Medical Summary

Hereditary Hemorrhagic Telangiectasia (HHT) is a multisystem vascular dysplasia characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Small AVMs, called telangiectases, close to the surface of skin and mucous membranes often rupture and bleed. The most common clinical manifestations are spontaneous and recurrent epistaxis and multiple telangiectases, which commonly appear on the lips, face, tongue or hands in adulthood. A minority of individuals with HHT have symptomatic GI bleeding, which most commonly begins after age 50 years. Large AVMs often cause symptoms when they occur in the brain or lung; complications from bleeding or shunting may be sudden and catastrophic.

Synonyms: Osler-Weber-Rendu (OWR) disease. Includes: HHT1 and HHT2

 

Differential Diagnosis

Epistaxis is relatively common in otherwise healthy individuals. Recurrent epistaxis can be a sign of various bleeding diatheses, including von Willebrand disease. Telangiectases occur in ataxia-telangiectasia, CREST syndrome, and hereditary benign telangiectasia, as well as a number of other clinical settings such as pregnancy or chronic liver disease. Most individuals with pulmonary AVM, especially multiple ones, have HHT. The majority of individuals with cerebral AVMs do not have HHT, but many do. Any individual with even an apparently isolated pulmonary or cerebral AVM should be evaluated for other manifestations of HHT and a targeted family history should be obtained.

 

Signs & Symptoms

About 95% of affected individuals eventually have recurrent epistaxis, with one third having onset by age ten years and 80-90% by age 21 years. However, many do not have nosebleeds that are frequent or severe enough to cause anemia or to result in medical treatment or consultation. While a similar proportion of affected individuals eventually develop telangiectases of the face, mouth, or hands, the average age of onset is generally later, in the decade of the 30s or 40s. Telangiectases vary in size from pinpoint to that of a small pea. Telangiectases can also occur in the gastrointestinal tract, most commonly in the stomach and small intestine. GI bleeding is usually low-grade in the 20-25% of patients that develop this symptom, but is often persistent and can become increasingly severe with age. Epistaxis and/or GI bleeding can cause mild to severe anemia.


Pulmonary AVMs have been reported to occur in approximately 40% of patients and Cerebral AVMs in 5-20% which may present with anything from seizure to cerebral hemorrhage. Spinal AVMs are less common. Hepatic AVMs are relatively common, but are usually asymptomatic. Most pulmonary and hepatic AVMs present as a consequence of blood shunting through the abnormal vessel and bypassing the capillary bed, not hemorrhage. Shunting of air, thrombi, and bacteria through pulmonary AVMs, thus bypassing the filtering capabilities of the lungs, may cause transient ischemic attacks (TIAs), embolic stroke, and cerebral or other abscess. Neurologic complications of pulmonary AVM may occur in patients with near normal oxygen tension. Massive hemoptysis, spontaneous hemothorax, migraines, polycythemia, and hypoxemia with cyanosis and clubbing are other possible complications. Hepatic AVMs can cause high output heart failure or portal hypertension.

 

Etiology / Epidemiolgy

HHT is an autosomal dominant disorder caused by a mutation in one of at least several genes. HHT type 1 (HHT1) is caused by a mutation in the endoglin gene (chromsomal locus 9q34); HHT type 2 is caused by a mutation in the ALK 1 (chromosomal locus 12q1). There are no common mutations or mutation types in either gene; indeed, thus far almost every family with HHT studied has been found to have a unique mutation. New mutations are rare. Data suggest that certain clinical manifestations, in particular pulmonary AVMs, may be more common in HHT type 1, and hepatic AVMs may be more common in HHT type 2. However, both types are clearly multisystem vascular dysplasias, with all of the above-mentioned manifestations found in individuals with each type of HHT.

A syndrome consisting of symptoms of HHT and juvenile polyposis was described in 2004 and is due to mutations in the MADH4 gene (chromosomal locus 18q21.1). Linkage analysis in one recently reported HHT family identified an additional locus at 5q31.3-32.

HHT occurs with wide ethnic and geographic distribution. The overall incidence of HHT in North America is estimated to be about 1:5,000.

 

Diagnosis

The clinical diagnosis of HHT is considered:

Definite when three or more of the criteria below are present

Possible or suspected when two of the criteria below are present

Unlikely when fewer than two of the criteria below are present

Diagnostic criteria for HHT:

  1. Nosebleeds(epistaxis): spontaneous and recurrent
  2. Telangiectases: multiple, at characteristic sites, including face, lips, oral cavity and fingers
  3. Visceral AVM (pulmonary, cerebral, hepatic, spinal) or gastrointestinal telangiectases (with or without bleeding)
  4. Family history: a first degree relative with HHT according to these criteria

Genetic testing is recommended to diagnose younger at risk relatives - after the diagnosis of HHT has been confirmed according to the above criteria in one or more family members. Consultation with a medical geneticist or genetics counselor is usually helpful to determine whether a given individual or family is a candidate for genetic testing, understands that a negative result does not rule out HHT, and to coordinate testing within the family which begins with testing a clearly affected member.

