History
Telangiectases of the skin and mucous membranes, epistaxis, and a positive family history make up the classic triad of Osler-Weber-Rendu disease (OWRD; ie, hereditary hemorrhagic telangiectasia [HHT]). Visceral and central nervous system (CNS) involvement may be asymptomatic but is important because of associated complications that may be preventable. The diagnosis is made on clinical grounds, in accordance with the Curaçao criteria (see DDx). [9]
The estimated frequency of manifestations in patients with HHT is as follows:
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Spontaneous, recurrent epistaxis - 90%
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Skin telangiectases - 75%
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Hepatic or pulmonary involvement (arteriovenous malformations [AVMs]) - 30%
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Gastrointestinal (GI) bleeding - 15% [32]
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CNS lesions [42]
It is recognized that the manifestations of HHT are not generally present at birth but develop with increasing age. Data suggest that by age 16 years, 71% of individuals will have developed some sign of HHT, and by age 40 years, more than 90% will have done so. However, these data mean that during their childbearing years, an apparently unaffected child of an HHT patient still has a 5-20% chance of actually carrying the HHT disease gene. [32]
A known progression in the onset of symptoms over time begins with epistaxis, continues with pulmonary AVMs, and then proceeds to cutaneous and mucous telangiectases. [32]
Epistaxis
Nosebleeds may occur as often as every day or as infrequently as once a month. Patients with epistaxis usually present before the second decade of life. Blood transfusions are required in 10-30% of patients, and as many as 50% of patients require surgical treatment.
At present, there is no universally accepted method of measuring epistaxis severity. Rebeiz developed a classification that stratified epistaxis as follows [43] :
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Mild - A few episodes per week without transfusion requirement
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Moderate - One or two episodes per day, with fewer than 10 transfusions required in the patient’s lifetime
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Severe - Daily episodes lasting longer than 30 minutes, with more than 10 transfusions required in the patient’s lifetime
More than 900 respondents from 21 countries are currently participating in a study intended to create an epistaxis severity score for use in patients with OWRD. [44]
Pulmonary symptoms
Pulmonary AVMs affect approximately 50% of patients with HHT. [45] and are particularly common in HHT1, with 85% of ENG mutation carriers demonstrating right-to-left shunts on contrast echocardiograms. [45, 46]
Pulmonary AVMs are present in 15-33% of patients with the disease. Dyspnea and exercise intolerance are often presenting symptoms of pulmonary AVMs; however, most patients with pulmonary AVMs have no significant respiratory symptoms. [47, 48] Pulmonary AVMs may cause enough right-to-left shunting to cause cyanosis, hypoxemia, and secondary polycythemia. Pulmonary AVMs also increase the incidence of infection as a result of septic emboli formation in the pulmonary vasculature.
Pulmonary hypertension is another vascular manifestation of HHT. Although much less common than pulmonary AVMs, it can result from systematic arteriovenous shunting in the liver that increases cardiac output, or it can be clinically and histologically indistinguishable from idiopathic pulmonary hypertension. [49]
Telangiectasia
Telangiectases often appear 1 year after the first episode of epistaxis. The mucous membranes are almost invariably involved. About 30% of affected individuals report telangiectases first appearing before age 20 years, and two thirds report first appearances before age 40 years. [50] Patients usually have a family history of telangiectasia and recurrent bleeding in other family members.
Neurologic symptoms
Migraine headaches occur in 13-50% of patients with OWRD. Although the reason is unclear, the headaches are more prevalent in patients with pulmonary AVMs. Other neurologic involvement occurs in 8-12% of patients with OWRD. A history of headache, seizures, and focal neurologic symptoms (eg, paraplegia or paralysis) may be presenting symptoms.
Stroke and brain abscess are more common in patients with OWRD than in the healthy population. This is because the normal filtering function of the pulmonary vasculature is lost in patients with pulmonary AVMs. These AVMs allow thrombotic and septic emboli to travel to the brain. Untreated patients have a 2% risk of stroke and a 1% risk of brain abscess per year. [51]
Spinal AVMs represent a rare manifestation that mainly affects children. Acute paraplegia due to spinal arteriovenous fistula has been described. [52, 53] Examining any child with a family history of HHT for spinal AVMs may be advisable for decreasing the risk of neurologic sequelae.
