Are You Confident of the Diagnosis?
Hereditary hemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu syndrome, is a disorder of the vascular system that results in arteriovenous malformations (AVMs) or telangiectasias. Traditionally these telangiectasias affect the skin, lip, buccal and nasal mucosa and the gastrointestinal tract (Figure 1, Figure 2). It is increasingly recognized that AVM formation also occurs in the pulmonary, cerebral and liver circulation as well as the gastrointestinal tract and pancreas.
The clinical presentation of HHT is variable. The most common presentation is recurrent, spontaneous epistaxis that occurs early in life. Telangiectasias of the skin and buccal mucosa typically starts in the teenage years and increases with advanced age (Figure 1) Patients can also present with anemia secondary to recurrent, chronic blood loss from epistaxis and gastrointestinal loss. Recurrent gastrointestinal bleeding affects 15% to 20% of patients and usually occurs later in life. Other clinical presentations include dyspnea, pulmonary hypertension, ischemic strokes, brain abscess and high output heart failure.
The diagnosis of HHT is a clinical diagnosis based on the Curacao criteria. These criteria are 1) recurrent, spontaneous epistaxis; 2) cutaneous/oral telangiectasia; 3) visceral AVMs and 4) a first-degree relative with HHT. Three or more criteria are required for a definite diagnosis. The presence of two criteria make the diagnosis probable. The diagnosis is unlikey if there are fewer than two criteria.
Who is at Risk for Developing this Disease?
HHT is an autosomal dominant disorder that affects the vascular system. It is estimated to affect 1 in 5000 to 8000 people. Although it is reported across a wide variety of ethnic groups, it is more common in Caucasians. Males and females are equally affected.
Although this is an inherited disorder, up to 20% of patients will have a negative family history. This may be due to either a spontaneous mutation, differences in the clinical presentation among family members, or incomplete screening of family members. All affected individuals will be heterozygous as the homozygous form is lethal. The penetrance of the disease is estimated to be 97% to 100%. Despite the high percentage of penetrance, the clinical presentation is age dependent with some patients presenting after the age of 30 years.
What is the Cause of the Disease?
There are 5 types of HHT based on genetic mutations and clinical presentations. The two most common types are HHT types 1 and 2. HHT type 1 is associated with a mutation of the ENG gene on chromosome 9, which results in an abnormal endoglin protein. Pulmonary and cerebral AVMs are more commonly associated with type 1. HHT type 2, which is associated with a mutation ACVRL1 gene on chromosome 12, results in an abnormal activin receptor like kinase (ALK-1) protein. Hepatic and pancreatic AVMs are more common in type 2. Type 3 HHT is associated with a mutation of the SMAD4 gene and is associated with juvenile polyposis syndrome.
More recently, two additional types have been identified and mapped to mutations on chromosomes 5 and 7 respectively.
The exact mechanism of AVM formation is not known. In the normal order of vascular structure, the venules and arterioles are connected via a capillary bed. The first changes noted are a loss of capillaries with dilation of the venules. As the venules dilate, they become convoluted and connect to the arterioles directly. Patients with HHT type 1 and type 2 express about 50% of the normal endoglin and ALK-1 protein in their endothelial cells respectively. Endoglin and ALK-1 are part of the TGF-β signaling pathway. TGF-β is one of the superfamily of ligands that regulates cellular growths and differentiation. Abnormal signaling of the TGF-β pathway is thought to result in the abnormal blood vessels.
Systemic Implications and Complications
The major systemic complications are related to visceral AVMs. Although AVMs can occur in any organs, they are most commonly found in the lung, brain, liver and gastrointestinal tract.
It is estimated that 20% to 35% of patients with HHT will have pulmonary involvement. Although most patients are asymptomatic, pulmonary AVMs can lead to life-threatening complications. Most of the clinical symptoms are due to right-to-left shunting. The most frequent symptom is dyspnea on exertion, which occurs in about 50% of patients. Other complications from right-to-left shunting include hemoptysis, chest pain, clubbing of the fingers, cyanosis and pulmonary hypertension. Bleeding from AVM rupture can occur in up to 8% of patients. Rupture from intrabronchial AVMs presents as hemoptysis while hemothorax is the result of interpleural AVM rupture.
