You are in: eMedicine Specialties > Vascular Surgery > MEDICAL TOPICS Osler-Weber-Rendu DiseaseArticle Last Updated: Jun 5, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Perry A Soriano, MD, Fellow in Surgical Oncology, Department of General Oncologic Surgery, City of Hope National Medical Center Perry A Soriano is a member of the following medical societies: American College of Surgeons, American Society of Clinical Oncology, Massachusetts Medical Society, Pancreas Club, and Society of Surgical Oncology Coauthor(s): James Petros, MD, Associate Professor of Surgery, Program Director, Surgical Residency Program, Department of Surgery, Boston University School of Medicine; James F McKinsey, MD, FACS, Associate Professor of Clinical Surgery, Columbia University College of Physicians and Surgeons; Site Chief, Department of Surgery, Division of Vascular Surgery, Columbia University Medical Center Editors: William H Pearce, MD, Chief, Division of Vascular Surgery, Violet and Charles Baldwin Professor of Vascular Surgery, Department of Surgery, Northwestern University School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Vincent Lopez Rowe, MD, Assistant Professor of Surgery, Department of Surgery, Division of Vascular Surgery, University of Southern California Medical Center; Michael E Zevitz, MD, Assistant Professor of Medicine, Finch University of the Health Sciences, The Chicago Medical School; Consulting Staff, Private Practice; William H Pearce, MD, Chief, Division of Vascular Surgery, Violet and Charles Baldwin Professor of Vascular Surgery, Department of Surgery, Northwestern University School of Medicine Author and Editor Disclosure Synonyms and related keywords: Osler-Weber-Rendu disease, OWRD, hereditary hemorrhagic telangiectasia, HHT, Rendu-Osler-Weber disease, ROWD, pulmonary arterial venous malformation, PAVM, epistaxis, nosebleed, gastrointestinal bleeding, GI bleeding, contrast echocardiography, activinlike receptor kinase, ALK-1, endoglin INTRODUCTIONSection 2 of 11
  Sutton first described Osler-Weber-Rendu disease (OWRD) in 1864 as a disorder of epistaxis and degeneration of the vascular system. Benjamin Guy Babington noted the familial nature of OWRD in his 1865 paper "Hereditary Epistaxis" in the Lancet. Henri Rendu, in 1896, first emphasized the hallmark blanching cutaneous and mucous membrane angiomata of OWRD. Both Sir William Osler and Frederick Parks Weber published detailed observations of this syndrome, which bears their names, in 1901 and 1907. F. Hanes coined the term hereditary hemorrhagic telangiectasia (HHT) at Johns Hopkins University in 1909. With the development of gastrointestinal endoscopy, Renshaw described the "millet seed to pinhead sized bright red spots" typical of mucosal HHT. ProblemHHT is an autosomal dominant disorder manifested by telangiectases of the skin and mucous membranes and arteriovenous malformations (AVMs), a potential source of serious morbidity and mortality. Larger telangiectases can affect the nasopharynx, central nervous system (CNS), lung, liver, and spleen, as well as the urinary and GI tracts. Epistaxis is the most common manifestation, and gastrointestinal bleeding is also prevalent. Because onset of symptoms may be delayed into the fourth decade of life (approximately 90% of patients manifest by age 40 y) or later decades (97% manifest by age 60 y), genetic testing has been advocated. Appropriate screening programs aim to limit complications. 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. More stringent than previous guidelines, the goals of the new criteria are to standardize research and to improve management of HHT. 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 include the following:
Shovlin et al in their summary of the Curacao criteria, which was published in 2000,emphasize the varied presentation of HHT among families and even within the same family. 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." FrequencyHHT has been reported in all racial groups and most ethnic groups, and it occurs in a wide geographic distribution. Men and women are affected equally. A small number of cases are sporadic.
