Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a genetic disorder affecting how blood vessels develop throughout the body. This condition causes the formation of abnormal blood vessels that rupture easily, leading to chronic bleeding. While common symptoms include recurrent nosebleeds and small red spots on the skin, HHT is potentially life-threatening due to malformations that can occur in vital organs like the lungs and brain. Proactive medical management and early detection of these internal complications are necessary to reduce the risk of sudden, catastrophic events. With appropriate care, people living with HHT often have a life expectancy similar to that of the general population.
Genetic Basis and Vascular Malformations
HHT is inherited in an autosomal dominant pattern, requiring only one copy of the mutated gene from a parent. Most cases are caused by mutations in the ENG (Endoglin) or ACVRL1 (ALK-1) genes. These genes produce proteins essential for the Bone Morphogenetic Protein (BMP) signaling pathway in endothelial cells, which line blood vessels. When mutated, this deficiency disrupts the normal development of vascular structure, leading to characteristic malformations. These malformations include telangiectasias and arteriovenous malformations (AVMs).
Telangiectasias are small, dilated blood vessels found on the skin, lips, or the lining of the nose and gastrointestinal tract. AVMs are larger lesions where arteries connect directly to veins, bypassing the normal capillary network. This direct connection allows high-pressure arterial blood to flow into lower-pressure veins, creating a fragile shunt prone to rupture or excessive blood flow.
Critical Organ Complications and Mortality Risk
The life-threatening nature of HHT stems from the development of AVMs in major organs, which can fail if left untreated. If these internal AVMs are not managed, approximately 10% of affected individuals may die prematurely or suffer major disability. The primary risk is associated with these specific organ lesions, not the common, chronic bleeding from telangiectasias.
Pulmonary AVMs (PAVMs)
Pulmonary AVMs (PAVMs) are the most frequent severe complication, occurring in 15% to 45% of HHT patients. These AVMs bypass the lungs’ capillary system, which normally filters small clots, bacteria, and air bubbles from the bloodstream. The loss of this filtering function allows unfiltered material to pass directly from the right side of the heart into the systemic circulation. This process, known as a paradoxical embolus, is the primary mechanism for neurological complications. Paradoxical emboli can travel to the brain, causing ischemic stroke or transient ischemic attacks. Additionally, bacteria bypassing the lungs can seed the brain, leading to the formation of a brain abscess. A severe risk is the spontaneous rupture of a large PAVM, which can cause life-threatening hemorrhage within the chest cavity or lungs.
Cerebral AVMs (CAVMs)
Cerebral AVMs (CAVMs) affect about 10% of HHT patients and pose a direct threat to the central nervous system. The thin walls of these malformations are under high arterial pressure, making them susceptible to rupture. A rupture results in an intracranial hemorrhage, or bleeding directly into the brain tissue, which can be life-threatening or cause permanent neurological damage and seizures.
Hepatic AVMs (Liver)
Liver AVMs (HAVMs) occur in up to 78% of patients, though they rarely cause hemorrhage. The danger lies in the large volume of blood shunted directly from arteries to veins within the liver. This high-volume shunting forces the heart to work hard to maintain circulation throughout the body. This persistent overload can lead to high-output cardiac failure, where the heart cannot meet the body’s demand for blood flow despite pumping rapidly. The resulting high-output cardiac failure is a source of morbidity and mortality for some patients.
Screening Protocols for High-Risk AVMs
Since the most dangerous AVMs are often silent, proactive screening is the standard of care for HHT patients. The goal is to identify these high-risk lesions before they cause a stroke, brain bleed, or heart failure. Screening is recommended for all individuals with confirmed or suspected HHT, even if they are asymptomatic.
Screening for cerebral AVMs (CAVMs) uses Magnetic Resonance Imaging (MRI) of the brain, combined with magnetic resonance angiography (MRA). This allows physicians to visualize the structure of the brain’s blood vessels and detect malformations. For children, an initial brain MRI is recommended early in life, with consideration for a follow-up scan around puberty.
Detecting pulmonary AVMs (PAVMs) begins with a non-invasive test called a transthoracic contrast echocardiography (TTCE), or bubble study. This procedure involves injecting agitated saline solution into a vein. If microbubbles appear in the left side of the heart, it indicates blood is bypassing the lung’s capillaries through an AVM. A positive bubble study is followed by a Computed Tomography (CT) scan of the chest. The CT scan provides detailed images of the lungs, allowing doctors to precisely locate and measure the size of the PAVMs. PAVM screening is repeated every three to five years if initial tests are negative, as new lesions can develop.
Targeted Treatments to Prevent Catastrophic Events
The primary strategy for mitigating life-threatening risks involves targeted interventions to eliminate or neutralize high-risk AVMs identified during screening. This preventative approach focuses on PAVMs and CAVMs, which pose the greatest immediate threat of stroke or hemorrhage. Treating these malformations reduces the risk of major disability or early death.
The mainstay of treatment for PAVMs and many CAVMs is embolization, a minimally invasive procedure performed by an interventional radiologist. During embolization, a catheter is threaded to the AVM site. Tiny coils or a specialized glue are deployed to block the abnormal connection, diverting blood flow and causing the AVM to shrink. Embolization is highly effective for PAVMs and is recommended for any lesion large enough to pose a neurological risk. For CAVMs, high-risk lesions may be treated with embolization, stereotactic radiosurgery, or surgical resection, depending on size and location. Since the risk from hepatic AVMs is primarily high-output cardiac failure, treatment focuses on managing the heart condition, as embolization of liver AVMs is avoided due to complication risks.