Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome) Andrew Avery A.M. Report 06/26/09

Introduction HHT is an autosomal dominant genetic disorder that leads to vascular malformations HHT is an autosomal dominant genetic disorder that leads to vascular malformations First recognized in the 19th century as a familial disorder with abnormal vascular structures causing bleeding from the nose and gastrointestinal tract HHT is characterized by telangiectatic lesions of the nose, lips, and visceral organs including the liver, spleen, gastrointestinal tract, lungs, brain, and spinal cord HHT is characterized by telangiectatic lesions of the nose, lips, and visceral organs including the liver, spleen, gastrointestinal tract, lungs, brain, and spinal cord

Epidemiology Incidence in Europe and Japan at rates between 1:5000 and 1:8000; but widely variable in other regions More frequently occurs in whites

Pathophysiology Mutations in at least four genes can cause HHT The two major disease genes responsible for HHT are on chromosome 9 (ENG, protein product: endoglin) and chromosome 12 (ACVRL1, protein product: activin receptor-like kinase 1, ALK-1); designated HHT1 and HHT2, respectively

Pathophysiology HHT results from endoglin or ALK-1 haploinsufficiency (ie, lack of sufficient protein for normal function) ALK-1 is a transforming growth factor (TGF)- beta superfamily type I receptor, and endoglin associates with different signaling receptors and can modify TGF-beta-1 signaling Thus, it is thought that abnormal vessels in HHT probably develop because of aberrant TGF-beta signaling at some stage during vascular development

Pathophysiology HHT1: pulmonary and cerebral AVMs are more common HHT2: hepatic AVMs are more common However, understanding whether a pt has an endoglin or ALK-1 mutations does not allow a strong prediction of the likely course of HHT, since all features of HHT can be seen in both HHT1 and HHT2.

Clinical Features Majority of patients with HHT experience only epistaxis, mucocutaneous telangiectasia, and a tendency to develop iron deficiency anemia secondary to the blood loss In pts who do not present spontaneously to a clinician before the age of 60 years, there is no excess mortality There is significant morbidity and mortality in younger patients, predominantly attributed to the consequences of visceral involvement

Clinical Features Epistaxis-most common manifestation. Severity is widely variable GI Bleeding-occur in ≈1/3 of pts; telangiectasia more common in the stomach or duodenum, but can occur anywhere Mucocutaneous telangiectasia- occur in the skin and buccal mucosa of about 75 percent of individuals, typically presenting after the age of 20, and increasing in size and number with age; mostly occur on the face, lips, tongue, buccal mucosa, fingertips, and dorsum of the hand, but can occur elsewhere

Colon Angiodysplasia

Superficial telangectasias

Pulmonary AVMs Definition: thin walled abnormal vessels that replace normal capillaries between the pulmonary arterial and venous circulations Provide a direct capillary-free communication between the pulmonary and systemic circulations The majority of pulmonary AVM patients have no respiratory symptoms Only 1/3 of affected individuals exhibited physical signs indicating a substantial right-to-left shunt (eg, cyanosis, clubbing, polycythemia)

Complications of Pulmonary AVMs Neurological sequelae 2/2 to paradoxical emboli are most common and include both catastophic embolic cerebral events (e.g. cerebral abscess and embolic stroke) and TIAs Hemorrhage may occur vessels in a bronchus or the pleural cavity, causing hemoptysis or hemothorax High-output heart failure may develop in the presence of marked shunting arterial blood to the venous circulation

Pulmonary AVMs

Cerebral AVMs Cerebral AVMs affect approximately 10 percent of HHT patients (usually silent) May lead to headache, seizures, hemorrhage, or ischemia of the surrounding tissue (due to a steal effect) One large observational study showed that HHT pts under the age 46 years were 23 times more likely to have a stroke than their counterparts in the general population

Cerebral AVMs

Hepatic AVMs Silent hepatic involvement occurs in up to 30 percent of patients with HHT Symptoms are much less frequent and include high- output heart failure, portal hypertension, and biliary disease Large AVMs between the hepatic artery and vein can cause a significant left-to-right shunt with steal syndromes that can cause angina Portal hypertension and hepatic encephalopathy, particularly after episodes of gastrointestinal bleeding, may result from shunts between the hepatic artery and portal vein

Diagnostic Criteria Spontaneous and recurrent epistaxis Multiple mucocutaneous telangiectasias Visceral involvement (eg, gastrointestinal, pulmonary, cerebral, or hepatic AVMs) A first-degree relative with HHT -three or four criteria->”definite;” two criteria ->”suspected;” none->”unlikely The diagnosis may be confirmed by formal genetic testing for mutations involving endoglin, ALK-1, or SMAD4

Physical Exam When HHT is suspected, PE focuses on searching for teleangiectasias, which are usually most commonly located on the digits, pinna, bridge of the nose, tongue or palate. When HHT is suspected, PE focuses on searching for teleangiectasias, which are usually most commonly located on the digits, pinna, bridge of the nose, tongue or palate. Auscultation of the liver for presence of bruits, and heart for high-output cardiac failure should be performed Auscultation of the liver for presence of bruits, and heart for high-output cardiac failure should be performed A detailed neurological examination should foucs on uncovering prior evidence of a stroke A detailed neurological examination should foucs on uncovering prior evidence of a stroke

Management Epistaxis: Epistaxis: Treatments are generally directed to patients either experiencing massive hemorrhages or experiencing daily epistaxis, and include laser ablation, arterial ligation, septodermoplasty, and unilateral or bilateral surgical closure of the nostrils GI Bleed: GI Bleed: Repeated endoscopic ablation of gastrointestinal lesions may be used to control bleeding in the short term. Surgery has limited success due to recurrent disease, but may be useful for emergency control of hemorrhage from discrete lesions, as may embolization

Management GI Bleed: Estrogen-Progesterone has been found to be useful in managing recurrent bleeds; GI Bleed: Estrogen-Progesterone has been found to be useful in managing recurrent bleeds; role of antifibrinolytics is being investigated Iron Deficiency Anemia: Pts with minimal degrees of bleeding can receive oral iron therapy. However, bleeding may be severe enough to require blood transfusions and/or parenteral iron therapy

Management of AVMs Pulmonary AVMs: embolotherapy is recommended Cerebral AVMs: may be treated with embolectomy, surgical removal, or stereotactic radiotherapy Hepatic AVMs: if medical management fails, liver transplantation is the treatment of choice.