EtiologyTwo genes implicated in HHT have been well described, with a third locus recently reported. Also, the HHT-juvenile polyposis overlap syndrome (JPHT) due to mutations of SMAD4 has been described. Consequently, the following 4 types of HHT are now described: HHT type 1, HHT type 2, JPHT, and HHT type 3. HHT type 1 and HHT type 2 show gene defects that involve endoglin (ENG) and activinlike receptor kinase (ALK1), respectively. Mutations of ENG are located on the long arm of chromosome 9 (9q33-34); whereas ALK1 mutations involve the long arm of chromosome 12 (12q13). The 40% incidence of pulmonary AVM with ENG (type 1), versus 3% for ALK1 (type 2), distinguishes these 2 types. A risk for primary pulmonary hypertension is associated with type-2 HHT. JPHT is also autosomal dominant, involves chromosome 18, and combines clinical manifestations of HHT and juvenile polyposis. The implicated genes ENG, ALK1, and SMAD4 are involved in the signaling of transforming growth factor (TGF)–b. HHT type 3 involves mutations of the long arm of chromosome 5 (5q31.1-32) and is distinct from hereditary benign telangiectasia (HBT), a gene defect in RASA1 (chromosome 5q14). Although the defect for HHT type 3 is thought to involve similar pathways as the prior 3 types, namely signaling of the TGF-b superfamily, the specific gene has not been unidentified. PathophysiologyThe underlying disorder in HHT is abnormal vascular architecture at discrete sites. Unaffected areas show normal vessel architecture based on ultrastructural analysis. Thus, researchers postulate that an initiating event combined with abnormal repair results in HHT lesions. Abnormal vessel repair may be caused by defects in the proteins coded by ENG or ALK1. This occurs in association with TGF-b, which mediates vascular remodeling through effects on extracellular matrix production. Although the precise mechanism remains poorly understood, bleeding tendency is largely attributed to localized vessel wall weakness. ClinicalTelangiectases of the skin and mucous membranes, epistaxis, and a positive family history comprise the classic triad of HHT. The typical telangiectasia is smaller than 5 mm and is found directly beneath the skin or mucosal surfaces of the alimentary, respiratory, and urinary tracts, as well as in the liver, brain, and spleen. The pattern of distribution is distinct and involves the mucosa of the nose, lips, oral cavity, conjunctiva, finger tips, ears, and face. AVMs can occur at multiple sites, with those in the CNS and lungs being most significant clinically. 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 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. Lesions may manifest later in life but typically arise during the teenage years, with most cases manifesting by age 40 years, and almost all by age 60 years. 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. Bleeding may be severe and spontaneously occurs from telangiectases of the nasal mucosa. Iron supplementation and blood transfusion may be required. Two thirds of patients experience increased bleeding tendency with advancing age. Central nervous system CNS manifestations of HHT are due to 2 causes: inherent CNS vascular lesions and pulmonary AVM, with their inherent risk of paradoxical emboli. Inherent lesions are implicated in subarachnoid hemorrhage, migraine, seizure, or paraparesis. Spinal AVMs have also been reported. Inherent lesions are implicated in one third of patients, whereas the remaining complications are attributed to pulmonary AVM. Estimated incidence of CNS AVM in patients with HHT is 5-10%, and approximately 7% of patients have cerebral aneurysms. Migraine occurs in 50% of patients with HHT. Lung Pulmonary AVM is perhaps the most important manifestation of HHT because of its devastating neurologic sequelae and its treatability. Transient ischemic attack, brain abscess, and ischemic stroke occur with right-to-left pulmonary shunt because of 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. Brain abscess and stroke account for much of the 10% mortality rate seen in HHT, underscoring the significance of pulmonary involvement. 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. 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 not observed because of similar resistance across pulmonary AVMs versus the overall pulmonary vascular tree. 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. The subgroup with ENG mutations has a higher risk (40%). GI tract GI bleeding is observed in 20-40% of patients and, as with epistaxis, tends to worsen in later life. Usually manifesting in the fifth or sixth decade, lesions can arise in any portion of the GI tract and have been well documented in the stomach and in both large and small bowel. Both telangiectases and AVMs occur, although the larger vascular lesions are less common. Massive transfusion requirements of more than 100 units of blood have been reported. Liver Eight to 31% of patients with HHT show a diffuse telangiectatic process in the liver with numerous arteriovenous fistulas. Although many patients are asymptomatic, high-output heart failure, hepatomegaly, portal hypertension, encephalopathy, biliary manifestations of right upper quadrant pain and jaundice, and even abdominal angina from mesenteric arterial "steal" are well described. Patients with clinically significant liver lesions most often present with hyperdynamic circulation (cardiac indexes of 4.6-6.8 L/min/m2). This phenomenon is observed even 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 hepatic artery to portal vein causes arterialization of the portal system with nodular transformation of parenchyma without fibrous septa, a condition termed pseudocirrhosis. INDICATIONSSection 3 of 11
