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Osler-Weber-Rendu Disease
Updated: Dec 15, 2008
Introduction
In 1864, Sutton described a disorder of epistaxis and degeneration of the vascular system that would later bear the names Osler-Weber-Rendu disease (OWRD) and hereditary hemorrhagic telangiectasia (HHT).1
Benjamin Guy Babington noted the syndrome’s familial nature in his 1865 paper "Hereditary Epistaxis.".2
Henri Rendu first emphasized the hallmark blanching cutaneous and mucous membrane angiomata of HHT and differentiated this disease from hemophilia.3 Subsequently, Sir William Osler and Frederick Parks Weber published detailed descriptions of the syndrome that, along with Rendu, bears their names).4,5
The term, hereditary hemorrhagic telangiectasia (HHT) was coined by the pathologist Hanes in 1909.6
With the development of gastrointestinal endoscopy, Renshaw described the "millet seed to pinhead sized bright red spots" typical of mucosal HHT.7
Problem
HHT is an autosomal dominant disorder manifested by mucocutaneous telangiectases and arteriovenous malformations (AVMs), a potential source of serious morbidity and mortality. Lesions can affect the nasopharynx, central nervous system (CNS), lung, liver, and spleen, as well as the urinary and GI tracts.8 Epistaxis is the most common manifestation, and gastrointestinal bleeding is also prevalent.9 Onset of symptoms may be delayed until the fourth decade of life (approximately 90% of patients manifest by age 40 y) or later decades.10,11
Diagnosis of HHT is made clinically by the Curaçao criteria, established in June 1999 by the Scientific Advisory Board of the HHT Foundation International, Inc.12 More stringent than previous guidelines, the goals of its use are to improve patient care and to standardize research.
The HHT diagnosis is classified as definite if 3 criteria are present, possible or suspected if 2 criteria are present, and unlikely if fewer than 2 criteria are present. The Curaçao criteria are as follows:
- Epistaxis - Spontaneous, recurrent nosebleeds
- Telangiectases - Multiple at characteristic sites (lips, oral cavity, fingers, nose)
- Visceral lesions - Such as gastrointestinal (GI) telangiectasia (with or without bleeding), pulmonary AVM, hepatic AVM, cerebral AVM, spinal AVM
- Family history - A first-degree relative with HHT
Shovlin et al emphasized the varied presentation of HHT among families and even within the same family.13,14,12 Cutaneous findings may be subtle; epistaxis, the most common overt feature, is also common in the general population. Given the lack of consensus on the number of episodes or degree of epistaxis necessary for diagnosis, the criteria highlight that "nosebleeds should occur spontaneously on more than one occasion, with night-time bleeds being particularly suspicious."
Genetic testing of patients and their family members can confirm the presence of mutations within implicated genes, most commonly endoglin (ENG) or ALK-1 involved in HHT types 1 and 2, respectively.15
Frequency
HHT affects varied racial and ethnic groups and occurs in a wide geographic distribution. Men and women are affected equally.16
- United States: In Vermont, frequency has been estimated at 1 case per 16,500 persons.8
- Europe and Asia: In Europe and Japan, incidence is estimated to be between 1 in 5000 to 8000 people.17,18
- Specific populations: Incidence may vary considerably between populations. The highest rates are seen in parts of the Dutch Antilles among the Afro-Caribbean population with a prevalence of between 1 case per 200 persons and 1 per 1,331 in the Curaçao and Bonaire regions.19,20 Prevalence in the French department of Ain is 1 case per 2351 persons and in France overall, 1 per 8345.10 Other examples include the Danish island of Funen, 1 per 3500, and in northern England, 1 in 39,216.21,11
Etiology
HHT is an autosomal dominant disorder attributed to genetic mutations that involve signaling of transforming growth factor beta (TGF-b), an important pathway in vascular formation and repair.14 Defects in at least 4 genes are implicated in HHT. Mutations in ENG (encoding the endoglin protein) characterize HHT type 1 and involve chromosome 9, 9q33-34.22 Mutations of ALK1 (encoding activin receptor-like kinase 1), also called ACVRL1 (activin A receptor kinase, type II like 1), are implicated in HHT type 2 and involve chromosome 12, 12q13.23
A third locus involves mutations of chromosome 5 (5q31.1-32) and is distinct from hereditary benign telangiectasia (HBT), a gene defect in RASA1 (chromosome 5q14).15
Mutations of a fourth gene, MADH4 (encoding SMAD4) is described in the HHT-juvenile polyposis overlap syndrome (JPHT).24 JPHT is also autosomal dominant, involves chromosome 18, and combines clinical manifestations of HHT and juvenile polyposis. Consequently, at least the following 4 types of HHT are known: HHT type 1, HHT type 2, HHT type 3 and JPHT.
