Understanding Hereditary Hemorrhagic Telangiectasia (HHT)
Hereditary Hemorrhagic Telangiectasia, often referred to by its acronym HHT, is a genetic disorder that affects the body's blood vessels. The condition is also known as Osler-Weber-Rendu syndrome, named after the physicians who first described it. In a healthy circulatory system, arteries connect to veins through a network of tiny capillaries. In individuals with HHT, this delicate capillary network is absent in certain areas, causing arteries to connect directly to veins. These abnormal vessel connections can be small (telangiectasias) or large (arteriovenous malformations, or AVMs) and are characteristically fragile and prone to bleeding. This can result in significant bleeding events, particularly frequent nosebleeds, which affect over 90% of those with HHT.
The Question of Rarity: Official Status vs. Emerging Evidence
The question of is HHT a rare disease is complex. It is officially classified as a rare disease based on older prevalence estimates that suggested it affected roughly 1 in 5,000 to 1 in 10,000 people worldwide. However, experts in the field have long suspected that these numbers are an underestimate due to a significant rate of underdiagnosis. Many people with HHT, especially those with less severe symptoms, may go undiagnosed for years or decades. A major 2025 study using genetic data from the Genome Aggregation Database (gnomAD) calculated a potentially much higher HHT prevalence, suggesting it could be as high as 11.9 in 5000—well above the US Food and Drug Administration's official threshold for a rare disease. This study's findings reinforce the notion that HHT is not as rare as previously thought and highlights the importance of raising awareness among both the public and medical professionals.
What Causes HHT? The Genetics Behind the Disorder
HHT is an autosomal dominant genetic disorder, meaning a person only needs one copy of an altered gene from one parent to inherit the condition. This also means there is a 50% chance of passing the gene on to each child. The condition is caused by mutations in several genes that are vital for the proper development of blood vessels. The most common genes involved include:
- ENG: Mutations in this gene cause HHT type 1 (HHT1), which is associated with a higher prevalence of pulmonary and brain AVMs.
- ACVRL1: This gene is responsible for HHT type 2 (HHT2), which is more commonly linked with liver AVMs and gastrointestinal bleeding.
- SMAD4: Mutations here can cause a combined syndrome of HHT and juvenile polyposis, a condition that increases the risk of intestinal polyps and cancer.
These genetic variants disrupt a key signaling pathway that regulates blood vessel formation, leading to the characteristic fragile and malformed vessels.
Common Symptoms and Complications
The symptoms of HHT vary widely among individuals, even within the same family. The most common and often first symptom to appear is frequent, spontaneous nosebleeds (epistaxis), which can start in childhood.
Beyond nosebleeds, symptoms and complications can include:
- Visible telangiectasias: Small red or purple spots, especially on the lips, face, fingertips, and inside the mouth.
- Iron-deficiency anemia: Chronic blood loss, especially from the nose and gastrointestinal tract, can lead to severe anemia, causing fatigue, shortness of breath, and chest pain.
- Pulmonary AVMs (PAVMs): Malformations in the lungs can cause low blood oxygen levels, leading to shortness of breath. They also pose a risk of stroke and brain abscesses because they bypass the lungs' natural filtering system.
- Cerebral AVMs (CAVMs): Malformations in the brain can cause headaches, seizures, or a life-threatening brain hemorrhage.
- Gastrointestinal (GI) bleeding: Bleeding from telangiectasias in the GI tract can cause blood in the stool and severe anemia, though this is more common in adults.
- Liver AVMs: These can sometimes lead to high-output heart failure, portal hypertension, or biliary disease.
How is HHT Diagnosed? The Curacao Criteria and Genetic Testing
Diagnosis of HHT is typically made using a combination of clinical evaluation and genetic testing. The international standard for diagnosis is based on the Curacao criteria, which consider four key features:
- Epistaxis: Spontaneous and recurrent nosebleeds.
- Telangiectasias: Multiple telangiectasias on characteristic sites like the lips, oral cavity, fingers, and nose.
