Osler-Weber-Rendu Disease (Hereditary Hemorrhagic Telangiectasia) Workup

Updated: May 15, 2017
  • Author: Klaus-Dieter Lessnau, MD, FCCP; Chief Editor: Vincent Lopez Rowe, MD  more...
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Workup

Approach Considerations

Currently, no laboratory studies are widely available to confirm the diagnosis of Osler-Weber-Rendu disease (OWRD; ie, hereditary hemorrhagic telangiectasia [HHT]). However, certain laboratory tests may be helpful in identifying specific complications.

Because of the prevalence of arteriovenous malformations (AVMs) and associated sequelae, screening with multiple (presumably complementary) imaging modalities is increasingly employed. Some investigators advocate helical computed tomography (CT); others, chest radiography with pulse oximetry. Contrast echocardiography is noninvasive and sensitive [82] and identifies intracardiac shunts, whereas arterial blood gas evaluation and pulse oximetry do not. Magnetic resonance imaging (MRI) also appears highly effective. [83]

Some centers screen asymptomatic children with a family history of OWRD in an effort to reduce serious complications associated with AVMs.

At specific centers and laboratories, genetic tests are available for various mutations in the endoglin gene (ENG) found on chromosome 9 and the activin receptorlike kinase type I (ALK-1) gene (ALK1) found on chromosome 12. These tests should be ordered in coordination with a physician and genetic counselor.

Currently, prenatal diagnosis is rarely used in families affected by OWRD. These families are encouraged to have DNA diagnosis of affected individuals where available. If the specific mutation within the family is revealed, cord blood from neonates may be analyzed for the presence of the disease, and multiple screening modalities for AVMs may be used.

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Laboratory Studies

When a complete blood count (CBC) is done, hemoglobin may be decreased because of chronic bleeding and iron-deficiency anemia, or the patient may be polycythemic because of chronic hypoxemia from a right-to-left shunt. The platelet count may be normal or slightly increased. The white blood cell (WBC) count should be within the reference range unless an infectious complication (eg, a brain abscess) is present.

Coagulation profile findings may exclude a concurrent disorder or coagulopathy. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) values should be normal, unless severe liver involvement is present. A preliminary study also points to the usefulness of factor VIII antigen levels; elevated levels may influence thrombotic risk in OWRD. [84]

Urinalysis should be done to assess for hematuria. [85] Stool should be evaluated to look for the presence of blood. Liver function tests may reveal elevated enzyme levels.

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Oximetry

Oximetry is performed with the patient standing and supine for 10 minutes in each position. An oxygen saturation level of less than 96% in either position is considered an indication for further testing. It is recommended that screening for pulmonary AVM using pulse oximetry in conjunction with chest radiography be performed once in childhood, once after puberty, before pregnancy, and at 10-year intervals thereafter. [86]

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Arterial Blood Gas Assessment

Arterial blood gas measurement can also be used as a screening test for pulmonary AVM. The quantification of a right-to-left shunt can be measured with the patient breathing 100% oxygen for at least 20 minutes. An arterial blood gas analysis is performed at the end of the study and shunt fraction is measured. This study can be performed in the pulmonary function laboratory.

If a right-to-left shunt is present, the arterial partial pressure of oxygen (PaO2) will be low. If such a shunt is suspected, PaO2 is measured while the patient is on 100% oxygen (so-called hyperoxic test). If PaO2 shows only a minor increase in this setting, the diagnosis of a right-to-left shunt is confirmed. If no shunt is present, PaO2 should increase to a much larger extent. Screening with a hyperoxic test has been shown to be 100% sensitive and 40% specific for the detection of pulmonary AVMs in OWRD patients suspected of having an AVM.

Technetium-99m–tagged albumin microspheres have also been used for shunt detection in the brain and kidneys. [87]

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Radiography

Posteroanterior and lateral chest radiographs may reveal a mass of enlarged arteries and veins typical of pulmonary AVM. Commonly found in the posterior lung bases, these lesions may also be hidden by the diaphragm. Chest radiography may also show a peripheral noncalcified coin lesion attached by vascular strands to the hilum. [88]

Chest radiography followed by agitated saline solution transthoracic contrast echocardiography (TTCE) with grading has been recommended as the screening test of choice for pulmonary AVMs in patients with OWRD. Initial studies of this modality suggested that it might be more sensitive than CT; however, because long-term follow-up data are not yet available, all patients with even low-grade evidence of pulmonary pathology on TTCE require CT as a confirmatory study. [89]

Barium enema is useful if an ulcer or neoplasm is suspected.

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Computed Tomography

Helical CT has been advocated as a screening method for pulmonary AVM. However, detractors believe that the radiation exposure is unnecessary and the cost is prohibitive. CT with contrast may be used to delineate AVMs of the lung or the brain. CT of the head is indicated in the workup of stroke and brain abscess and may reveal AVM. Abdominal CT may be useful for liver, kidney, and splenic lesions.

