What is Hereditary Hemorrhagic Telangiectasia (HHT)?

What is Hereditary Hemorrhagic Telangiectasia (HHT)?
HHT is an inherited genetic disorder that affects the vascular system. It causes arterial blood to flow directly into the veins, through abnormal weakened and distended vessels that can rupture. HHT occurs in about 0.02% of the population, in men and women alike, and in equal proportions across the ethnic spectrum.

The disorder is also sometimes referred to as Osler-Weber-Rendu (OWR) named for three doctors who discovered HHT over 100 years ago. In 1896, Dr. Rendu first described HHT as a hereditary disorder involving nosebleeds and characteristic red spots that was distinctly different from hemophilia. A few years later, Osler and Weber publicised additional findings related to the disease. Nonetheless, despite the passage of more than a century, HHT is often misdiagnosed in affected individuals.

What is the disease?
The disease is characterized by the formation of abnormal blood vessels in certain organs in the body. Normally, blood vessels are comprised of interconnected arteries, veins and capillaries. The heart pumps blood through the arteries at high pressure to the various body organs at which point the arteries diffuse into smaller capillaries. The capillaries drain into veins which return blood to the heart and lungs. In healthy people, capillaries form the junction between artery and vein with no direct link between them. In HHT sufferers, there is a direct link between artery and vein in various organs. Since there is high pressure in the arteries and low pressure in the veins, the junction between them tends to widen and sometimes hemorrhage. The intersection points are termed telangiectases when the malformed vessels are small, or arteriovenous malformations (AVMs) when they are larger.

Telangiectases appear mainly on the skin's surface and mucosa while AVMs are present internally. Initial symptoms are mostly nosebleeds and telangiectases on the skin and mucosa, while the AVMs are often "quiet" until the onset of complications outlined below. Therefore, the disease is frequently misdiagnosed in childhood and adolescence.

How is the disease expressed?
Symptoms generally appear during late childhood and early adulthood.

Nosebleeds
Nosebleeds are the most common symptom of HHT, and affect about 95% of patients. Bleeding emanates from telangiectases in the nasal mucosa and appears in late childhood or young adulthood and worsens over time. Yet there are huge dissimilarities between patients. There are cases where nosebleeds start in infancy, others where nosebleeds do not appear until adulthood. There are also instances of improvement over the years. Even the severity of nosebleeds differ from patient to patient: some have light and infrequent occurrences; others have heavy nosebleeds every day so much so that they require ongoing iron supplements and periodic blood transfusions.

Telangiectases
These involve distended blood vessels in the skin and mucosa, which look like red dots on the skin's surface of the face, hands and mucosa of the mouth and tongue. Telangiectases frequently appear only in adulthood and their numbers are increasing every year. Here too, the differences between patients are broad. The spots in the mouth's mucosa can hemorrhage, albeit less so than nosebleeds. Telangiectases can also appear in the mucosa of the digestive tract mainly in the stomach and small intestine or found along the entire length of the digestive tract. They do not cause pain but between 20-25% of patients suffer prolonged bleeding that can lead to weakness, anemia and shortness of breath.

Arteriovenous Malformations (AVMs)

Lung AVMs
Lung AVMs occur in about 30-50% of HHT patients and can lead to life-threatening complications ranging from lung hemorrhage to a stroke or a brain abscess. In general, the lung's capillary network has a role in filtering the blood coming from the lower limbs and the rest of the body. A thrombosis formed for instance in the veins of the leg, or bacteria that invaded the blood stream, could potentially reach the brain and cause severe damage. In healthy people, the lung's capillaries "trap" the thrombosis or bacteria blocking its path to the brain's arteries. In HHT patients with lung AVMs however, the capillary network is bypassed, and the bacteria or thrombosis coming from the limbs detour the lung's filtering system via the AVM and thus reach the brain. HHT patients are therefore at risk of developing complications in the brain. In addition, lung AVMs can cause cyanosis, weakness and inability to handle physical stress.

