Hereditary Hemorrhagic Telangiectasia (HHT) - Brain Arteriovenous Malformation (BAVM)
HHT is an autosomal dominant disease with an estimated prevalence of 1/5000 (1) and is thought to be present in all races and parts of the world. Though epistaxis is the most common symptom of HHT and mucocutaneous telangiectasia the most common sign (2), HHT is also frequently complicated by the presence of arteriovenous malformations (AVMs) in the brain, lung, gastrointestinal (GI) tract and liver.
Making the diagnosis of HHT in a patient allows for the appropriate screening and preventative treatment for the patient and their affected family members. HHT has traditionally been diagnosed on the basis of its clinical features but can now also be diagnosed using genetic testing. The clinical diagnostic criteria (3) for HHT are detailed in the Table. The clinical diagnosis is considered “definite” if three or more criteria are present, "possible" if 2 criteria are present and “uncertain” when only one criterion is present (3). Disease expression is age-related, with an average age of onset for epistaxis of 12 years, with nearly 100% affected by age 40 years (2, 4-6). Most patients report the appearance of telangiectasia of the mouth, face or hands 5-30 years after the onset of nosebleeds; most commonly during the third decade. The goal of genetic testing for HHT is to clarify the specific HHT mutation in an HHT family, allowing diagnosis among those relatives (often children and young adults) who do not yet meet clinical diagnostic criteria, but may have unrecognized organ AVMs. Genetic testing is performed first on the index case, for mutations in the endoglin gene (ENG) and the activin A receptor type II-like 1 gene (ACVRL1). Mutations in these genes account for the majority of cases of HHT. At least two other HHT loci have been described, though specific genes at these loci are not yet identified (7, 8). Mutations in the SMAD4 gene can cause a rare syndrome of combined juvenile polyposis and HHT (9).
HHT is associated with cerebral vascular malformations, primarily brain AVMs (BAVMs), in 5-23%. The bleeding risk of BAVMs in HHT has been estimated retrospectively at approximately 0.5% per year (10), though there are no prospective natural history studies. In larger series of sporadic BAVMs (11), the annual rate of rupture is 2-4%/year (11). Asymptomatic screening for BAVMs has been recommended for HHT patients and is routinely performed across North America, though there is less consensus internationally (12). The goal of treatment is to obliterate the BAVM in order to eliminate the future risk of hemorrhage. Although current treatments may provide a large relative risk reduction for cerebral bleeding, procedural risks are significant. There are no published studies of the efficacy or safety of any form of treatment of BAVMs in HHT patients. However, there are several large case series of embolization, microsurgery and stereotactic radiation in non-HHT BAVMs, showing effectiveness for these modalities, though widely ranging (13-26). Based on this non-HHT literature, these treatment modalities are all considered likely effective treatment strategies, alone or in combination, for HHT BAVMs. However, given the rarity of BAVMs and the associated risks of treatment, the International HHT Guidelines (12) recommended that each case should be managed in an individualized manner and that decisions about invasive testing and therapy should occur at centers with significant experience and expertise in all treatment modalities.
PAVMs are present in approximately 15-50% of people with HHT (27, 28). PAVMs have been shown to be associated with disabling and life-threatening complications, such as stroke, TIA, cerebral abscess, massive hemoptysis and spontaneous hemothorax (27, 29-32) in retrospective series. The neurologic complications are presumed to occur via paradoxical embolization through PAVMs whereas the hemorrhagic complications occur due to spontaneous PAVM rupture. These complications have been demonstrated in largely adult series of HHT patients, though they have also been demonstrated in pediatric HHT series (33-35), albeit smaller in size. There have also been small series reporting these same complications during pregnancy (36, 37) and the complication risk appears to be greater during pregnancy. The International HHT Guidelines recommended routine screening all HHT patients for PAVMs, with contrast echocardiography, and preventative treatment with transcatheter embolotherapy (12).
Recurrent spontaneous epistaxis is the most common symptom of HHT and often leads to iron-deficiency anemia (38). Epistaxis appears before the age of 20 years in about 50% of patients, with 78 – 96 % of all HHT patients developing it eventually (2). Non-invasive management of chronic recurrent epistaxis in HHT has focused to date on prevention of epistaxis events through measures to maintain integrity of the nasal mucosa, such as humidification. Procedural therapies for chronic HHT-related epistaxis include endonasal laser, electrical or chemical coagulation techniques, replacement of the fragile endonasal mucosa by skin or buccal mucosa (dermoplasty), nasal artery embolization and closure of the nasal cavity (known as Young’s procedure). There have been no controlled or well-designed comparative studies of any of these procedures in HHT-related epistaxis, for either acute or chronic management. The International HHT Guidelines (12) recommended endonasal coagulation as a first approach, if surgical management is deemed necessary, but also recommended that patients considering surgical management consult an otorhinolarnygologist with HHT expertise, given the likely need for recurrent procedures for this chronic symptom and the risks of surgical management in these cases. There are no well-designed studies of the first-line management of acute epistaxis in HHT. The International HHT Guidelines (12) did, however, recommend that the treatment for acute epistaxis requiring intervention include packing with material or products that have a low likelihood of causing re-bleeding with removal (e.g., lubricated low-pressure pneumatic packing).
