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Hereditary Haemorrhagic Teleangiectasia/Mb Osler

Hereditary Haemorrhagic Teleangiectasia/Mb Osler. The HTT-center

In around 800 Danes nose bleeding is part of having Mb Osler. The patients are bothered by severe, sometimes disabling and transfusion requiring nose bleedings. Furthermore, there may occur bleeding from the gastrointestinal tract. Pulmonary arteriovenous malformations (PAVM) with the risk of respiratory distress and brain abscesses can be seen as well as cerebral arteriovenous malformations (CAVM).

 

The picture shows telangiectasias in the left nasal cavity (superficial, light bleeding blood vessels)

Description of HHT

Mb. Osler (Hereditary haemorrhagic telangiectasia (HHT)) is a dominantly inherited condition that causes altered structure of the blood vessels; in particular small peripheral blood vessels are affected. The condition is not associated with disturbances in the blood's ability to clot. In the vast majority of cases, the disease is caused by a mutation in one of two genes: ENG (chromosome 9) or ACVRL1 (chromosome 12). In a small number of families a mutation in the Smad4 gene is detected, giving rise to the HHT-JP; a syndrome involving both HHT and juvenile polyposis, which, in addition to HHT symptoms, causes an increased incidence of gastrointestinal cancer.

In all cases, endothelial growth and repair are disturbed. A disease-causing mutation can be detected in 89% of the Danish HHT families with clinically proven HHT.
In Denmark, the incidence of HHT is estimated to be 1:6500, equalling approximately 800 Danes with HHT, the majority of patients (95%) experience nose bleedings. The extent of nose bleedings, however, varies greatly. Moreover, some patients are bothered by bleeding from telangiectatic lesions in the mouth. Finally, many, especially elderly patients, are suffering from bleeding from the gastrointestinal tract. The bleeding tendency may be controlled by diodelaser treatment of the telangiectasias.

 

The arteriovenous malformations may occur in the internal organs, and about 25% of patients develop pulmonary arteriovenous malformations (PAVMs). In some patients with PAVMs up to 30-40% of the blood is shunted around alveoli of the lungs, and as a result, the patients have dyspnea. Since the filter function of the lungs is invalidated in patients with PAVMs, they are at increased risk of developing thrombosis and/or brain abscess. To prevent this, it is recommended that all HHT-patients are examined if they have PAVMs so that treatable PAVMs can be embolizated in the Department of Radiology.

Around 10-15% of the patients have cerebral arteriovenous malformations (CAVM). If patients have neurological symptoms, they should be referred to MR angiography in preparation for diagnosis and treatment of CAVM. Not all patients are screened for CAVM; as the treatment of CAVM can cause neurological sequelae, an individual risk assessment is made.
It has been reported that HHT patients may have an increased incidence of severe infections in general, with no direct correlation to the occurrence of PAVMs. Therefor it has been suggested that the mutation and thus the HHT condition in itself can depress the immune system.
Furthermore, a relation between HHT and cancer with a possible decreased risk of cancer in HHT patients has been considered.
In a previous Danish study an increased mortality among HHT1 patients has been demonstrated however this has not been definitely elucidated among HHT2 patients. The only study on mortality among HHT patients in general, is an Italian study. According to this study HHT patients probably has a shorter life than not HHT patients.

History of HHT

HHT was first described in Denmark by E. Gjessing in Hospitaltidende in 1915. In the first years there was no suitable treatment. But gradually treatment of nose bleeding in the form of dermatoplastic procedures  was established at OUH by Professor Poul Stoksted. From 1973 until 1985, Poul Vase collected medical data on Funen HHT patients, which resulted in Defence of the doctoral thesis in 1988. Title: Telangiectasia haemorragica hereditaria, Mb Osler [An epidemiological, genetic and clinical study]. For several years thereafter, patients with HHT was seen by consultant, Poul Vase at Svendborg Hospital. However, there was no screening offers and treatment of PAVMs was sparse. In the early 90's the international HHT patient association was established and Poul Vase was invited to participate in the meetings. The establishment of international contacts and research related opportunities for genetic analysis made further research possible. Soon as a junior doctor Anette Kjeldsen  was involved in a PhD project. This resulted in the establishment of the HHT- Center at Odense University Hospital and the defence of her PhD thesis: "Epidemiological and clinical aspects of Hereditary haemorrhagic Telangiectasia, Mb Osler" in March 1998. Since then, several research projects have carried been out. Recently in the shape of the PhD project by Pernille Mathiesen Tørring: "Genotyping and gene expression profiling in hereditary haemorrhagic telangiectasia". This PhD was defended in August 2014.

