The HHT Working Group, is built upon Multidisciplinary Centres of Excellence that have been collaborating since our first international meeting in 1996

The HHT-WG is chaired by Pr. Claire SHOVLIN, HHTIC London, Hammersmith Hospital, and Imperial College London, UK. The WG is co-chaired by Dr. Sophie DUPUIS-GIROD, HHT Center of Reference, Lyon, France in cooperation with Deputy Co-chair Pr. Elisabetta BUSCARINI, HHT Center, Maggiore Hospital, Crema, Italy.

These chairs, and the majority of the Working Group as well as Centers cooperating with the HHT-WG (A. KJELDSEN, H.J. MAGER, C. SABBA, L. BOTELLA, and U. GEISTHOFF) have been longstanding members of the Global Research and Medical Advisory Board (GRMAB) of the HHT Foundation International (now Cure HHT) with Hans-Jurgen MAGER the current GRMAB Vice Chair and we continue our warm collaborations with non-European HHT Colleagues.

VASCERN HHT-WG cooperates with the Patient Group (ePAG), whose representative participating to the WG is Claudia CROCIONE, HHT Europe.

VASCERN HHT Year 1 Output
  • Patient pathway defined and revised
  • Priorities defined by 61 patients/professionals
  • Drug Registry designed and first data published
  • 5 Outcome Measures defined and applied
  • 11 cross-border clinical cases discussed
  • 1 Guideline (Clinical Statement) produced*
  • 13 Do’s and Don’ts for General Care produced
  • 8 research projects with >1 vascern hht centre
  • 2 YouTube Videos (published online 2018)
  • 2 Educational workshops (published 2017)

in addition to VASCERN members’ existing activities, e.g.

  • 3 HHT clinical trials completed/in progress (Dupuis Girod)
  • 17 PubMed-publications; >40 research projects

Milestones

1994    1st HHT Gene identified McAllister et al, 1994
1996    1st International Conference (occur biannually)
2000    HHT Diagnostic Criteria Shovlin et al, 2000
2006    Liver Consensus Statement Buscarini et al 2006
2008    Pregnancy Recommendations Shovlin et al 2008
2011    International Guidelines Faughnan et al 2011
2012    Bevacizumab trial Dupuis-Girod et al 2012
2015    11th International Conference
2016    EASL Liver Guidelines EASL 2016
2017     Launch of VASCERN HHT
2018     Year 1 Outputs completed

While so much has been achieved, the next stages require formal acknowledgement, status and funding to ensure that European HHT patients are not left out of the current transformational changes through personalised medicine and therapeutics

Our Network Goals are to

  • continue to assist patients in their choices, by evaluating the natural history of HHT compared to the benefits and complications of diagnostic tests and treatments;
  • obtain funding for the Clinical Trials that we see as essential to provide further improvements in clinical care;
  • educate our international colleagues in the management of this challenging but highly rewarding disorder;
  • consolidate the position of HHT at the high-table of Rare Diseases, as befits its prevalence (circa 1 in 5,000, yet subject to substantial under ascertainment)

The HHT-WG is a distinct entity because in the more than 20 years that the Partners have been working together, there has been little professional need to overlap with our colleagues and friends in the Rare Vascular Anomalies Working Group (VASCA-WG).

Hereditary haemorrhagic telangiectasia (HHT) is a single, relatively common “Rare” Vascular Disease with distinct screening and management recommendations.  Abnormal vascular structures occur non randomly, and are responsible for complications: currently used treatments are symptomatic and not pathophysiological. Unlike the other ERN components, the clinical phenotype is dominated by the consequences of chronic bleeding from the abnormal vascular structures; paradoxical emboli through pulmonary arteriovenous malformations AVMs; and the wider circulatory consequences due to systemic AVMs, in turn exacerbated by anaemia and low oxygen levels.