Indications for surgery vary with the site of involvement. Severe epistaxis refractory to ablative treatment may require septoplasty. Intermittent GI bleeding can be managed medically; however, brisk hemorrhage may require endoscopic intervention or surgical resection. Surgical intervention may be indicated for pulmonary AVM if it is localized and resectable because of the risk of CNS and hemorrhagic complications. Multiple AVMs may be amenable to resection if adequate lung tissue can be preserved. RELEVANT ANATOMYSection 4 of 11
Please refer to Histologic Findings for information regarding lesion morphology. For anatomy pertinent to specific procedures (eg, pulmonary wedge resection, CNS AVM embolization), please refer to the respective eMedicine articles. CONTRAINDICATIONSSection 5 of 11
Contraindications to surgical intervention vary with the planned procedure. Known comorbidities, such as cardiac disease or pulmonary hypertension, should be considered and addressed. WORKUPSection 6 of 11
Lab Studies
Imaging Studies
Other Tests
Diagnostic Procedures
Histologic FindingsHistologic 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. TREATMENTSection 7 of 11
Medical therapyEpistaxis
Skin lesions
Pulmonary arteriovenous malformation
GI bleeding
CNS arteriovenous malformation
Further details Aminocaproic acid blocks the conversion of plasminogen to plasmin and thus acts as a powerful inhibitor of fibrinolysis. Although coagulation is thought to be normal in hemorrhagic telangiectasia (HHT), some investigators believe the cause of bleeding tendency is multifactorial. Increased plasminogen-activator activity has been demonstrated in the telangiectatic vessel walls of some patients with HHT. Epistaxis is often recurrent, requiring multiple treatments. Severe epistaxis requires surgical treatment. Moderate and mild forms can be treated medically or with endoscopic ablation. Rebeiz developed a classification for epistaxis that defines mild epistaxis as a few episodes per week without transfusion requirement. Moderate epistaxis is defined as 1-2 episodes per day and requiring fewer than 10 transfusions in the patient's lifetime; the severe form, as daily epistaxis lasting longer than 30 minutes and requiring more than 10 transfusions in the patient's lifetime. When ablative therapy is indicated, for example, with the use of the ND:YAG laser, multiple treatments are typically required. Surgical therapyEpistaxis: Patients with recurrent intractable epistaxis despite medical treatment or with sufficiently severe epistaxis may consider more aggressive intervention such as septal dermoplasty. Pulmonary AVM: Surgical resection can effectively address localized lesions. Diffuse, multiple small AVMs smaller than 1.5 cm can be observed. As with non-HHT AVMs, an enlarging or symptomatic lesion should be resected. Small solitary lesions in a patient with HHT should be considered for resection because of the tendency to enlarge over time. Special consideration is necessary in women planning pregnancy, as the risk of rupture is increased. GI bleeding: A distinction is made between the malformations of HHT and lesions of angiodysplasia, both of which tend to manifest with age. The lesions of HHT are most often diffuse, and extensive surgical resection is generally not indicated for episodic bleeding but may be indicated for massive hemorrhage. CNS AVM: Neurovascular surgery may be indicated in select lesions. Preoperative detailsPlease refer to the following articles for further information:
Follow-upThoughtful long-term follow-up is crucial for the quality care of patients with HHT because additional manifestations may develop over time. COMPLICATIONSSection 8 of 11
Identification of asymptomatic arteriovenous malformations (AVMs) of the lung and CNS is important in order to prevent hemorrhagic or embolic complications that can be devastating and are potentially preventable. Most interventions can be accomplished via catheter-based therapies that obviate the need for surgical intervention, such as thoracotomy or craniotomy. Either approach, however, has risks, including death or stroke. Therefore, when identified, optimal management of AVMs may be best accomplished using a multidisciplinary approach. OUTCOME AND PROGNOSISSection 9 of 11
Poor outcome in patients with hemorrhagic telangiectasia (HHT) is largely associated with pulmonary arteriovenous malformation (AVM) complications, specifically CNS abscesses and stroke. These 2 problems are responsible for most of HHT's 10% mortality rate. Hemorrhage due to extensive visceral involvement, once the source of a 4% mortality rate, has largely been eliminated by the availability of transfusion. Despite varied and progressive manifestations, as well as multivisceral involvement in some cases, patients with HHT are thought to have a normal life expectancy. FUTURE AND CONTROVERSIESSection 10 of 11
Prospective trials that determine ideal management of hemorrhagic telangiectasia (HHT) are limited by the small and varied population and by the multiorgan nature of the disease. A coordinated team approach is required. Screening for pulmonary arteriovenous malformation (AVM) continues to generate controversy, with helical CT scan being advocated by some investigators and chest radiographs with pulse oximetry being advocated by others. Contrast echocardiography has also proven effective and has the advantage of identifying intracardiac shunts, whereas arterial blood gases or pulse oximetry shunt studies do not. Contrast echocardiography is noninvasive and has been shown to be highly sensitive. Some combination of the above studies would likely provide the best results. Work in identification of specific gene mutations continues, and 4 distinct genetic loci are currently described. Early diagnosis of family members or confirmation with genetic testing of patients who fulfill Curaçao criteria may assist in the identification of those most at risk for specific sequelae. Participation in research and clinical trials, when available, will aid in discovery or clarification of the most appropriate interventions for this disease. REFERENCESSection 11 of 11
Osler-Weber-Rendu Disease excerpt Article Last Updated: Jun 5, 2006 |