 

Management / Treatment

HHT Clinical Guidelines - published in Journal of Medical Genetics

Management issues include treatment of identified complications such as nosebleeds, GI bleeding, anemia, and AVMs, as well as surveillance for undiagnosed AVMs. All patients should have a brain MRI with and without gadolinium to screen for cerebral AVM (Adults: at least once  Children: in the first year of life, or at the time of diagnosis, and at least one follow-up MRI at puberty). Starting at about 10 years of age, contrast echocardiography (echo bubble) to screen for pulmonary AVM should be done. When contrast echocardiography demonstrates evidence of pulmonary shunting, chest CT should be done to determine if there are AVMs of a size requiring treatment by transcatheter embolization. Life long, periodic surveillance for pulmonary AVMs is recommended, but frequency and method is dependent on initial screening results and/or treatment. There is less consensus regarding screening for lung AVMs in the first decade of life, but it should be done by at least performing finger oximetry every 1-2 years in affected or at risk children. Children with oxygen saturations consistently below 97% should be evaluated for the presence of pulmonary AVM.

Treatment of identified pulmonary AVMs is indicated for dyspnea, exercise intolerance, or hypoxemia, but even in the asymptomatic patient is indicated for prevention of pulmonary/pleural hemorrhage and of neurologic complications such as cerebral abscess and stroke. Pulmonary AVMs with feeding artery diameter greater than or equal to 3 mm require treatment. Transcatheter embolotherapy with coils is the treatment of choice. New data suggests that follow-up by the treatment center at one year and every 3-5 years is important to detect growth of untreated PAVM and uncommonly, recurrence of treated PAVM. A .22 micron IV filter is recommended for all HHT patients with known PAVMs, untreated PAVMs, or those not yet screened by an HHT Center of Excellence. Untreated pulmonary AVMs are a common cause of ischemic stroke and brain abscess in HHT families.  Print Clinical Guidelines Checklist for Pulmonary AVMs.

Cerebral AVMs
greater that one cm in diameter are usually treated. There is yet no consensus on the best method of treatment, though often involves embolotherapy, surgery and/or stereotactic radiosurgery. The recommendation for treatment should come from a center experienced in management of cerebral AVM and more specifically in the management of CAVM associated with HHT. Print Clinical Guidelines Checklist for Brain AVMs.

Nosebleeds, skin lesions, and GI bleeding should all be treated symptomatically. Aggressive iron therapy is necessary in many adult patients to combat iron deficiency anemia. If nosebleeds are not adequately controlled by humidification and daily application of nasal lubricants by the patient, laser ablation may be the most effective intervention for moderate epistaxis. Septal dermoplasty using skin grafts is an option for individuals with severe epistaxis unresponsive to laser treatment. Electric and chemical cautery should usually be avoided. Laser ablation can be used for the rare skin or oral lesion that bleeds repeatedly or when desired by the patient for cosmetic reasons. Print Clinical Guidelines Checklist for Nosebleeds.

Endoscopic application of a heater probe, bicap, argon photocoagulation or laser are used by some to treat symptomatic GI bleeding. In some trials, hormonal treatment with estrogen-progesterone has decreased transfusion needs. Like telangiectases of the nose and skin, GI tract telangiectases will usually recur over time regardless of treatment.

Heart failure secondary to hepatic AVMs is problematic but fortunately affects only a few patients and can usually be treated medically. Embolization of the hepatic artery should not be used to treat liver shunting as the results are unpredictable with a post-procedure mortality of 20% due to liver necrosis. Similarly, liver biopsy or ERCP can cause serious complications and most experts agree that the diagnosis of liver involvement associated with HHT is easily made by imaging. Liver transplantation for severe symptomatic liver involvement by HHT has been performed successfully in small numbers of patients worldwide.


Anti-coagulants:
patients with HHT who develop thrombophlebitis or atrial fibrillation tolerate heparinization with low-molecular weight heparin surprisingly well. There may be an increase in epistaxis but that can usually be managed by an experienced Otolaryngologist. In general, aspirin is avoided. Non-steroidal anti-inflammatory agents such as ibuprofen can usually be taken for a short period of time. The risk vs. benefits of prescribing an anti-coagulant must be weighed on a case-by-case basis.


Antibiotic prophylaxis:
recommended before dental and surgical procedures is recommended in all patients with pulmonary AVMs, even once embolized. We warn patients to alert their doctors when starting IVs to be especially careful of air emboli. Use of air filters, while once recommended, is difficult because blood transfusion, CT contrast and gadolinium do not pass easily through an air filter. All IVs should be bubble free.

Because of danger of intrapartum or postpartum pulmonary hemorrhage, a pregnant woman with HHT who has not had a recent pulmonary evaluation should be evaluated as soon as pregnancy is recognized.