Besides pulmonary symptoms, neurologic symptoms are very common in patients with pulmonary AVMs, occurring in up to 13% of patients. Brain abscess, ischemic strokes, transient ischemic attacks and migraine can all be the presenting symptom of pulmonary AVMs. Right-to-left shunting, which allows for bacteria and small emboli to enter the systemic circulation, is proposed as the etiology for the increased neurologic complications.
Due to the high risk and potential lethal complications that occur with pulmonary AVMs, it is recommended that patients with HHT be screened for pulmonary AVMs. Approximately 50% of HHT patients with pulmonary AVMs are diagnosed at screening. A helical, multidetector computed tomograph (CT) of the chest is the gold standard for diagnosing pulmonary AVMs.
Transthoracic bubble echocardiography is the test of choice for detecting a right-to-left shunt. In a small percentage of patients, the bubble echocardiography is positive and the chest CT is negative. Also, the bubble echocardiography remains positive in over 90% of patients after embolization of the pulmonary AVMs.
Either study can be used as a screening test for pulmonary AVMs. Some authors prefer to start with the bubble echocardiography and, if positive, confirm with a chest CT. This will avoid unnecessary radiation exposure.
Pulmonary AVMs are treated with transcatheter ablation when the feeding vessel is more that 3mm in diameter. If technically possible, AVMs with feeding vessels greater that 1.5 to 2mm in diameter should also be ablated. Surgical excision is rarely used today and is an option when transcatheter ablation is not amenable.
Although rare, pulmonary hypertension is a lethal complication that occurs in patients with HHT. It occurs in 1% of patients and is due to the high cardiac output and hyperdynamic state that is associated with systemic AVMs. It is most commonly associated with hepatic AVMs. The most common presenting symptom is dyspnea on exertion, and treatment is medical therapy.
Neurologic complications can occur in 8% to 12% of patients with HHT. Common complications include brain abscess, ischemic strokes, transient ischemic attacks (TIA), intracranial bleeding, seizures and migraine. About two thirds of the neurologic complications are assoicated with right-to-left shunting from pulmonary AVMs. Thus, patients presenting with a neurologic complication should be screened for pulmonary AVMs. Screening for cerebral AVMs is controversial, with American centers recommending screening while European centers do not. An MRI of the brain is the most sensitive test for detecting cerebral AVMs. Treatment is tailored toward the specific complication.
Recurrent gastrointestinal blood loss occurs in a small percentage of patients with HHT and typically presents later in life. It is due to AVM formation in the gastrointestinal tract, mainly in the stomach and proximal small bowel. Most commonly it clinically presents as iron deficiency anemia and rarely as overt gastrointestinal bleeding. Treatment is with iron supplementation and blood transfusions. Endoscopic ablation using argon plasma coagulation (APC) is used to treat the AVMs. Cessation of all blood loss is rarely met, but reduction in transfusion requirements is frequently achieved. The use of hormonal therapy using estrogen/progesterone has not shown to be beneficial. Surgery and arterial embolization are reserved for patients whose bleeding cannot be controlled endoscopically.
Hepatic AVMs are found more frequently in HHT type 2 patients with a prevalence range from 41% to 84%. It is more common in women and is age related with increased prevalence in older patients. The vascular lesion in the liver is the result of intrahepatic shunts. There are three types of shunts identified: hepatic artery to portal vein (most common), hepatic artery to hepatic vein, and portal vein to hepatic vein. These shunts result in sinusoidal hypertension, which increases fibrous tissue in the portal and periportal region. Despite this increase in fibrosis, true cirrhosis rarely occurs.
There are two specific lesions associated with intrahepatic shunting and fibrosis that occur in patients with HHT. When the process is diffuse, it results in nodular regenerative hyperplasia, which resembles cirrhosis. When the process is localized, the resulting lesion is focal nodular hyperplasia.
The clinical symptoms due to hepatic AVMs are high-output heart failure, portal hypertension and biliary disease. High-output heart failure is the most common complication and is due to severe intrahepatic shunting. Patients can present with dyspnea, dyspnea on exertion, orthopnea, cardiac ascites and edema. High-output heart failure is associated with pulmonary hypertension. Portal hypertension is due to shunting of blood from the hepatic artery to the portal vein and veno-occlusive disease associated witth nodular regenerative hyperplasia. These patients present with ascites, esophageal and gastric varices and possibly variceal bleeding.