Although 80% of patients with HHT have gastric or small intestinal telangiectasia (39) on endoscopy or capsule examination, only 25-30% of patients will develop symptomatic GI bleeding (1, 2, 40, 41) which usually does not present until the fifth or sixth decades of life. Patients rarely develop significant GI bleeding before 40 years of age (1, 2, 40, 41). Women are affected with GI bleeding in a ratio of 2-3:1 (42, 43). Patients with HHT and GI bleeding may or may not be symptomatic, as the bleeding is usually in a slow, chronic and intermittent fashion, often without notable melena. Patients often have few symptoms until they become anemic. In severe cases, HHT GI bleeding causes morbidity, dependency on blood transfusions and increased mortality (42).
Esophagogastroduodenoscopy is the recommended initial test for evaluation of GI bleeding in HHT patients with anemia or iron deficiency, particularly when out of keeping with the severity of epistaxis. Though the majority of patients with HHT will have GI telangiectasia, the utility of endoscopic evaluation is in the anemic or iron-deficient patient. The International HHT Guidelines (12) recommended aggressive management of anemia and iron deficiency, with consideration of limited endoscopic therapy and potential medical therapies (hormonal therapy, anitfibrinolytics) in refractory cases, though evidence is limited.
Liver VMs are present in 32-78% of HHT patients (44-48) (See Table). Though there is no published natural history data regarding liver VMs in HHT, it appears that symptoms occur in only about 8% of the patients with HHT and liver VMs (46, 49). The clinical presentations of liver VMs include high-output heart failure, portal hypertension and biliary necrosis, as detailed in a recent review (50). In patients who have symptoms suggestive of liver VMs(50), Doppler ultrasound or triphasic hepatic CT can be used to confirm the diagnosis. There are uncontrolled case series of treatments of liver VMs, specifically hepatic artery embolization and liver transplantation. Hepatic artery embolization has the objective of reducing arteriovenous or arterioportal shunting by embolizing branches of the hepatic artery. Embolization appears to be effective in improving symptoms related to high output heart failure and mesenteric steal syndrome, (51), however, the effect is transient and symptoms generally recur. More importantly, ischemic complications (ischemic cholangitis, ischemic cholecystitis and/or hepatic necrosis) leading to transplant or death occur in approximately 30% of the treated cases, including 50% of treated portal hypertension cases (51). The 2-year survival with embolization was approximately 73%. With liver transplantation, symptoms resolved in the majority of patients (52, 53). Liver transplantation is associated with high blood transfusion requirements, prolonged hospital stay and a relatively high rate of postoperative complications. However, the reported 5-year survival rate of 83% in the larger series (53) compared favorably to overall survival rates for liver transplantation. The International HHT Guidelines recommended that referral for liver transplantation be considered in patients with liver VMs that develop ischemic biliary necrosis, intractable heart failure or intractable portal hypertension. Though there are no controlled studies to date, there is growing interest in antiangiogenic therapy in HHT, with recent case reports of clinical response to antiangiogeneic therapy (54-56), and even with improvement in symptoms from liver VMs (55).
Diagnostic Criteria (Curaçao Criteria) for clinical diagnosis of HHT
Spontaneous and recurrent
Multiple, at characteristic sites: lips, oral cavity, fingers, nose
GI Telangiectasia, pulmonary, hepatic, cerebral or spinal AVMs
A first degree relative with HHT according to these criteria
- Kjeldsen AD, Vase P, Green A. Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med. 1999;245(1):31-9.
- Plauchu H, de Chadarevian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989;32(3):291-7.
- Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91(1):66-7.
- Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992;29(8):527-30.
- Berg J, Porteous M, Reinhardt D, et al. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet. 2003;40(8):585-90.
- OS AA, Friedman CM, White RI, Jr. The natural history of epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 1991;101(9):977-80.
- Cole SG, Begbie ME, Wallace GM, Shovlin CL. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet. 2005;42(7):577-82.
- Bayrak-Toydemir P, McDonald J, Akarsu N, et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A. 2006;140(20):2155-62.
- Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363(9412):852-9.
- Willemse RB, Mager JJ, Westermann CJ, Overtoom TT, Mauser H, Wolbers JG. Bleeding risk of cerebrovascular malformations in hereditary hemorrhagic telangiectasia. J Neurosurg. 2000;92(5):779-84.
- MacDonald RL, Stoodley M, Weir B. Vascular malformations of the central nervous system. Neurosurgery Quarterly. 2001;11(4):231-247.
- Faughnan ME, Palda VA, Garcia-Tsao G, et al. International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. J Med Genet. 2009.
- Willinsky RA, Lasjaunias P, Terbrugge K, Burrows P. Multiple cerebral arteriovenous malformations (AVMs). Review of our experience from 203 patients with cerebral vascular lesions. Neuroradiology. 1990;32(3):207-10.
- Haw CS, terBrugge K, Willinsky R, Tomlinson G. Complications of embolization of arteriovenous malformations of the brain. J Neurosurg. 2006;104(2):226-32.
- Lawton MT, Du R, Tran MN, et al. Effect of presenting hemorrhage on outcome after microsurgical resection of brain arteriovenous malformations. Neurosurgery. 2005;56(3):485-93; discussion 485-93.
- Lunsford LD, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg. 1991;75(4):512-24.
- Meisel HJ, Mansmann U, Alvarez H, Rodesch G, Brock M, Lasjaunias P. Cerebral arteriovenous malformations and associated aneurysms: analysis of 305 cases from a series of 662 patients. Neurosurgery. 2000;46(4):793-800; discussion 800-2.
- Morgan MK, Zurin AA, Harrington T, Little N. Changing role for preoperative embolisation in the management of arteriovenous malformations of the brain. J Clin Neurosci. 2000;7(6):527-30.
- Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D. Hemorrhage risk after stereotactic radiosurgery of cerebral arteriovenous malformations. Neurosurgery. 1996;38(4):652-9; discussion 659-61.
- Suzuki J, Onuma T, Kayama T. Surgical treatment of intracranial arteriovenous malformation. Neurol Res. 1982;4(3-4):191-207.
- Schwartz M, Sixel K, Young C, et al. Prediction of obliteration of arteriovenous malformations after radiosurgery: the obliteration prediction index. Can J Neurol Sci. 1997;24(2):106-9.
- Taylor CL, Dutton K, Rappard G, et al. Complications of preoperative embolization of cerebral arteriovenous malformations. J Neurosurg. 2004;100(5):810-2.
- Yoshimoto T, Kayama T, Suzuki J. Treatment of cerebral arteriovenous malformation. Neurosurg Rev. 1986;9(4):279-85.
- Zhao J, Wang S, Li J, Qi W, Sui D, Zhao Y. Clinical characteristics and surgical results of patients with cerebral arteriovenous malformations. Surg Neurol. 2005;63(2):156-61; discussion 161.
- Berman MF, Hartmann A, Mast H, et al. Determinants of resource utilization in the treatment of brain arteriovenous malformations. AJNR Am J Neuroradiol. 1999;20(10):2004-8.
- Spetzler RF, Martin NA, Carter LP, Flom RA, Raudzens PA, Wilkinson E. Surgical management of large AVM's by staged embolization and operative excision. J Neurosurg. 1987;67(1):17-28.
- Gossage JR, Kanj G. Pulmonary arteriovenous malformations. A state of the art review. Am J Respir Crit Care Med. 1998;158(2):643-61.
- Cottin V, Plauchu H, Bayle JY, Barthelet M, Revel D, Cordier JF. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med. 2004;169(9):994-1000.
- Mager JJ, Overtoom TT, Blauw H, Lammers JW, Westermann CJ. Embolotherapy of pulmonary arteriovenous malformations: long-term results in 112 patients. J Vasc Interv Radiol. 2004;15(5):451-6.
- Moussouttas M, Fayad P, Rosenblatt M, et al. Pulmonary arteriovenous malformations: cerebral ischemia and neurologic manifestations. Neurology. 2000;55(7):959-64.
- Pollak JS, Saluja S, Thabet A, Henderson KJ, Denbow N, White RI, Jr. Clinical and anatomic outcomes after embolotherapy of pulmonary arteriovenous malformations. J Vasc Interv Radiol. 2006;17(1):35-44; quiz 45.
- Swanson KL, Prakash UB, Stanson AW. Pulmonary arteriovenous fistulas: Mayo Clinic experience, 1982-1997. Mayo Clin Proc. 1999;74(7):671-80.