Brain AVMs
Brain AVMs occur in about 5-20% of HHT patients and can lead to a stroke where there is hemorrhage. There are often no warning signs of brain AVMs until the appearance of hemorrhage with life-saving complications. AVMs of the spine are much rarer.

Liver AVMs
AVMs in the liver are common but, as opposed to lung and brain AVMs that can cause sudden complications, liver AVMs show a slower clinical picture. Usually they are completely asymptomatic but when they are large, they can cause heart dysfunction with increased heart output followed by heart failure. Liver failure can also develop in such cases.

How is the disease caused?
HHT is an autosomal inherited dominant disease.

What is an autosomal dominant disease?
"Autosomal" means that the causative gene of the disease is not on the sex chromosome and therefore the incidence is the same in both boys and girls.

What does "dominant" mean?
The genetic code carried by each one of us comprises a duplicate set of genes – one derived from the father and one from the mother. In an inherited dominant disease, one abnormal gene is sufficient to cause the disease. Since HHT is a dominant disease, sufferers carry one normal and one abnormal gene. It is not possible to anticipate which gene is inherited by the child. The chances are the same for inheriting an abnormal gene as they are for inheriting a healthy one and thus the risk of a child being born with the disease is 50%. The disease is passed from one generation to the next and does not skip generations. Nonetheless, sometimes there are no symptoms or they are mild which could give the mistaken impression that the disease was passed from grandparent to grandchild having skipped the parent's generation.

What is the disease's abnormal gene?
Although three different genes that might cause the disease have been discovered thus far, it seems that there are others that have not yet been identified. Those found play an important role in building the body's vascular system so an abnormality could interfere with the structure of blood vessels and the disease. One of the genes identified as a cause of HHT appears to be part of a syndrome that also includes the appearance of polyps in the digestive system at a young age. This group is in the minority of HHT patients but require special attention.

Can HHT be treated?
There are two key objectives in the treatment of HHT:
1. Treating symptoms that affect the patient's health and quality of life (most commonly, nosebleeds)
2. Preventive care of malformations to avoid life-threatening complications

Nosebleeds are the most common complaint of HHT patients as well as the most significant symptom affecting quality of life. Treating nosebleeds is challenging that requires skill and broad knowledge. Oil or water-based localized creams can be helpful. When these are ineffective, localized laser treatments should be considered. Laser treatment is preferable to electrical or chemical ablation. Laser therapy requires great skill both in laser treatment and in HHT. Incorrect use of the laser could be ineffective and even detrimental.

In severe cases, septal dermoplasty may be suggested where bleeding nasal mucosa is replaced with a skin graft. The operation is not without its risks. Hormonal treatment might also be suggested and is in use in Israel. Embolization of the nasal artery is only recommended in certain cases. It should be remembered that periodic nosebleeds cause anemia and require prolonged supplements of iron. There are also cases where repeated blood transfusions are required.

Telangiectases on the skin's surface can be ablated by laser although no treatment is needed in the majority of cases. Telangiectases within the digestive system generally do not require treatment unless anemia develops. However, there is a need to boost iron reserves that are depleted through bleeding.

In lung and brain AVMs, treatment should be given prior to the onset of complications:
Although lung AVMs can cause cyanosis and fatigue, in many cases the patient is asymptomatic and unaware of the illness until the appearance of life-threatening complications. Therefore, malformations should be treated even when the patient is asymptomatic and this is usually done by closure of the artery through catheterization. Recovery is rapid with discharge the same or following day. Catheterization involves insertion of a catheter via the femoral vein where it reaches the vessel supplying blood to the AVM in the lung. A blocking device is threaded through the catheter where it is deposited in the artery thus effectively blocking it.

Access to brain AVMs depends upon the location and size of the malformation. These too can be closed via catheterization.

Liver AVMs are treated only if there are symptoms and treatment usually is via medication. As opposed to AVMs in the lung or brain, liver catheterization and AVM closure are risky and are not standard practice.