Gastrointestinal and hepatic symptoms
The risk of GI tract bleeding increases at approximately 50 years of age. Recurrent painless GI bleeding occurs in 10-40% of patients and generally occurs later in life than epistaxis does. Visceral AVMs may be evident. [54] Patients may report abdominal pain, which may be due to thrombosis of GI AVMs.
Liver involvement (often asymptomatic) is reported in as many as 40% of patients. Symptoms may include right-upper-quadrant pain, jaundice, symptoms of high-output cardiac failure, and bleeding from esophageal varices. The complication of cardiac failure is caused by a large left-to-right shunt that can occur between the hepatic arteries and veins. Occasionally, patients with HHT may present with atypical cirrhosis.
Other symptoms
Fatigue may be elicited on history and may be due to an iron deficiency anemia caused by recurrent blood loss.
Visual disturbances may be noted, possibly caused by intraocular hemorrhage. Patients may notice bloody tears, which are due to conjunctival telangiectases.
Physical Examination
The areas involved dictate the signs that may be found on physical examination. Obvious physical findings of OWRD (ie, HHT) are limited to those in the skin and mucous membranes. However, physical findings may also be present in many other organs. Common sites of involvement include the following:
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Skin
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Nasal and oral mucosa
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CNS
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Respiratory system
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GI tract
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Liver
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Cardiovascular system
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Eyes
Skin
Skin lesions begin as dark red lines or as punctate, pulsating vascular papules the size of match heads. These may be found on the skin, oral mucosa, nasal mucosa, and conjunctiva. [40] More rarely, skin lesions are star-shaped and 1-3 mm in diameter; alternatively, they are nonpulsating telangiectases resembling spider angiomas. (See the images below.)
Typical manifestations in patient with Osler-Weber-Rendu disease (ie, hereditary hemorrhagic telangiectasia) with red nodules and starry telangiectasia on cheeks.
Close-up view of typical manifestations in patient with Osler-Weber-Rendu disease (ie, hereditary hemorrhagic telangiectasia) with red nodules and starry telangiectasia on lips.
Close-up view of typical manifestations in patient with Osler-Weber-Rendu disease (ie, hereditary hemorrhagic telangiectasia) with red nodules and starry telangiectasia on cheeks.
The lesions blanch partially with pressure. Fine telangiectases may be difficult to appreciate in patients with anemia. Lesions often are conspicuous in the nail beds.
Half of patients manifest cutaneous lesions by age 30 years, though lesions may arise during the teenage years. [6] The face, lips and mouth, nares, tongue, ears, hands, chest, and feet are most often affected, in descending order of frequency and in any combination. Lesions are multiple and may be of cosmetic concern, and the number of lesions may increase with age. Bleeding is rarely clinically significant.
Almost invariably, all of the mucous membranes are involved, including membranes throughout the GI, respiratory, and urinary tracts and those in the nasal septum, oral cavity, and nasopharynx.
Nose
Recurrent epistaxis is usually the presenting symptom in HHT. Recurrent epistaxis is present in 90% of patients with HHT and appears at a young age, manifesting in most patients by age 21 years. [55] Bleeding occurs spontaneously from telangiectases of the nasal mucosa.
Recurrent epistaxis results in fatigue and anemia. Iron supplementation and blood transfusion may be required. Bleeding symptoms are progressive with increasing age. The presence of pulmonary AVM does not predict a better or worse natural history for epistaxis. [56]
Lung
The majority of pulmonary AVMs occur as part of HHT, [45, 46] affecting approximately 50% of HHT patients. Pulmonary AVM, with right-to-left pulmonary shunting, is the major cause of transient ischemic attack, brain abscess, and ischemic stroke in HHT patients as a result of paradoxic embolization of bland or septic material into the cerebral vasculature. These symptoms may be either the first manifestation of pulmonary HHT involvement or the presenting symptoms of HHT itself. [6]
Small AVMs with shunting of less than 25% of pulmonary blood flow are asymptomatic in half of cases. These patients show no cyanosis but demonstrate dyspnea on exertion and easy fatigability. Larger AVMs, especially when multiple, may result in dyspnea, fatigue, cyanosis, clubbing, and polycythemia. [57] Such severe shunting, defined as more than 25% of pulmonary blood flow, is seen in 20% of cases.