Thus, HHT may require management from almost all specialist groupings. Small (telangiectasia) lead to nosebleeds (epistaxis), gastrointestinal bleeding and iron deficiency anaemia. Large arteriovenous malformations (AVMs) in pulmonary, hepatic, and cerebral circulations may hemorrhage; pulmonary AVMs cause preventable ischemic strokes, cerebral abscesses, and hypoxaemia; and systemic AVMs demand higher cardiac outputs aggravated by iron deficiency and/or hypoxaemia. 1 in 100 women die in pregnancy, and the SMAD4 subgroup (~2%) are also at risk of aortic rupture, juvenile polyposis and GI cancers. Paradoxically, where managed appropriately, life expectancy can be very good indeed, with likely explanations including apparent protection from certain cancers, and myocardial infarctions.

The clinical diagnosis of HHT is based on the Curaçao criteria  Shovlin et al, 2000. Molecular diagnosis is available for the ALK1, ENG, and SMAD4 genes and mutations are found in over 90% of patients with a definite clinical diagnosis.

The PubMed List*  of 296 HHT publications from the Working Group Members is provided.

Bases for the estimated incidence and prevalence numbers: 500 Million inhabitants within European union with about 6 million newborns annually.

sub-thematic areas of expertise Rare or complex disease(s) or condition(s) or highly specialized interventions Code/ICD/ Orphacode / Group of Codes Incidence (Number of cases / year)

(in the EU)

Prevalence

 (in the EU)

HHT Pulmonary arteriovenous malformations Pulmonary AVMs ICD10: IX, I28.0 2346 195,460

(1 in 2,600)

HHT Recurrent, severe epistaxis in HHT ICD10:XVIII: R04.0 300 25 000
HHT Iron deficiency anaemia and  HHT ICD10:IV: D50.0 660 55 000
HHT Juvenile polyposis and HHT (SMAD4) IICD10: II: D12.6 29 2 400
HHT SMAD4

Aortopathy

ICD10: IX: I71 4 300
HHT HHT hepatic arterio-venous malformations IX; Q27.3 324 27 000

 

All HCP in the HHT-WG are covering this sub-thematic area of expertise.

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UNITED KINGDOM

Chair

Pr. Claire SHOVLIN
VASCERN HHT London
Hammersmith Hospital, Imperial College Healthcare NHS Trust
London, UK

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FRANCE

Co-chair

Dr. Sophie DUPUIS-GIROD
CRMR Rendu-Osler Disease – HHT Center of Reference
CHU de Lyon HCL, GH Est-Hôpital Femme Mère Enfant
Lyon, France

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ITALY

Deputy co-chair

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DENMARK

allemagne

GERMANY

Pr. Ulrich SURE

 

 

 

Dr. Freya DROEGE

 

HHT Center, Essen Center for Rare Diseases 
Essen University Hospital
Essen, Germany

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ITALY

Patient co-chair (ePAG)

Claudia CROCIONE
HHT Europe
Associazione Italiana Teleangectasia Emorragica – HHT ONLUS

Dr. Fabio PAGELLA
Dr. Sara UGOLINI
HHT Center, Department of Otorhinolaryngology
Fondazione IRCCS Policlinico San Matteo, University of Pavia
Pavia, Italy

Pr. Carlo SABBÀ
Center for Hereditary Haemorrhagic Telangiectasia
Azienda Ospedaliero-Universitaria Consorziale di Bari Policlinico-Giovanni XXIII
Bari, Italy

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NETHERLANDS

Dr. Hans-Jurgen MAGER
Department of Pulmonology
Dutch HHT expertise center
St. Antonius Hospital
Nieuwegein, The Netherlands

EN

Our HHT-WG Goals are to

  • continue to assist patients in their choices, by evaluating the natural history of HHT compared to the benefits and complications of diagnostic tests and treatments;
  • obtain funding for the Clinical Trials that we see as essential to provide further improvements in clinical care;
  • educate our international colleagues in the management of this challenging but highly rewarding disorder;
  • consolidate the position of HHT at the high-table of Rare Diseases, as befits its prevalence (circa 1 in 5,000, yet subject to substantial under ascertainment)

VASCERN HHT PRIORITY EVALUATIONS 2016-2017

  • To establish VASCERN HHT Priorities, between 11/2016 and 01/2017, members were surveyed and in free text, asked what they considered to be the 3 most important problems for HHT.

