Clinical Tools & Resources
Diagnostic criteria, the test reference, referral pathways, and patient-facing materials for clinicians managing hereditary hemorrhagic telangiectasia (HHT).
The Curaçao Criteria
Clinical diagnosis rests on four criteria. Genetic testing supports the diagnosis but does not replace it, and a negative result does not exclude HHT, since no pathogenic variant is identified in roughly 10 to 15 percent of families who meet clinical criteria.
- Epistaxis. Spontaneous and recurrent nosebleeds.
- Telangiectases. Multiple lesions at characteristic sites, including the lips, oral cavity, fingers, and nose.
- Visceral lesions. Arteriovenous malformations of the lung, liver, or brain, or gastrointestinal telangiectases.
- Family history. A first-degree relative with HHT diagnosed by these same criteria.
Three or more criteria establish a definite diagnosis. Two make the diagnosis possible or suspected and warrant further evaluation. Zero or one makes HHT unlikely. Criteria are less reliable in children, who may not yet show telangiectases or epistaxis, so a child with an affected parent should be evaluated regardless of the count.
Genetics at a glance
HHT follows autosomal dominant inheritance. Each child of an affected parent has a 50 percent chance of inheriting the condition, and penetrance is high, approaching complete by middle age.
Once a pathogenic variant is identified in a family, cascade testing of at-risk relatives is straightforward and definitive. Relatives who test negative for the familial variant need no further HHT screening, which spares them years of imaging.
Which gene a family carries changes what to watch for, and in the case of SMAD4 it adds a surveillance requirement that has nothing to do with bleeding.
~90%
of cases involve ENG or ACVRL1
3–5%
involve SMAD4, with juvenile polyposis overlap
10–15%
have no variant identified on current testing
50%
chance of inheritance for each child
Test reference
What each test detects, and when to order it
Filter by organ system or by whether the test is a first-line screen or a confirmatory study. Open a test for what it detects, how it performs, and the practical caveats.
10 tests
Transthoracic contrast echocardiography (bubble study)
What it detects. Right-to-left shunt, which in HHT usually indicates one or more pulmonary AVMs. Agitated saline appears in the left heart after a delay of three to eight cardiac cycles; earlier appearance suggests an intracardiac shunt instead.
How it performs. Highly sensitive for pulmonary AVMs large enough to warrant treatment. Specificity is lower, because small shunts that will never need intervention also produce a positive study. Results are graded by the volume of contrast crossing.
When to order it. At diagnosis in every patient with confirmed or suspected HHT, again after puberty, before or early in pregnancy, and at roughly five-year intervals in adults with a previously negative study. A grade-zero study is reassuring enough to defer computed tomography.
Chest computed tomography, without contrast
What it detects. The anatomy of pulmonary AVMs: number, location, and feeding artery diameter. This is what determines whether a lesion can be treated by embolization.
How it performs. The reference standard for characterizing pulmonary AVMs. Intravenous contrast is not required and should be avoided; a non-contrast study answers the question.
When to order it. After a positive or equivocal bubble study, not as the initial screen. Use the lowest dose protocol available, since many of these patients are young and will be imaged repeatedly over a lifetime.
Pulse oximetry and chest radiography: why neither is sufficient in adults
What they detect. Only advanced disease. Oxygen saturation stays normal in many patients with pulmonary AVMs, including some with lesions large enough to cause stroke or brain abscess.
How they perform. Both miss clinically important lesions. A normal saturation and a clear chest film together do not exclude pulmonary AVMs in an adult.
What to do instead. Order a bubble study. Pulse oximetry with chest radiography does have a defined role as the initial screen in asymptomatic children, where avoiding radiation and sedation carries more weight; in adults it is not an adequate substitute.
Brain magnetic resonance imaging, with and without contrast
What it detects. Cerebral AVMs and other brain vascular malformations. Sequences should include susceptibility-weighted or gradient-echo imaging, which picks up small lesions that standard sequences miss.
How it performs. The most sensitive non-invasive study available for these lesions. Computed tomography of the head is not an adequate substitute for screening.
When to order it. Once at the time of diagnosis, including in children, and early in life for a child with a parent who has HHT. Consider one adulthood study after a negative childhood study. Repeat imaging is otherwise not needed unless new neurological symptoms appear.
Doppler ultrasonography of the liver
What it detects. Hepatic vascular malformations and the shunt pattern they create: arteriovenous, arterioportal, or portovenous. Hepatic artery diameter and flow velocity grade the severity.