Unlike the hepatocytes that receive dual bood supply from the portal and hepatic system, the biliary system is exclusively dependent on the hepatic artery. Shunting blood from the hepatic artery results in ischemic injury to the biliary system. This leads to stricture formation with cholestasis and recurrent cholangitis.
Color Doppler ultrasound and helical, multidectector CT scans are used in diagnosis of hepatic AVMs. Although angiography remains the gold standard, it has been replaced by the non-invasive ultrasound and CT scan. Asymptomatic patients are not treated and thus screening for hepatic AVMs is controversial. When hepatic AVMs become symptomatic, treatment is tailored toward the symptoms.
There is no specific treatment to the underlying genetic defect that occurs in hereditary hemorrhagic telangiectasia. Treatment is based on complications that occur in the affected organ.
Significant bleeding in the form of epistaxis can occur from AVMs of the nasal mucosa. Initial therapy would be nasal packing to stop the acute bleed followed by more definitive therapy. Treatment options are local ablation (argon, Nd-YAG), surgery (septal dermatoplasty, septal closure, arterial ligation), embolization and systemic therapy with estrogen/progesterone.
With the exception of nasal AVMs that can cause epistaxis, severe bleeding from cutaneous AVMs rarely occus. Laser therapy can be used to ablate cutaneous AVMs.
AVMs in the gastrointestinal tract can be asymptomatic, cause iron deficiency anemia or present with recurrent gastrointestinal bleeding. When AVMs are symptomatic, they can be ablated. The most commom ablative method is the use of laser (argon, Nd-YAG). Bipolar probe and cryotherapy are sometimes used. Since AVMs can occur anywhere in the gastrointestinal tract, patients may need referral to a tertiary care center for push enteroscopy, single-balloon enteroscopy or double-balloon enteroscopy to treat small bowel AVMs. Arterial embolization and surgery are usually reserved for those patients who failed endoscopic therapy.
The majority of the complications that occur in patients with HHT are due to pulmonary AVMs. Catheter vaso-occlusive embolization is the therapy of choice. The most commonly used method is detachable steel coils. For very large vessels, detachable balloons or Amplatzer occluders may be required. Surgery with either segmental or lobar resection may be required when multiple AVMs are clustered together or complex. Surgery may also be required in the setting of a hemothorax.
It is controversial whether asymptomatic hepatic AVMs should be treated. When high-output heart failure occurs, initial management is correcting anemia with blood transfusions and the correction of cardiac arrhythmias with medication such as beta-blockers. Those presenting with ascites are treated with salt restriction and diuretics. A combination of spironolactone and furosemide is used. For those who do not respond to maximal diuretic therapy or are intolerant to diuretics, repeated large volume paracentesis is used. Non-bleeding esophageal varices are treated using non-selective beta-blockers or endoscopic band ligation if they cannot tolerate beta-blockers. For bleeding esophageal varices, treatment is with blood transfusion, vasoconstrictor medications (octreotide, vasopressin, terlipressin), and endoscopic band ligation or sclerotherapy.
When patients with hepatic AVMs do not respond to the appropriate medical therapy, transarterial embolization and surgical ligation of hepatic artery can be used. Liver transplantation can be used when all other therapies have failed.
The management of cerebral AVMs is controversial. American centers recommend screening for cerebral AVMs using magnetic resonance imaging (MRI) with or without gadolinium. The European centers do not recommend screening. When present, cerebral AVMs can be treated by embolization, surgery or stereotactic radiotherapy. The majority of cerebral infections such as brain abscesses are related to pulmonary AVMs. Thus, patients with cerebral infections should be screened for pulmonary AVMs. If a brain abscess occurs, surgical drainage with prolonged intravenous antibiotics (6 to 8 weeks) is usually required.
Optimal Therapeutic Approach for this Disease
Genetic analysis in not required for the diagnosis. In about 20% of families, no mutation is found.
Screen all patients for pulmonary and cerebral AVMs. If present, consider referral to pulmonary and neurology specialists respectively.
Manage blood loss from epistaxis and gastrointestinal bleeding with transfusion. The transfusion goal is to achieve an Hbg of 8mg/dL in most patients. If the patient has a history of coronary artery disease, then the Hbg goal in 10mg/dl. Currently there is not sufficient evidence to recommend routine testing of hemoglobin or stool hemoccult. Hemoglobin testing should be done based on clinical symptoms. Consider referral to ear/nose/throat (ENT) surgeon and gastroenterologist.