- Visceral Lesions: Arteriovenous malformations in major organs, such as the lungs, brain, or liver.
- Family History: A first-degree relative (parent, sibling, or child) with a confirmed diagnosis of HHT.
Meeting three or more of these criteria indicates a definite diagnosis of HHT. Genetic testing can also confirm the diagnosis by identifying a known mutation in an HHT-associated gene. For families where a mutation has been identified, genetic testing is often used to screen at-risk relatives.
Management and Treatment Options
Given the multisystem nature of HHT, management requires a multidisciplinary approach involving several specialists. The main goal of treatment is to control bleeding, prevent serious complications, and manage anemia caused by chronic blood loss. Treatment options include:
- Moisturizing and topical treatments: Nasal saline sprays, lubricants, and humidifiers help prevent nosebleeds by keeping nasal passages moist.
- Ablative therapies: Laser, radiofrequency, and electrosurgery can be used to cauterize nasal telangiectasias that cause frequent or severe nosebleeds.
- Embolization: This minimally invasive procedure involves blocking AVMs in the lungs, brain, or other organs by inserting a blocking agent via a catheter, effectively cutting off blood flow to the malformation.
- Surgical intervention: In some cases, particularly for certain brain or lung AVMs, surgical removal may be necessary.
- Medications: Anti-angiogenic drugs like bevacizumab can help reduce the number and size of telangiectasias, while antifibrinolytic agents such as tranexamic acid can help promote blood clotting. Hormonal therapies have also been used.
- Iron therapy: Severe anemia caused by chronic bleeding is managed with oral iron supplements or, for more severe cases, intravenous (IV) iron infusions.
Comparison of HHT with other bleeding disorders
| Feature | Hereditary Hemorrhagic Telangiectasia (HHT) | Von Willebrand Disease (VWD) |
|---|---|---|
| Underlying Mechanism | Artery-vein malformations (AVMs) and telangiectasias lead to localized, fragile bleeding points. | Deficiency or defect in von Willebrand factor (VWF), a protein essential for blood clotting. |
| Common Bleeding Sites | Nose, GI tract, lips, and larger visceral organs like lungs and brain. | Mucous membranes (gums, nose), skin, and heavy menstrual bleeding. |
| Inheritance Pattern | Autosomal dominant. | Most common forms are autosomal dominant. |
| Key Complications | Stroke, brain abscess, high-output heart failure, severe anemia. | Excessive bleeding during surgery, dental work, or trauma; easy bruising. |
| Healthcare Utilization | Tends to be higher due to more frequent emergency department visits and hospital admissions for severe bleeding and complications. | Lower healthcare utilization compared to HHT, though varies by type and severity. |
Living with HHT: Outlook and Prognosis
With appropriate diagnosis and ongoing management, many people with HHT can live relatively normal, full lives. Life expectancy is near-typical for those who undergo regular screening and receive necessary treatments. However, the chronic nature of the symptoms, particularly frequent nosebleeds and anemia-related fatigue, can significantly impact a person's quality of life. Regular screening for visceral AVMs is crucial, as they can be life-threatening if untreated. Patients with HHT should avoid activities that increase the risk of complications, such as scuba diving for those with pulmonary AVMs. For individuals and families, joining a support group can provide invaluable emotional and practical support. For more information and resources, the organization Cure HHT provides extensive guidance and community support.
Conclusion: The Evolving Understanding of a 'Rare' Disease
While HHT is formally classified as a rare disease, this designation is increasingly being called into question by scientific evidence pointing toward significant underdiagnosis. The condition, which can cause mild to life-threatening symptoms depending on the location of the vascular malformations, requires careful management and regular monitoring. By increasing awareness among both the public and medical community, a greater number of individuals with HHT can receive timely diagnoses and effective treatment, ultimately leading to better health outcomes and a higher quality of life. Understanding that HHT is a treatable condition, despite its 'rare' label, is the first step toward better patient care.