How it performs. Accurate in experienced hands, without radiation or contrast, which is why it is the preferred first-line investigation.
When to order it. When symptoms or signs suggest complicated hepatic involvement: heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension, or encephalopathy. Presymptomatic screening of every adult is not currently recommended and can be discussed case by case.
Multiphase computed tomography or magnetic resonance of the liver
What it detects. The same shunts the ultrasound identifies, in more anatomical detail, along with focal nodular hyperplasia and other parenchymal changes seen in HHT.
How it performs. Magnetic resonance provides both multiphase anatomical assessment and hemodynamic characterization. Computed tomography is recommended where Doppler expertise is lacking.
When to order it. When ultrasonography is equivocal, or when symptomatic hepatic involvement is being worked up. Liver biopsy should be avoided in any patient with proven or suspected HHT, and hepatic artery embolization should be avoided because of its associated morbidity and mortality.
Echocardiography and right heart catheterization for cardiac output and pulmonary pressure
What they detect. High-output cardiac failure driven by hepatic shunting, and pulmonary hypertension, which occurs in HHT both from high output and, less commonly, as pulmonary arterial hypertension associated with ACVRL1 variants.
How they perform. Echocardiography is adequate for detection and for following a known abnormality. Right heart catheterization is what distinguishes high-output failure from pulmonary arterial hypertension, and the two are managed differently.
When to order them. Echocardiography once hepatic vascular malformations are found, or when a patient reports dyspnea, exercise intolerance, or edema that anemia alone does not explain. Catheterization where there are signs or symptoms of heart failure or possible pulmonary hypertension.
Complete blood count, iron panel, and ferritin
What it detects. Iron deficiency, with or without anemia. A normal hemoglobin does not rule out depleted iron stores, and iron deficiency causes fatigue and exercise intolerance before the hemoglobin falls.
How it performs. Straightforward and inexpensive, and the single most under-ordered test in HHT care. Ferritin is an acute-phase reactant, so interpret it alongside transferrin saturation when inflammation is present.
When to order it. Annually in every adult with HHT regardless of symptoms, in any child with recurrent bleeding or symptoms of anemia, and more often when clinically indicated. Treat to repletion rather than to the bottom of the reference range.
Upper endoscopy, capsule endoscopy, and colonoscopy
What they detect. Gastrointestinal telangiectases, most often in the stomach and duodenum. Capsule endoscopy extends the examination through the small bowel when upper endoscopy does not explain the bleeding.
How they perform. Direct visualization, so detection is reliable. The harder question is attribution: whether the anemia is out of proportion to the epistaxis is what should drive the referral.
When to order them. Endoscopy when anemia exceeds what the nosebleed history accounts for. Regular colonoscopy for patients who meet standard colorectal cancer screening criteria, and for any patient with a SMAD4 variant, proven or suspected, starting at age 15.
Molecular genetic testing: ENG, ACVRL1, SMAD4, and GDF2
What it detects. A pathogenic variant in one of the genes associated with HHT. Testing the affected family member first, then testing relatives for that specific variant, is faster and far less expensive than testing each relative de novo.
How it performs. A variant is identified in roughly 85 to 90 percent of families who meet clinical criteria. A negative result therefore does not exclude HHT, and a patient who meets three Curaçao criteria has HHT whatever the genetic result says.
When to order it. To confirm a suspected diagnosis, to enable cascade testing of at-risk relatives, including asymptomatic children of an affected parent, and before prenatal or preimplantation decisions. A SMAD4 result changes management, because it carries juvenile polyposis and its own surveillance schedule.
Adapted from the Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia (Faughnan et al., Annals of Internal Medicine, 2020, 173(12), 989–1001). This summary does not replace the published guidance, clinical judgment, or center-specific protocols.
At the point of care
Practice points that change outcomes
1
Screen for pulmonary arteriovenous malformations in every patient with confirmed or suspected HHT
They are frequently asymptomatic, and untreated they carry risk of stroke and brain abscess through paradoxical embolism.
2
Use bubble contrast echocardiography as the first-line pulmonary screen
Reserve computed tomography for positive or equivocal studies.
3
Advise antibiotic prophylaxis before dental and other procedures
This applies to patients with known or unscreened pulmonary malformations. Avoid air in intravenous lines.
4
Test all adults with HHT for iron deficiency, and treat it
Anemia in HHT is frequently undertreated because the bleeding is visible and therefore assumed to be accounted for.
5
Anticoagulation is not absolutely contraindicated
It requires a considered risk assessment rather than a reflexive refusal, ideally with input from an HHT center.