 

The HHT centre at OUH

In 1996, a HHT centre at Odense University Hospital was established. The head of the HHT centre is Professor Anette Kjeldsen from the Department of ORL - Head & Neck Surgery. The centre was established in connection with Anette Kjeldsen's PhD project which focused on the evaluation and treatment of Danish HHT patients. Thus screening for and treatment of PAVMs was established. The treatment is carried out by Department of Interventional Radiology under the leadership of Professor Poul Erik Andersen, while screening for PAVMs is handled by consultant Henrik Nissen MD PhD from the Department of Cardiology. In order to improve genetic counselling, screening for disease-causing mutations is carried out under the leadership of consultant Lilian Booms Ousager MD PhD in collaboration with Molecular biologist Klaus Brusgaard and Pernille Mathiesen Tørring MD PhD. In addition there is a close cooperation with the Department of Medical Gastroenterology regarding the gastrointestinal haemorrhages. Also the Department of neurology, Department of neurosurgery, Department of infectious diseases and the Department of gynaecology are included in the cooperation.

Genetics diagnosing of HHT patients

The laboratory at Odense University Hospital performs the mutation diagnostics, and in 89% of patients with clinically definite HHT, one can detect a pathogenic mutation. Most families have a unique mutation, but some mutations are repeated in several families with no known direct relation. Symptoms of HHT occurs in most patients in the teen-age years in the form of nose bleeding, but not always. Mutational diagnostics of 1.degree relatives without clinical manifestations of HHT can ensure proper screening for and treatment of pulmonary arteriovenous malformations. In families where no mutations can be detected, 1. degree relatives should be offered screening for pulmonary arteriovenous malformations.

Survival analysis

Patients with HHT have an increased morbidity, but mortality does not appear to be significantly increased. At the HHT centre OUH we have performed survival analysis based on 7.5 years of follow-up. In 2015 we plan to perform a 20-year follow-up study focusing on admissions (diagnoses and frequency) and with a focus on survival and causes of death.

International partners

Anette Kjeldsen is a member of the International Scientific Board of the International HHT organization. This has helped us getting in contact with many of the other HHT centres. Pernille Mathiesen Tørring has been on a study visit in Lyon, while Anette Kjeldsen has been on study visits at Yale University and at St. Vincents Bridgeport in the United States. Moreover, we have close contacts to Hammersmith's in London, St. Antonius Ziekenhuis in the Netherlands, Riks Hospital in Norway, as well as centres in Italy, Germany and Spain. 
Moreover, HHT-Center OUH is part of Vascern.

 

Ongoing and future projects

MD Katrine Saldern Ågaard is currently working on a research project entitled: Twenty years of follow-up in 73 HHT patients and their controls
In addition, two PhD projects under planning:

  • Risk of trombosis- and infection in patients with Hereditary Hemorrhagic telangiectasia. This project should be performed by MD Thomas Vedtofte
  • The optimal screening protocol for HHT patients

Publications from the HHT-centre

Prevalence of hereditary hemorrhagic telangiectasia in patients operated for cerebral abscess: a retrospective cohort analysis.
Larsen L, Marker CR, Kjeldsen AD, Poulsen FR.
Eur J Clin Microbiol Infect Dis. 2017 Jun 3. doi: 10.1007/s10096-017-3023-7. [Epub ahead of print]

Familial cerebral abscesses caused by hereditary hemorrhagic telangiectasia
Pernille Mathiesen Tørring, Mathilde Faurholdt Lauridsen, Christine i Dali, Poul Erik Andersen, Lillian Bomme Ousager, Klaus Brusgaard, Anette Kjeldsen
Clin Case Rep. 2017 Jun; 5(6): 805–808.