How is HHT diagnosed?
HHT can be genetically identified through a regular blood test. The blood sample is examined for mutations (gene abnormalities) that cause HHT. Diagnosis is complex and its sensitivity incomplete, meaning that the mutation is not found in all patients. Where a family seeks genetic analysis, the genetic analysis should first

be performed in a family member with clear signs of the disease. Should a mutation be identified in this index case, other family members should be checked. There is less significance to conducting a genetic test in an HHT patient with obvious symptoms. Identifying the mutation in this patient is mostly important to establish or rule out the disease in family members with no clear symptoms.

The disease can also be diagnosed clinically. A committee of specialists decided upon the existence of four criteria to confirm HHT. The presence of any 3 criteria represents a definite diagnosis; the presence of 2 criteria indicates suspected HHT.

The criteria for diagnosis
1. Repeated nosebleeds
2. Multiple telangiectases in typical locations – lips, mouth cavity, fingers, nasal mucosa
3. AVMs or telangiectases in internal organs of the digestive tract, liver, lungs, brain and spine
4. First-degree family relative suffering from the disease according to the above criteria

Can genetic testing be done in Israel?
Genetic mutations – genetic changes causing the disease in the majority of patients – are a recent discovery. Until now, tests were conducted by a few laboratories worldwide at high cost. In 2010, Schneider Children's and Hadassah Hospital in Ein Kerem agreed to collaborate on genetic testing for mutations causing the disease. Patients are referred by the clinic at Schneider Children's and undergo tests at Hadassah by Dr. Neta Goldshmidt from the laboratory of Dr. Shula Metzger. It should be noted that it is not possible to identify mutations in all cases, and there are those cases where, despite the presence of the disease, the mutation is unknown. Thus far, about 30 families have undergone testing, the majority of whom were found to carry the mutation.

In order to undergo the test, contact Dr. Mei Zahav, Director of the HHT Center at Schneider Children's (Tel for appt: 03-9253210) or Dr. Neta Goldshmidt, at the Hematology Clinic at Hadassah Hospital (Tel for appt: 02-5842111).

What can I, as an HHT patient or a family member, do?
Since lung and brain AVMs can cause life-threatening complications even in the absence of any prior symptoms, all HHT patients must be examined for the presence of AVMs in these organs. First-degree relatives should also undergo evaluation.

Lung AVMs
Each patient and first-degree family member (who may also suffer from the disease) must be examined. AVMs are typically seen in a chest x-ray as a circular mass surrounded by distended veins and arteries. While the test is easy to do, small AVMs may not be identified and therefore an x-ray is not the test of choice. Oxygen saturation in the blood can also assist in the search for AVMs in the lungs, but the test is insensitive. Digitized tomography (CT) with contrast media was considered the test of choice until recently. However, since it involves a high amount of radiation, other methods were sought.

More recently, cardiac contrast echocardiography has gradually evolved as the definitive test. The test is simple and except for the need of an intravenous line, is not invasive. The test requires intravenous infusion of a physiologic fluid that has undergone agitation and contains microscopic bubbles. In the absence of AVMs, these bubbles will be absorbed into the lung's capillary network and will not be detected in the left side of the heart. If the bubbles appear in the left side of the heart, suspicion is raised of a lung capillary bypass due to the presence of lung AVMs. This test has proven to be the most sensitive and is currently the recommended tool of choice for screening in children and adults.

Brain AVMs
The accepted test for the presence of AVMs in the brain is a brain MRI.

Liver and the Digestive Tract AVMs
Since AVMs in these organs are not treated unless there are symptoms, there is no need for any scanning study.

AVMs in the lungs pose a specific danger during dental treatment when bacteria that normally reside in the mouth cavity can enter the bloodstream and reach the brain via the lung "bypass". HHT patients should receive antibiotic treatment prior to any dental procedure. Patients whose scans have not revealed lung AVMs are not required to take antibiotics prior to dental procedures.

HHT patients should be followed in a specialized center and treated for symptoms including an annual test of iron levels.

 

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