  • The top 7 priorities across all 61 respondents, in order were

1.Anaemia
2.Arteriovenous malformations
3.Bleeding
4.Childhood/young people
5.The hereditary nature of the disease
6.Lack of effective medications
7.Problems finding informed care. 

  • The findings were presented at the 12th International Scientific Conference, June 8-11, 2017 (Dubrovnik, Croatia), and published in Angiogenesis 2017

The goal of HHT-WG is to provide guidance to enable wise choices of investigations to maximise patient health, safety, and psychological balance, mindful of off-target consequences such as radiation exposure and unintended life-style impacts.

Guidance will be wise, distinguishing baseline, essential screening studies for all patients, from investigations that would be superfluous except in specific settings of clinical need, or research protocols.

Our core values were approved as
“PATIENT FIRST, SAFETY FIRST”.

Our first VASCERN HHT Risk Mitigation index was approved as
“COMBINING EVIDENCE AND EXPERIENCE TO WORK TOGETHER”

Our first VASCERN “Never Event” was approved as
“NO HHT PATIENT SHOULD UNDERGO A TEST/PROCEDURE THAT IS NOT USEFUL FOR THEIR MANAGEMENT, EXCEPT WITHIN AN IRB-APPROVED RESEARCH PROTOCOL”

Our 5 Outcome Measures developed and implemented in order to maximise the number of patients receiving good care are:

1.At least 90% of definite HHT patients will have a screen for pulmonary arteriovenous malformations (PAVMs).
2.At least 90% of definite HHT patients will have received nosebleed advice in writing.  
3.At least 70% of definite HHT patients will have an assessment of iron deficiency at each consultation. 
4.100% of patients with PAVMs will have written advice on antibiotics prior to dental and surgical procedures
5.100% of patients with pregnant women with PAVMs identified by CT scan/imaging will be provided with written advice on HHT pregnancies

These are discussed and explained further within our first manuscript, currently in review

VASCERN HHT Drug Registry

  • A recommendation of the auditing authority to European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), was to foster information on safety standards for rare disease patients.
  • In Drug Registry- Part 1. the HHT working group prioritized the antiangiogenic drugs Thalidomide and Bevacizumab (Avastin), that have been increasingly used in the latest decade in HHT patients.
  • Separate questions were provided for patients, scientists and doctors
  • >100 patient responses in review
  • The findings were presented at the 12th International Scientific Conference, June 8-11, 2017 (Dubrovnik, Croatia), and published in Angiogenesis 2017

We are currently adding to the Guidance already generated by WG Members (see list), and have implemented the first stage of our 3 part plan to realise in an efficient and timely manner.

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 ( >1230 citations)

  • HHT WG  Approved Comment July 2017
    “These clinical criteria are very important for daily practice in assessing suspected HHT”
International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

Faughnan ME, Palda VA, Garcia-Tsao G, Geisthoff UW, McDonald J, Proctor DD, Spears J, Brown DH, Buscarini E, Chesnutt MS, Cottin V, Ganguly A, Gossage JR, Guttmacher AE, Hyland RH, Kennedy SJ, Korzenik J, Mager JJ, Ozanne AP, Piccirillo JF, Picus D, Plauchu H, Porteous ME, Pyeritz RE, Ross DA, Sabba C, Swanson K,Terry P, Wallace MC, Westermann CJ, White RI, Young LH, Zarrabeitia R; J Med Genet. 2011(>500 citations)

  • HHT WG  Approved Comment July 2017
    “This is the most recent comprehensive, international guideline on HHT. But it is 11 years old and outdated in several aspects by new evidence”
European Association for Liver Studies – Clinical Practice guidelines: Vascular diseases of the liver.

Garcia-Pagan, Buscarini E  Janssen, Leebeek F, Plessier, Rubbia Brandt, Senzolo, Shouten, Tripodi. J Hepatol 2016. (>50 citations)

British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations.

Shovlin CL, Condliffe R, Donaldson JW, Kiely DG, Wort SJ; British Thoracic Society. Thorax. 2017 (cited).