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Magnetic Resonance Imaging

Contrast-enhanced MRI is appropriate as a screening modality for pulmonary AVM. Planning for embolic treatment is possible with three-dimensional (3D) reconstructed images. [83] MRI is also a useful screening modality for telangiectasias in the central nervpus system (CNS). When clinical suspicion is high, MRI or magnetic resonance angiography (MRA) may be useful in identifying CNS lesions not observed with CT.

One-step MRI may be useful for evaluating liver involvement in HHT, revealing vascular abnormalities, telangiectases, arteriovenous shunting, focal liver lesions, and ischemic cholangitis. [90]

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Angiography

Preoperative or preablative assessment of pulmonary AVM may warrant angiography for treatment planning. Mesenteric angiography may reveal a bleeding site or mesenteric AVM and facilitate surgical extirpation. [91] As with other causes of gastrointestinal (GI) bleeding, a hemorrhage rate of at least 1 mL/min is necessary for detection with angiography, though GI bleeding at rates as low as 0.5 mL/min may be detected with technetium-99m–labeled autologous RBC scanning. Cerebral angiography may be indicated in the preoperative workup of CNS lesions.

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Ultrasonography and Contrast Echocardiography

Doppler ultrasonography of the liver may be used for screening and first-line imaging in patients with OWRD who have hepatic AVM or other associated sequelae.

Contrast echocardiography has been shown to reveal pulmonary AVM when pulse oximetry examination or even pulmonary angiography findings were negative. Agitated saline, with its small air bubbles, creates visible contrast that can be observed in the left atrium on echocardiography. The presence of contrast in the left atrium indicates right-to-left shunt.

The ability to detect intracardiac shunts is an advantage that contrast echocardiography has over other shunt studies. [82] Higher-grade shunts (>20-30 microbubbles/frame) have higher positive predictive value. [92]

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Genetic Testing

The sensitivity of molecular diagnosis is highest in probands with a clinically confirmed diagnosis of HHT. [24] However, a substantial fraction of probands do not carry an identifiable mutation in the coding exons of either of the two responsible genes, ENG and ALK1. Targeted family-specific mutation analysis for ENG exon deletions could lead to misdiagnosis of some affected family members with HHT, as was illustrated by the findings of a study in which two distinct ENG deletions were found in a single family. [93]

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Endoscopy

Upper and lower GI endoscopy may reveal telangiectases or AVMs. Colonoscopy reveals GI telangiectasias as small well-defined lesions surrounded by an anemic halo.

Push enteroscopy allows visualization of the proximal small bowel distal to the ligament of Treitz, though this or further intubation of the jejunum is technically demanding. Similarly, a skilled endoscopist can use a colonoscope placed proximal to the ileocecal valve to examine the distal ileum. The entire small bowel can be visualized with push enteroscopy; however, general anesthesia and intraperitoneal access (laparotomy or laparoscopy) are needed to manipulate and thread the small bowel over the endoscope inserted per os or per rectum.

Video capsule endoscopy is useful in the evaluation of occult GI bleeding of small-bowel origin. [94] Telangiectases from HHT can be visualized with this approach. [95] Using the capsule for diagnosis in a series of 18 patients, investigators noted small bowel involvement in patients with known gastric telangiectases in 56% of patients. [96]

A study of 30 patients with HHT and overt gut bleeding or severe anemia found video capsule endoscopy to have a high diagnostic yield. [97] This approach enables precise mapping of accessible lesions that are amenable to endoscopic treatment; innumerable diffuse lesions require a medical approach. Video capsule endoscopy may be a first-line, noninvasive digestive tract examination in selected patients with HHT.

Spiral enteroscopy has been shown to be a safe method of accessing the small bowel in patients with HHT. [98]

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Biopsy

Skin biopsy findings are often helpful in confirming the diagnosis of OWRD. Punch biopsy is usually adequate. Findings are localized in the dermal upper-horizontal plexus. The classic features are dilated capillaries and new vessel formation. In the dermis, the walls of dilated vessels may be thickened.

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Histologic Findings

Telangiectases manifest as focal dilatation of the postcapillary venules. Early lesions maintain a portion of intervening capillary bed. Perivascular lymphocytic infiltrate is observed. Fully developed lesions lack an intervening capillary bed. Markedly dilated arterioles and venules connect directly in a tortuous network. The mature lesion also shows lymphocytic infiltrate, as well as multiple layers of thickened smooth-muscle cells around connecting venules. [99]

Orthodeoxia may be detected in patients with pulmonary AVM because of increased shunting of blood through lesions in inferior areas of the lung. [100]

Liver specimens from patients with significant liver involvement often reveal pseudocirrhosis attributable to shunting from the hepatic artery to the hepatic vein or shunting from the hepatic artery to the portal vein.

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