Educate patients and their families on the early signs of a stroke. Early investigation to rule out a hemorrhage, ischemic stroke or brain abscess is warranted as the treatment differs.
Educate patients on the importance of good dental care and the need for antibiotic prophylaxis prior to dental procedures if they have pulmonary AVMs. The recommended antibiotic coverage is according to the American Heart Association guidelines.
Avoid antiplatelet agents and anticoagulation if possible.
Management of HHT is based on management of symptoms and complications. Anemia from recurrent blood loss is managed with transfusion and directed therapy to decrease blood loss. Multiple transfusions through life can lead to secondary hemochromotosis. Patients with HHT should be screened according to the HHT Foundation recommendations:
–MRI of the brain once at an early age and then once as an adult
–Contrast bubble echocardiography at age 10. If contrast echocardiography suggestive of pulmonary AVMs, CT chest.
–Pulse oximetry every 1 to 2 years in children less than 10 years. If evidence of hypoxia is present, a contrast echocardiogram should be done. If contrast echocardiogram shows the presence of a right-to-left shunt, then a chest CT is indicated.
–Annual physicals with a check of a complete blood count (CBC)
All patients with pulmonary AVMs are at increased risk of cerebral infection when they undergo dental procedures. It is recommended that they receive antibiotic (amoxicillin, clindamycin, or azithromycin) prophylaxis prior to the procedure.
Unusual Clinical Scenarios to Consider in Patient Management
HHT patients who become pregnant should be screened immediately for pulmonary AVMs if they were not screened previously. Pulmonary AVMs increase in number and size during pregnancy. In the majority of patients, the pregnancy is uneventful. Occasionally there can be hemorrhaging that requires embolization or surgery. It is esitmated that 1% to 2% of patients will have spinal AVMs, which places them at an increased risk with epidural analgesia. A spinal MRI may be necessary before epidural analgesia. As the majority of pregnancies are uneventful, routine referral to a high-risk obstetric center is warranted. If a spinal AVMs is found, then referral to a teritary care center may be warranted.
What is the Evidence?
Sabba, C, Pasculli, G, Lenato, GM, Suppressa, P, Lastella, P, Memeo, M. “Herediatary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carries”. J Thromb Haemost. vol. 5. 2007. pp. 1149-57. (A study of 135 patients with the two most common mutations in HHT, looking at visceral and phenotypic differences.)
Sabba, C, Pompil, I. “Review article: the hepatic manifestations of hereditary hemorrhagic telangiectasia”. Aliment Pharmacol Ther. vol. 28. 2008. pp. 523-33. (An excellent review of the liver complications that can occur in patients with hemorrhagic telangiectasia.)
Govani, FS, Shovlin, CL. “Hereditary hemorrhagic telangiectasia: clinical and scientific review”. Eur J Human Genet. vol. 17. 2009. pp. 860-71. (An excellent review and up to date on HHT.)
Shovlin, CL, Guttmacher, AE, Buscfarini, E, Faughnan, ME, Hyland, RH, Westermann, CJJ. “Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)”. Am J Med Genet. vol. 91. 2000. pp. 66-7. (The establishment of the Curacao criteria for the diagnosis of HHT.)
Begbie, ME, Wallace, GM, Shovlin, CL. “Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view for the 21st century”. Postgrad Med J. vol. 79. 2003. pp. 18-24. (A thorough review of HHT.)
Sell, B, Evans, J, Horn, D. “Brain abscess and hereditary hemorrhagic telangiectasia”. South Med J. vol. 101. 2008. pp. 618-25. (A summary of 55 cases of brain abscess in HHT. Also a review of the common cerebral complications that can occur with the disease.)
Sadick, H, Sadick, M, Gotte, K, Naim, R, Riedel, F, Bran, G. “Hereditary hemorrhagic telangiectasia: an update on clinical manfestations and diagnostic measures”. Wien Klin Wochenschr. vol. 118. 2006. pp. 72-80. (A excellent review of the genetics and pathophysiology of HHT.)
Cottin, V, Dupuis-Girod, S, Lesca, G, Cordier, J. “Pulmonary vascular menifestation of hereditary hemorrhagic telangiectasia (Rendu-Osler disease)”. Respiration. vol. 74. 2007. pp. 361-78. (Excellent review of the pulmonary complications as well as pathophysiology.)
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