- Al-Saleh S, Mei-Zahav M, Faughnan ME, et al. Screening for pulmonary and cerebral arteriovenous malformations in children with Hereditary Hemorrhagic Telangiectasia. Eur Respir J. 2009.
- Faughnan ME, Thabet A, Mei-Zahav M, et al. Pulmonary arteriovenous malformations in children: outcomes of transcatheter embolotherapy. J Pediatr. 2004;145(6):826-31.
- Curie A, Lesca G, Cottin V, et al. Long-term follow-up in 12 children with pulmonary arteriovenous malformations: confirmation of hereditary hemorrhagic telangiectasia in all cases. J Pediatr. 2007;151(3):299-306.
- Shovlin CL, Winstock AR, Peters AM, Jackson JE, Hughes JM. Medical complications of pregnancy in hereditary haemorrhagic telangiectasia. QJM. 1995;88(12):879-87.
- Ference BA, Shannon TM, White RI, Jr., Zawin M, Burdge CM. Life-threatening pulmonary hemorrhage with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. Chest. 1994;106(5):1387-90.
- Shah RK, Dhingra JK, Shapshay SM. Hereditary hemorrhagic telangiectasia: a review of 76 cases. Laryngoscope. 2002;112(5):767-73.
- Ingrosso M, Sabba C, Pisani A, et al. Evidence of small-bowel involvement in hereditary hemorrhagic telangiectasia: a capsule-endoscopic study. Endoscopy. 2004;36(12):1074-9.
- Kjeldsen AD, Vase P, Green A. [Hereditary hemorrhagic telangiectasia. A population-based study on prevalence and mortality among Danish HHT patients]. Ugeskr Laeger. 2000;162(25):3597-601.
- Vase P, Grove O. Gastrointestinal lesions in hereditary hemorrhagic telangiectasia. Gastroenterology. 1986;91(5):1079-83.
- Longacre AV, Gross CP, Gallitelli M, Henderson KJ, White RI, Jr., Proctor DD. Diagnosis and management of gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol. 2003;98(1):59-65.
- Proctor DD, Henderson KJ, Dziura JD, Longacre AV, White RI, Jr. Enteroscopic evaluation of the gastrointestinal tract in symptomatic patients with hereditary hemorrhagic telangiectasia. J Clin Gastroenterol. 2005;39(2):115-9.
- Memeo M, Stabile Ianora AA, Scardapane A, et al. Hereditary haemorrhagic telangiectasia: study of hepatic vascular alterations with multi-detector row helical CT and reconstruction programs. Radiol Med. 2005;109(1-2):125-38.
- Ravard G, Soyer P, Boudiaf M, et al. Hepatic involvement in hereditary hemorrhagic telangiectasia: helical computed tomography features in 24 consecutive patients. J Comput Assist Tomogr. 2004;28(4):488-95.
- Buscarini E, Danesino C, Olivieri C, et al. Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia -- results of extensive screening. Ultraschall Med. 2004;25(5):348-55.
- Buscarini E, Buscarini L, Danesino C, et al. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family. J Hepatol. 1997;26(1):111-8.
- Ocran K, Rickes S, Heukamp I, Wermke W. Sonographic findings in hepatic involvement of hereditary haemorrhagic telangiectasia. Ultraschall Med. 2004;25(3):191-4.
- Ianora AA, Memeo M, Sabba C, Cirulli A, Rotondo A, Angelelli G. Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement. Radiology. 2004;230(1):250-9.
- Garcia-Tsao G, Korzenik JR, Young L, et al. Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2000;343(13):931-6.
- Chavan A, Caselitz M, Gratz KF, et al. Hepatic artery embolization for treatment of patients with hereditary hemorrhagic telangiectasia and symptomatic hepatic vascular malformations. Eur Radiol. 2004;14(11):2079-85.
- Azoulay D, Precetti S, Emile JF, et al. [Liver transplantation for intrahepatic Rendu-Osler-Weber's disease: the Paul Brousse hospital experience]. Gastroenterol Clin Biol. 2002;26(10):828-34.
- Lerut J, Orlando G, Adam R, et al. Liver transplantation for hereditary hemorrhagic telangiectasia: Report of the European liver transplant registry. Ann Surg. 2006;244(6):854-62; discussion 862-4.
- Simonds J, Miller F, Mandel J, Davidson TM. The effect of bevacizumab (Avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 2009;119(5):988-92.
- Mitchell A, Adams LA, MacQuillan G, Tibballs J, vanden Driesen R, Delriviere L. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl. 2008;14(2):210-3.
- Flieger D, Hainke S, Fischbach W. Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab. Ann Hematol . 2006;85(9):631-2.