Short summary

Hereditary Hemorrhagic Telangiectasia is an autosomal dominant disease which causes abnormal formation of blood vessels. This results in fragile vessels in mucus membranes of the nose and mouth, but also affect the gastrointestinal tract and liver. This project will focus on the gastrointestinal complications of HHT, with specific focus on liver arteriovenous malformations and telangiectasia in the bowl.

Rationale

Hereditary Hemorrhagic Telangiectasia is an autosomal dominant disease which causes abnormal formation of blood vessels. The disease is linked to mutations in relation to at least three known genes (ENG, ACVRL1 and SMAD4), causing unbalance in the TNF-beta signalling pathway, which is responsible for angiogenesis. This leads to the formation of arteriovenous malformations in the visceral organs and telangiectasia in mucus membrans and skin.

The most common symptom of HHT is recurrent, spontaneous epistaxis due to telangiectatic lesions in the nasal mucosa. Usually, it debuts in childhood and progresses with age. Ultimately, around 90 % of the patients experience epistaxis. The epistaxis severity differs widely between patients, ranging from nosebleeds occurring occasionally and lasting less than one minute, to multiple hemorrhages daily resulting in transfusion dependence (7-9). Second to epistaxis, gastrointestinal (GI) bleeding is the most common cause of anemia in HHT. The bleeding occurs in the GI-tract from telangiectatic lesions in up to 30 % of HHT patients. Commonly, GI-bleeding is seen in patients over the age of 50 years, and it tends to become more severe with increasing age (10-12). Hepatic arteriovenous malformations (HAVMs) have been found in over 70% of HHT-patients (13). Commonly, hepatic lesions are asymptomatic, but they can cause biliary ischemia, portal hypertension or high-cardiac output, resulting in right heart failure (14). HAVMs are predominantly seen among women with HHT2(15). Screening for HAVMs has been widely debated internationally (16). At the HHT-center at Odense University Hospital (OUH) several cases of severe right heart failure as a consequence of HAVMs have been observed and treated with either liver transplantation or Bevacizumab.

Presently, all Danish HHT-patients are offered genetic testing. In addition, screening for anemia is performed and epistaxis severity is evaluated. Finally, a contrast echocardiogram is performed, to screen for PAVMs, pulmonary hypertension and/or right heart failure. Since we have seen several severe cases of HAVMs, we have decided to offer screening for HAVMs by triple-phase CT-scan as part of the screening program.

Aims This study consists of three sub-projects, and 160 HHT-patients will be invited to participate:

Project A: To establish if ultrasound of the liver is an equally sensitive screening tool for identification of HAVMs in comparison to triple-phase CT-scan of the liver. To establish when an echocardiogram should be introduced in the screening protocol to evaluate cardiac complications caused by HAVMs.

Project B: To quantitate and characterize telangiectatic lesions in the GI-tract and to investigate the correlation to hemoglobin and iron levels. Blood samples will be taken to investigate for anemia, iron levels and liver enzyme values. Project C: Evaluation of self-reported quality of life and correlation to the objective findings. The questionnaires, Epistaxis Severity Score (ESS), SF-36, version 2, EQ-5D-5L and VAS will be handed out. The epistaxis questionnaire will be correlated with the clinical examination of protruding vessels in the nasal mucosa. Moreover, a clinical examination and medical history, including previous and on-going medication will be performed. Patients will also be invited to participate in a follow-up study 10-years after the present study

Description of the cohort

Patients with Hereditary Hemorrhagic Telangiectasia (HHT) from the region of Southern Denmark.

Data and biological material

Patient data, age, gender, HHT type, symptoms. Hepatic ultrasound with focus on vessels Cardiac ultrasound with focus on right ventricle Blood samples. Questionnaire data

Collaborating researchers and departments

Department of Medical Gastrointestinal Diseases, Odense University hospital

• Department of Cardiology, Odense University hospital
• Clinical institute, University of Southern Denmark