A study published by Shovlin et al in 2014, which included 497 patients with computed tomography (CT)-proven pulmonary AVMs due to HHT, suggested that patients with compromised pulmonary capillary filtration due to pulmonary AVMs are at increased risk of ischemic stroke if they are iron-deficient and that mechanisms are likely to include enhanced aggregation of circulating platelets. [45]
Auscultation reveals a continuous thoracic bruit in half of patients with cyanosis. Cyanosis and clubbing are particularly associated with an increased risk of cerebral abscess and stroke. With pulmonary AVM, unlike hepatic AVM, increased cardiac output with high-output heart failure is unusual.
In one study, 36% of patients with a solitary pulmonary AVM had HHT. [58] With multiple lesions, the rate of HHT was 57%. Overall, as many as 60% of patients with pulmonary AVM have HHT. Conversely, a 20% incidence of pulmonary AVM can be expected in patients with HHT. ENG mutations of HHT type 1 are associated with a 30% incidence of pulmonary AVM, compared with 3% for HHT type 2 ALK1 mutations. [58]
In a French study of HHT patients with pulmonary AVMs, which included 79 women and 47 men, the AVM was diagnosed at a mean age of 43±17 years. [59] AVM was detected on screening in 29% of patients, incidentally detected by imaging in 15%, detected secondary to dyspnea in 22%, and detected secondary to CNS symptoms in 13%.
In this study, dyspnea on exertion was present in 56% of patients. [59] Thirteen cases of cerebral abscess were found, of which 54% were found concurrently with the diagnosis of HHT and the detection of pulmonary AVM. Eighty-three percent underwent treatment for their AVMs, 23% by surgical resection and 71% via embolization.
In an Italian study, diffuse pulmonary AVM was examined in 36 individuals out of a consecutive series of 821 AVM patients. [60] The study showed an 81% association with HHT (29 of 36 patients). Diffuse AVM was associated with female gender and bilaterality. This was a high-risk group, with nine deaths occurring in patients with bilateral involvement. Causes of death were as follows:
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Hemoptysis of bronchial artery origin (two patients)
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Duodenal ulcer with hemorrhage (one patient)
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Spontaneous liver necrosis (three patients)
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Cerebral hemorrhage (one patient)
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Cerebral abscess (one patient)
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Operative death during lung transplantation (one patient)
Despite shunt formation across the pulmonary tree from AVMs, HHT is also associated with pulmonary hypertension. Lung tissue of HHT patients with pulmonary hypertension appears histologically similar to that of patients with primary pulmonary hypertension. This manifestation of HHT is associated with ALK1 gene mutations. [61]
Central nervous system
CNS arteriovenous anastomoses and aneurysms may lead to paresthesia, stroke, brain abscess, or intracerebral hematoma with focal neurologic signs. Brain abscess and stroke account for much of the 10% mortality seen in HHT, underscoring the importance of this often initially silent entity. [62]
The estimated incidence of CNS involvement in HHT patients is 10-20%. [42] CNS manifestations stem from inherent CNS vascular lesions in one third of HHT patients, whereas most CNS complications are caused by paradoxic emboli from pulmonary AVMs. [63] Other CNS manifestations include the following [64] :
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Spinal AVMs
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Migraine (50% of patients)
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Seizure
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Paraparesis
Cerebral AVMs are associated with an annual hemorrhage rate of 1.4-2.0% per patient, a figure similar to that seen with non-HHT cerebral AVMs. [65] Patients with HHT-associated cerebral hemorrhage tend to have a good functional outcome. [66]
Spontaneous remission or regression of cerebral AVMs has been reported in three cases; this appears to be a rare phenomenon. [67, 68, 69]
Gastrointestinal tract
GI bleeding develops in 25-30% of patients with HHT. [70] Usually manifesting in the fifth or sixth decade, lesions can arise in any portion of the GI tract, though they most commonly involve the stomach and small bowel. Rectal examination may reveal frank blood. Nodular angiomas are visualized on endoscopy and are similar to cutaneous telangiectases in appearance. [38]
GI bleeding is the most common visceral manifestation of HHT; it presents later than epistaxis and has been shown to occur in both HHT1 and HHT2 families. [71] Massive transfusion requirements of more than 100 units of blood have been reported. [72] The presence and number of lesions detected in the stomach and duodenum on upper endoscopy correlate with the detection of lesions in the jejunum, though large (≥5 mm) upper-tract lesions do not necessarily suggest the presence of large jejunal lesions. [70]