Pathophysiology
The underlying disorder in HHT is abnormal vascular architecture at discrete sites. Unaffected areas show normal vessel architecture based on ultrastructural analysis.25 Thus, researchers postulate that an initiating event combined with abnormal repair results in HHT lesions.26 Interactions with TGF-b signaling result in disorganized cytoskeletal structure and poor vascular tubule formation. The gene expression profiles of the vascular endothelial cells grown from HHT patients reveals dysregulation of genes involved with angiogenesis, cytoskeletal integrity, cell migration, proliferation and nitric oxide synthesis.27 Telangiectases and AVM bleeding tendency is attributed to localized vessel wall weakness, in part due to abnormal remodeling resulting from an imbalance in TGF-b related functions.14
Presentation
Telangiectases of the skin and mucous membranes, epistaxis, and a positive family history comprise the classic triad of HHT. Visceral and CNS involvement may be asymptomatic but are of importance due to associated complications that may be preventable. An estimated 90% of HHT patients have spontaneous, recurrent epistaxis, 75% show skin telangiectases, 30% have hepatic or pulmonary involvement (AVMs), 15% manifest GI bleeding,28 and 10-20% have CNS lesions.29 A known progression in the onset of symptoms over time begins with epistaxis, then pulmonary AVM (PAVM), followed by cutaneous and mucous telangiectases.28
Skin
As Rendu described in his hallmark work, typical lesions appear as "small purplish stains, of the size of a pinhead, the largest reaching the size of a lentil." The typical telangiectasia is smaller than 5 mm and is found directly beneath the skin or mucosal surfaces.16 The lesions partially blanch with pressure, although fine telangiectases may be difficult to appreciate in patients with anemia. Color ranges from bright red to violaceous to purple. Macular, papular, or punctate lesions are typical; linear or spider-patterned lesions are rarely present.
Half of patients manifest cutaneous lesions by age 30, although lesions may arise during the teenage years.10 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.
Nose
Recurrent epistaxis is present in 90% of patients with HHT and appears at a young age, manifesting in most patients by age 21 years.30 Bleeding may be severe and spontaneously occurs from telangiectases of the nasal mucosa. Iron supplementation and blood transfusion may be required. Bleeding symptoms are progressive with increasing age and the presence of pulmonary AVM does not predict a better or worse natural history for epistaxis.31
Central nervous system
The estimated incidence of CNS involvement in HHT patients is 10-20%.29 CNS manifestations are due to inherent CNS vascular lesions in one third of HHT patients, whereas most CNS complications are secondary to associated pulmonary AVMs resulting in paradoxical emboli.32 Other CNS manifestations include spinal AVMs, migraine occurring in 50% of patients, seizure, and paraparesis.33 Cerebral AVMs are associated with an annual hemorrhage rate of 1.4-2.0% per patient, similar to that of non–HHT cerebral AVMs.34 HHT–associated cerebral hemorrhage tends to show good functional outcome.35
Spontaneous remission or regression of cerebral AVMs has been reported in 3 cases; this appears to be a recently reported and rare phenomenon.36,37,38
Lung
Pulmonary AVM, with right-to-left pulmonary shunting, is the major cause of transient ischemic attack, brain abscess, and ischemic stroke in HHT patients due to paradoxical embolization of bland or septic material into the cerebrovasculature. These symptoms may be the first manifestation of pulmonary HHT involvement or the presenting symptoms of HHT itself.10 Brain abscess and stroke account for much of the 10% mortality rate seen in HHT, underscoring the importance of this often initially silent entity.39
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.40 Such severe shunting, defined as more than 25% of pulmonary blood flow, is seen in 20% of cases. 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. Unlike in hepatic AVM, increased cardiac output with high-output heart failure is unusual.
In a recent review, patients with a solitary pulmonary AVM had HHT 36% of the time. With multiple lesions, the rate of HHT was 57%. Overall, up to 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 versus 3% for HHT type 2 ALK1 mutations.41
A multicenter review from Lyon, France by a large collaborative group (Groupe d’Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires), which studies rare pulmonary disorders or "orphan" disorders, examined the characteristics of 126 HHT patients.42 Between 1985 and 2004, 79 women and 47 men, mean age 34 +/-17 years, were examined. AVM was detected on screening in 29% of patients, incidentally detected by imaging in 15%, detected secondary to dyspnea in 22%, and secondary to CNS symptoms in 13%. Dyspnea on exertion was present in 56% of patients. Thirteen cases of cerebral abscess were found, of which 54% were found concurrent with the diagnosis of HHT and detection of pulmonary AVM. Eighty-three percent underwent treatment for their AVMs, 23% by surgical resection and 71% via embolization.