For pre-VASCERN activities, please see the Working group’s 296 HHT-related publications to 04/16 at PubMed List

VASCERN HHT Year 1 Research Outputs

  • 8 research projects with >1 vascern HHT centre
  • 3 single centre HHT clinical trials completed/in progress
  • >40 single centre research projects
  • 19 PubMed-publications

(1) YouTube Minipills of Knowledge (5 minute videos)
An Overview of Hereditary Haemorrhagic Telangiectasia
(SHOVLIN) https://youtu.be/z2gALD8xSNE
An introduction to HHT explaining aetiology and main features.
What an ENT doctor needs to know about HHT and why
(KJELDSEN) https://youtu.be/k2V92g87NhE

2) 12th HHT International Conference Workshops Dubrovnik, June 2017
Workshop on Management of Hepatic AVMs
(DUPUIS-GIROD & BUSCARINI)
Workshop on Inflammation, Immunity and Injury in HHT
(SHOVLIN & BOTELLA)

(3) Do’s and Don’ts spanning common situations for HHT patients:

(PDF available: here)

  1. Physical Activity
  2. Breast feeding
  3. Contraindicated medications
  4. Antiplatelets/ anticoagulants
  5. Venous thromboemboli (VTE)
  6. Haemorrhagic stroke
  7. Brain abscesses:
  8. Heart failure
  9. Kidney failure
  10. Multiple traumatic injuries
  11. Bronchoscopies
  12. Aortic dissection
  13. Pneumothorax

(4) Recent narrative reviews in English, French, Danish and German:

ENGLISH:

The Lung in Hereditary Hemorrhagic Telangiectasia. Dupuis-Girod S, Cottin V, Shovlin CL. Respiration. 2017;94(4):315-330

Pulmonary arteriovenous malformations: evidence of physician under-education. Shovlin CL, Gossage JR. ERJ Open Res. 2017 Apr 12;3(2). pii: 00104-2016

Circulatory contributors to the phenotype in hereditary hemorrhagic telangiectasia. Shovlin CL.  Front Genet. 2015 Apr 9;6:101. doi: 10.3389/fgene.2015.00101

Clinical implications of pulmonary shunting on saline contrast echocardiography. Velthuis S, Buscarini E, Gossage JR, Snijder RJ, Mager JJ, Post MC. JAm Soc Echocardiogr. 2015 Mar;28(3):255-63

Pulmonary arteriovenous malformations. Shovlin CL. Am J Respir Crit Care Med. 2014 Dec 1;190(11):1217-28

Hereditary hemorrhagic telangiectasia: from molecular biology to patient care. Dupuis-Girod S, Bailly S, Plauchu H.  J Thromb Haemost. 2010 Jul;8(7):1447-56.

Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Shovlin CL.  Blood Rev. 2010 Nov;24(6):203-19.

Pulmonary arteriovenous malformations emerge from the shadows. Shovlin CL, Condliffe R, Donaldson JW, Kiely DG, Wort SJ. Thorax. 2017 Dec;72(12):1071-1073. doi: 10.1136/thoraxjnl-2017-211072.

FRENCH: 

Rendu-Osler disease: clinical and molecular update. Bailly S, Dupuis-Girod S, Plauchu H. Med Sci (Paris). 2010 Oct;26(10):855-60

DANISH:

Diagnosis and treatment of morbus Osler. Kjeldsen AD, Andersen PE, Tørring PM.  Ugeskr Laeger. 2011 Feb 14;173(7):490-5.

GERMAN: 

Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) as an example of a rare disease relevant for oto-rhino-laryngology. Geisthoff UW, Maune S, Schneider G.. Laryngorhinootologie. 2011 Apr;90(4):230-42; quiz 243-4. doi: 10.1055/s-0031-1271809.

Pills of Knowledge (PoK) are the deliverable for VASCERN Work Package 4 on Pills of Knowledge, defined as short single video lessons (of approximately 3-5 minutes long) in which an expert talks about a specific topic that has been selected and validated by the Rare Disease Working Groups (RDWGs).

