Hereditary Hemorrhagic Telangiectasia

Key points

Genetics

Thus far, 5 putative HHT disease-causing genes have been located, but genetic screening is clinically available for only 3 of these: ENG encoding endoglin (HHT type 1); ACVRL1 encoding ALK-1 (HHT type 2); and MADH4 encoding SMAD4 (combined syndrome of HHT and juvenile polyposis syndrome that predisposes patients to both HHT and juvenile polyps of the GI tract, especially the colon and stomach, with a high risk of malignant transformation).7, 8, 9 The 2 remaining unidentified HHT-causing genes

Diagnosis

HHT is a clinical diagnosis, and the Curaçao criteria are the mainstay of diagnosis.¹⁸ Definite HHT is diagnosed in the presence of 3 or more features, including (1) spontaneous, recurrent nosebleeds; (2) mucocutaneous telangiectasias at multiple characteristic sites such as fingertips, lips, oral mucosa, and/or tongue; (3) visceral involvement with GI telangiectasia and pulmonary, hepatic, cerebral, and/or spinal AVMs; and (4) family history of an affected first-degree relative. If only 2

Nasal involvement

Recurrent spontaneous epistaxis is the most common symptom of HHT, and it manifests in approximately 50% of patients by age 20, and 96% develop this by age 40.44, 45 Because its occurrence and duration are quite variable, the Epistaxis Severity Score was created to objectively assess severity, thereby allowing care providers to tailor optimal treatment plans for HHT patients.⁴⁶ The goals of epistaxis management focus on reducing chronic nasal bleeding, management of anemia, and treatment of

Central nervous system involvement

A variety of vascular abnormalities with different morphologies have been described in the CNS in HHT, including cerebral arteriovenous malformations (CAVMs) (Fig. 2), arteriovenous fistulas (AVFs), telangiectasias, cavernous malformations, developmental venous anomalies (DVAs), and vein of Galen malformations.⁴⁸ Of these, CAVMs, AVFs, and telangiectasias are most commonly involved. AVFs of the brain and spinal cord occur mainly in children under 5 years of age, while CAVMs and telangiectasias

Gastrointestinal involvement

Telangiectasias can be found anywhere in the GI tract, but the stomach and small bowel are mainly affected in approximately 80% of patients.⁵² Despite this high frequency, only 25% of patients will develop symptomatic GI bleeding, which usually does not present until the fifth or sixth decades of life and tends to mainly afflict women.⁵² Gastric and duodenal telangiectasias are the main sources of bleeding, and the associated morbidity is proportional to the severity of resultant anemia.⁵²

Hepatic involvement

Hepatic VMs and telangiectasias have been observed to varying extents in the nearly 80% of patients with HHT, but only approximately 8% of these patients will develop symptomatic disease.³⁶ Clinical manifestations are determined by the predominant type of intrahepatic shunt: HOHF, ischemic cholangiopathy, and mesenteric ischemia are associated with hepatic artery–hepatic vein shunts; portal hypertension with hepatic artery–portal vein shunts; and hepatic encephalopathy with portal vein–hepatic

Summary

Research in the areas of translational genetics and angiogenesis regulation is yielding significant insights into the pathogenesis of HHT. In addition, development of safer and less-invasive management and screening protocols is improving the care of patients with HHT. Most notably, encouraging pathobiological data suggest a promising role for antiangiogenic medical therapy in disease management, and further evidence-based studies on the efficacy and safety of these agents are being conducted.