JP-HHT phenotype in Danish patients with SMAD4 mutations.
Jelsig AM, Tørring PM, Kjeldsen AD, Qvist N, Bojesen A, Jensen UB, Andersen MK, Gerdes AM, Brusgaard K, Ousager LB.
Clin Genet. 2016 Jul;90(1):55-62. doi: 10.1111/cge.12693. Epub 2015 Dec 21.

Global gene expression profiling of telangiectasial tissue from patients with hereditary hemorrhagic telangiectasia.

Tørring PM, Larsen MJ, Kjeldsen AD, Ousager LB, Tan Q, Brusgaard K.
Microvasc Res. 2015 May;99:118-26. doi: 10.1016/j.mvr.2015.04.002. Epub 2015 Apr 16.

Long non-coding RNA expression profiles in hereditary haemorrhagic telangiectasia.
Tørring PM, Larsen MJ, Kjeldsen AD, Ousager LB, Tan Q, Brusgaard K
PLoS One. 2014 Mar 6;9(3):

Sivapalan P, Demény AK, Almind M, Kjeldsen AD.
Ugeskr Laeger. 2014 Feb 8 Epub.

National mutation study among Danish patients with Hereditary Haemorrhagic Telangiectasia. 
Tørring PM, Brusgaard K, Ousager LB, Andersen PE, Kjeldsen AD.
Clin Genet. 2013 Sep 3. [Epub ahead of print]

Cerebral abscesses among Danish patients with hereditary haemorrhagic telangiectasia. 
Kjeldsen AD, Tørring PM, Nissen H, Andersen PE 
Acta Neurol Scand. 2014 Mar ;129(3):192-7. 2013 Aug 20. [Epub ahead of print]

Allelic dropout in the ENG gene, affecting the results of genetic testing in hereditary hemorrhagic telangiectasia. 
Tørring PM, Kjeldsen AD, Ousager LB, Brasch-Andersen C, Brusgaard K. 
Genet Test Mol Biomarkers. 2012 Dec;16(12):1419-23.

Embolization of pulmonary AVMs of feeding arteries less than 3 mm: reports of two cases and an 8-year follow-up without embolization. 
Andersen PE, Kjeldsen AD 
Acta Radiol Short Rep. 2012 Mar 29;1(2).

Efficiency of laser treatment in patients with hereditary hemorrhagic telangiectasia. 
Jørgensen G, Lange B, Wanscher JH, Kjeldsen AD
Eur Arch Otorhinolaryngol. 2011 Dec;268(12):1765-70. Epub 2011 Jun 26.

Interventionel treatment of pulmonary arteriovenous malformations
Andersen PE, Kjeldsen AD 
World Journal of radiology. 2010 September 28; 2(9):

Udredning og behandling af morbus Osler
Kjeldsen AD  Toerring PM, Andersen PE 
Ugeskr Laeger. 2011 Feb 14;173(7):490-5. Review. Danish.

Long-term follow-up after embolization of pulmonary arteriovenous malformations with detachable ballons.
Andersen PE, Kjeldsen AD 
Cardiovasc Intervent Radiol. 2008 May-June;31(3):569-74

Occlusion of pulmonary arteriovenous malformations by use of vascular plug.
Andersen PE, Kjeldsen AD
Acta Radiol. 2007 Jun;48(5):496-9.

Treatment of hereditary hemorrhagic telangiectasia. The Danish Society of Rhinology]
Kjeldsen AD; Dansk Rhinologisk Selskab
Ugeskr Laeger. 2007 Mar 19;169(12):1132. Danish. No abstract available

Clinical and radiological long-term follow-up after embolization of pulmonary arteriovenous malformations.
Andersen PE, Kjeldsen AD 
Cardiovasc Intervent Radiol. 2006 Jan-Feb;29(1):70-4

Brain abscess and hypoxia in a previously healthy young female. 
Gaïni S, Kjeldsen ADAndersen PE.
Scand J Infect Dis. 2005;37(4):301-3.

Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia. 
Kjeldsen AD, Moller TR, Brusgaard K, Vase P, Andersen PE
J Intern Med. 2005 Oct;258(4):349-55.

Selective embolization in the treatment of intractable epistaxis. 
Andersen PJ, Kjeldsen AD, Nepper-Rasmussen J.
Acta Otolaryngol. 2005 Mar;125(3):293-7. 

Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia. 
Brusgaard K, Kjeldsen AD, Poulsen L, Moss H, Vase P, Rasmussen K, Kruse TA, Horder M.
Clin Genet. 2004 Dec;66(6):556-61

[Pulmonary arteriovenous malformations. Current therapeutic principles] 
Andersen PE, Kjeldsen AD.
Ugeskr Laeger. 2001 Aug 13;163(33):4398-401. Review. Danish

[Percutaneous transluminal embolization of pulmonary arteriovenous malformations]
Andersen PE, Kjeldsen AD, Oxhoj H, Vase P.
Ugeskr Laeger. 2001 Feb 12;163(7):925-8. Danish. 

Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.
Kjeldsen AD, Brusgaard K, Poulsen L, Kruse T, Rasmussen K, Green A, Vase P.  
Am J Med Genet. 2001 Feb 1;98(4):298-302.

[Picture of the month]
Kjeldsen AD, Andersen PE, Oxhoj H. 
Ugeskr Laeger. 2000 Jun 19;162(25):3618. Danish.

[Hereditary hemorrhagic telangiectasia. A population-based study on prevalence and mortality among Danish HHT patients]
Kjeldsen AD, Vase P, Green A 
Ugeskr Laeger. 2000 Jun 19;162(25):3597-601. Danish

Concerning the original article of C. Weik and L. Greiner, 'The liver in hereditary hemorrhagic telangiectasia (Weber-Rendu-Osler disease)'.
Kjeldsen AD, Kjeldsen J
Scand J Gastroenterol. 2000 Jul;35(7):784.

Prevalence of pulmonary arteriovenous malformations (PAVMs) and occurrence of neurological symptoms in patients with hereditary haemorrhagic telangiectasia (HHT).
Kjeldsen AD, Oxhoj H, Andersen PE, Green A, Vase P.
J Intern Med. 2000 Sep;248(3):255-62.

Screening for pulmonary arteriovenous malformations: contrast echocardiography versus pulse oximetry. 
Oxhoj H, Kjeldsen AD, Nielsen G.
Scand Cardiovasc J. 2000 Jun;34(3):281-5

Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). 
Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H. 
Am J Med Genet. 2000 Mar 6;91(1):66-7.

Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. 
Kjeldsen AD, Kjeldsen J.
Am J Gastroenterol. 2000 Feb;95(2):415-8. 

Pulmonary arteriovenous malformations: screening procedures and pulmonary angiography in patients with hereditary hemorrhagic telangiectasia. 
Kjeldsen AD, Oxhoj H, Andersen PE, Elle B, Jacobsen JP, Vase P.
Chest. 1999 Aug;116(2):432-9.

Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients.
Kjeldsen AD, Vase P, Green A 
J Intern Med. 1999 Jan;245(1):31-9.

Embolotherapy for pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). 
Andersen PE, Kjeldsen AD, Oxhoj H, Vase P, White RI
Jr.
 Acta Radiol. 1998 Nov;39(6):723-6.

[Percutaneous transluminal embolization of pulmonary arteriovenous malformations]
Kjeldsen AD, Andersen PE, Oxhoj H, Vase P.
Ugeskr Laeger. 1998 Mar 2;160(10):1465-9. Danish.

Hereditary hemorrhagic telangiectasia.
Kjeldsen AD, Vase P, Oxhoj H.
N Engl J Med. 1996 Feb 1;334(5):331-2.

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