Diffuse pulmonary AVM was examined in 36 individuals out of a consecutive series of 821 AVM patients in Italy. 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 9 deaths occurring in patients with bilateral involvement. Causes of mortality were hemoptysis of bronchial artery origin (2 patients), duodenal ulcer with hemorrhage (1 patient), spontaneous liver necrosis (3 patients), cerebral hemorrhage (1 patient), cerebral abscess (1 patient), and operative death during lung transplantation (1 patient).43
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.44
Gastrointestinal tract
GI bleeding develops in 25-30% of patients with HHT.45 Usually manifesting in the fifth or sixth decade, lesions can arise in any portion of the GI tract, although they most commonly involve the stomach and small bowel. Nodular angiomas are visualized on endoscopy and are similar to cutaneous telangiectases in appearance.21 GI bleeding is the most common visceral manifestation of HHT, presents later than epistaxis, and has been shown in both HHT-1 and HHT-2 families.46 Massive transfusion requirements of more than 100 units of blood have been reported.47 The presence and number of lesions detected in the stomach and duodenum on upper endoscopy correlates with the detection of lesions in the jejunum, although large (greater or equal to 5mm) upper tract lesions do not necessarily suggest the presence of large jejunal lesions.45
Liver
Thirty to 60% of patients with HHT have liver involvement.48 Although many patients are asymptomatic,49 high-output heart failure, hepatomegaly, portal hypertension, encephalopathy, biliary manifestations of right upper quadrant pain and jaundice, and liver failure are described.50 The 3 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.51
Patients with clinically significant liver lesions most often present with hyperdynamic circulation (cardiac indexes of 4.6-6.8 L/min/m2).52 This phenomenon may be observed without symptoms of heart failure and is due to shunting from hepatic artery to hepatic vein, 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.
HHT and pregnancy
A study of 262 pregnancies in 111 HHT patients was published in 2008.53 The authors examined all pregnancies in 111 women diagnosed with HHT and pulmonary AVM between 1995-2005, whether or not HHT was known at the time of the first pregnancy. Most pregnancies proceeded normally. Thirteen patients had adverse events: major pulmonary AVM bleed in 1%, maternal death in 1%, and stroke in 1.2% (not all HHT related). In women experiencing a life-threatening event, prior knowledge of HHT or pulmonary AVM was associated with improved survival (P = 0.041).
Experience with a small series of 7 women suggests transcatheter embolization of pulmonary AVM can be accomplished safely by a skilled interventional radiologist after 16 weeks gestation.54
Indications
Indications for intervention vary according to site of involvement and presentation. For example, severe epistaxis refractory to ablative treatment may benefit from septoplasty. Control of intermittent GI bleeding may be managed medically; however, brisk hemorrhage may require endoscopic treatment or surgical resection. Embolization or surgical resection is indicated for pulmonary arteriovenous malformation (AVM) if it is localized and accessible with the goal of limiting the risks of embolic CNS complications, hemodynamic sequelae, or hemorrhage. Hemodynamically significant shunt from hepatic AVM may be amenable to embolization to stabilize heart failure or encephalopathy. Extensive or symptomatic liver disease may warrant evaluation for liver transplantation.
Relevant Anatomy
Please refer to Histologic Findings for information regarding lesion morphology.
Contraindications
Contraindications to specific interventions vary with the planned procedure. Known independent comorbidities or comorbidities directly related to HHT, such as cardiac failure or pulmonary hypertension, may require initial stabilization or be specifically addressed concurrent with intervention.
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References
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Further Reading
Keywords
Osler-Weber-Rendu disease, OWRD, Osler-Weber-Rendu syndrome, OWRS, hereditary hemorrhagic telangiectasia, HHT, Rendu-Osler-Weber disease, ROWD, pulmonary arterial venous malformation, PAVM, epistaxis, nosebleed, gastrointestinal bleeding, GI bleeding, contrast echocardiography, activin receptor-like kinase 1, ALK-1, endoglin, ENG, HHT-juvenile polyposis overlap syndrome, JPHT
