashes, oral and nasal sores, and red spots on the hands.

Each of these medical conditions shares some symptoms with HHT and must be ruled out in the diagnosis process.

What to expect with Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)

The research on the overall survival rates and prognosis for patients with Hereditary Hemorrhagic Telangiectasia (HHT), a genetic disorder that affects blood vessels, is not extensive. However, it suggests that these patients may have a shorter life expectancy. One study found the median age of death for patients with HHT to be 63.2, compared to 70.0 years for those without the condition.

A more recent study, involving 675 patients, reported that those with HHT generally had a lesser survival rate than those without, with a median age of death being 77 years for HHT patients, in contrast to 80 for the others. Interestingly, this study found that the risk of death after being diagnosed with HHT was highest in the first three years, but then started to reduce.

This reduction in risk could be why HHT is often diagnosed after a person has a serious health event like a stroke. The findings underline the significance of early detection and screening of HHT, which could help prevent severe complications and potentially enhance the life expectancy of these patients.

Possible Complications When Diagnosed with Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)

People with HHT, a genetic disorder that affects blood vessels, are more susceptible to bleeding and nerve-related problems. These include anemia, brain abscesses, strokes, blood clots in the veins, and heart failure. Certain preventative measures and treatments are recommended for these specific problems.

• Anemia: It’s advised that HHT patients should undergo annual screenings to monitor blood count, ferritin, the total capacity of iron-binding, and reticulocyte count. If ferritin levels fall below 50, iron should be replenished either through oral consumption or intravenous injections.
• Brain Abscess: To prevent brain abscess, HHT patients should have screenings and considered embolization, a procedure to block abnormal blood vessels, of the pulmonary AVMs, an abnormal connection between arteries and veins in the lung. Moreover, it’s recommended to take antibiotics as a preventive measure before any surgical procedures.
• Stroke: To avoid the risk of stroke, similar to brain abscess prevention, screen and consider embolization of pulmonary AVMs. Iron needs to be replenished either orally or through IV when ferritin levels are less than 50. It’s believed that low iron levels can escalate the chances of clot formation.
• Vein Blood Clots: To lower the risk of blood clots forming in the veins, iron should be supplemented when ferritin is less than 50. Iron deficiency can increase the risk of clotting events. Use of anticoagulants, medications that prevent blood clots, are not contra-indicated (discouraged), but should be discussed with specialists.
• Heart Failure: For patients who have Hepatic AVMs, an abnormal connection between arteries and veins in the liver, it’s recommended to check annually for brain natriuretic peptide (BNP), a hormone produced by your heart and blood vessels. This hormone can help indicate heart failure.

Recovery from Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)

Scarring is often a side-effect of processes like laser ablation or electrosurgical cauterization, which are methods used to treat intranasal telangiectasias (dilated blood vessels inside your nose). This happens because these treatments can impair the functioning of mucociliary clearance, or the nose’s natural cleaning process, leading to crusting. To prevent scars and adhesions (also called synechiae) from forming after the operation, you’ll need to practice good nasal care. This includes cleaning your nose with saline sprays and washes as well as consciously removing any crusts that form.

When it comes to treating arteriovenous malformations (AVMs), abnormal tangles of blood vessels in your body, there’s no set aftercare procedure for after endovascular interventions or surgeries. Aftercare for your AVMs, including any activities you should avoid for a while, is determined by various factors. These factors include the AVM’s location, size, quantity, and whether you got treatment through an endovascular procedure (such as coiling or embolization) or a more traditional open surgery, as well as the surgery’s extent.

Patients who get a cerebral AVM (an AVM in their brain) treated through microsurgery might need physical therapy afterward. Moreover, you may need additional imaging tests afterward to check the treatment site and see if the AVM has recurred.

Preventing Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu)

People diagnosed with HHT (Hereditary Hemorrhagic Telangiectasia) need to understand the potential impact of this diagnosis. As HHT is an inherited disease, meaning it’s passed down from parents to their children, it’s crucial to also check other family members for signs of this condition. Additionally, it’s recommended to receive genetic counseling before starting a family. Discovering if you have HHT before symptoms appear allows for quicker testing and treatment, and it can also help identify other family members who may be at risk.