Liver
Between 30% and 60% of patients with HHT have liver involvement. [73] Although many patients are asymptomatic, [74] the following manifestations have been described [75, 76] :
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High-output heart failure
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Hepatomegaly
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Portal hypertension
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Encephalopathy
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Right-upper-quadrant pain and jaundice
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Liver failure
The three most common clinical patterns are high-output cardiac failure, portal hypertension, and biliary disease. The biliary manifestations include biliary obstruction or sepsis in association with biliary strictures, dilatation, and bile cysts. [77]
Patients with clinically significant liver lesions most often present with hyperdynamic circulation (cardiac index, 4.6-6.8 L/min/m2). [78] This phenomenon may be observed without symptoms of heart failure and is due to shunting from hepatic artery to hepatic vein, from portal vein to hepatic vein, or both. Shunting from the hepatic artery to the portal vein causes arterialization of the portal system with nodular transformation of parenchyma without fibrous septa, a condition termed pseudocirrhosis.
Cardiovascular system
Vascular abnormalities deep in the digits have been detected in patients with HHT by using a handheld illuminator. [79]
Patients with anemia may be pale. As noted (see above), patients may have a hyperdynamic circulation if they have hepatic involvement and a large left-to-right shunt, and this hyperdynamic circulation may be exacerbated by anemia.
Eyes
Funduscopic examination may reveal retinal telangiectasias and hemorrhages. Bloody tears may be present because of conjunctival telangiectasias.
HHT in pregnancy
In pregnant women with HHT, pulmonary AVMs may cause life-threatening fetomaternal complications. Pulmonary hemorrhage can occur, compromising maternal and fetal health.
In a study of 262 pregnancies in 111 HHT patients, most pregnancies proceeded normally. [80] However, 13 patients had adverse events (not all of which were HHT-related): major pulmonary AVM bleed in 1%, maternal death in 1%, and stroke in 1.2%. In women experiencing a life-threatening event, prior knowledge of HHT or pulmonary AVM was associated with improved survival.
Most HHT experts recommend that pregnant women who have not had a recent evaluation for pulmonary AVMs be evaluated during pregnancy. Contrast echocardiography rules out evidence of pulmonary shunt and can be performed in the first trimester. If this study yields positive results, CT of the chest with abdominal shielding should be delayed until the second trimester.
Experience with a small series of seven women suggests that transcatheter embolization of pulmonary AVM can be accomplished safely by a skilled interventional radiologist after 16 weeks’ gestation. [81]
Complications
Complications that may occur in patients with OWRD (ie, HHT) include the following:
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Brain abscess
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Hemorrhagic or ischemic stroke
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High-output congestive heart failure
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Chronic GI bleeding and anemia
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Portal hypertension with esophageal varices
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Pulmonary hemorrhage
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Liver cirrhosis
Cerebral abscess due to impaired function of pulmonary vasculature is the most common neurologic manifestation of this condition. Ischemic strokes likely due to pulmonary AVMs are common, whereas hemorrhagic strokes due to cerebral AVMs are far less common. Of patients who have pulmonary AVMs, 2% per year are estimated to have a stroke, and 1% per year are estimated to develop a brain abscess.
The presence of large AVMs and blood loss may lead to high-output cardiac failure. This known complication of HHT has been linked with the onset of severe and recurrent epistaxis in a small sample of patients. [82]
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Typical manifestations in patient with Osler-Weber-Rendu disease (ie, hereditary hemorrhagic telangiectasia) with red nodules and starry telangiectasia on cheeks.
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Close-up view of typical manifestations in patient with Osler-Weber-Rendu disease (ie, hereditary hemorrhagic telangiectasia) with red nodules and starry telangiectasia on lips.
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Close-up view of typical manifestations in patient with Osler-Weber-Rendu disease (ie, hereditary hemorrhagic telangiectasia) with red nodules and starry telangiectasia on cheeks.