HHT-WG Pills of Knowledge videos playlist here

The first video entitled, “An Overview of Hereditary Haemorrhagic Telangiectasia” features an informative presentation by Prof Claire Shovlin (Chair of the HHT WG from Hammersmith Hospital – Imperial College Healthcare NHS Trust, UK). This PoK is accessible to everyone and gives viewers an introduction to HHT by explaining its main clinical features (and their frequency) in addition to the genetics and aetiology of this rare disease.

View this video here

The second video, “Hereditary Haemorrhagic Telangiectasia (HHT) is more than a bleeding Nose. What an ENT doctor needs to know about HHT and why”, is made by Prof Anette Kjeldsen (HHT-WG Member, from theHHT Centre at Odense University Hospital, Denmark) and is intended for Ear, Nose & Throat (ENT) Doctors in order to help them properly recognize the signs and symptoms of HHT. As ENT doctors are often the first healthcare professionals that HHT patients consult, it is essential for them to be able to identify a potential HHT patient and refer these patients to an HHT expert Centre for screening and treatment in order to decrease patient morbidity.

View this video here

The PubMed List of 296 HHT publications from the Working Group Members is provided, and emphasizes the importance of continued clinician education:

Using HHT-restricted search terms, between 1994-2016, the Working Group wrote or contributed 296 articles- 276 excluding individual case reports and only 20 Case Reports on particularly informative or unusual cases (a ratio of >13:1).  In contrast, the remaining literature comprised 902 articles excluding individual case reports, and 795 Case Reports, a ratio of 1.1:1.

VASCERN HHT Year 1 Publications

Feb-18 Executive summary of the 12th HHT international scientific conference.Andrejecsk JW, Hosman AE, Botella LM, Shovlin CL, Arthur HM, Dupuis-Girod S, Buscarini E, Hughes CCW, Lebrin F, Mummery CL, Post MC, Mager JJ. Angiogenesis.2017 Nov 16.doi: 10.1007/s10456-017-9585-2. [Epub ahead of print] PMID: 29147802
Dec-17 British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations.Shovlin CL, Condliffe R, Donaldson JW, Kiely DG, Wort SJ; British Thoracic Society.Thorax. 2017 Dec;72(12):1154-1163. doi: 10.1136/thoraxjnl-2017-210764. PMID: 29141890
Dec-17 Pulmonary arteriovenous malformations emerge from the shadows.Shovlin CL, Condliffe R, Donaldson JW, Kiely DG, Wort SJ. Thorax. 2017 Dec;72(12):1071-1073. doi: 10.1136/thoraxjnl-2017-211072. No abstract available. PMID: 29141889
Nov-17 Emerging role of bevacizumab in management of patients with symptomatic hepatic involvement in Hereditary Hemorrhagic Telangiectasia.Chavan A, Schumann-Binarsch S, Schmuck B, Oltmer F, Geisthoff U, Hoppe F, Wirsching K, Klempnauer J, Manns M, Philip Thomas R, Köhne CH. Am J Hematol. 2017 Nov;92(11):E641-E644. doi: 10.1002/ajh.24878. Epub 2017 Aug 24. No abstract available. PMID: 28776732
Oct-17 Long-term outcomes of patients with pulmonary arteriovenous malformations considered for lung transplantation, compared with similarly hypoxaemic cohorts.Shovlin CL, Buscarini E, Hughes JMB, Allison DJ, Jackson JE. BMJ Open Respir Res. 2017 Oct 13;4(1):e000198. doi: 10.1136/bmjresp-2017-000198. eCollection 2017.PMID: 29071074
Oct-17 Pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia: Correlations between computed tomography findings and cerebral complications. Etievant J, Si-Mohamed S, Vinurel N, Dupuis-Girod S, Decullier E, Gamondes D, Khouatra C, CottinV, Revel D. EurRadiol. 2017 Oct 10.doi: 10.1007/s00330-017-5047-x. [Epub ahead of print]PMID: 29018941
Oct-17 Pulmonary hypertension subtypes associated with hereditary haemorrhagic telangiectasia: Haemodynamic profiles and survival probability.Revuz S, Decullier E, Ginon I, Lamblin N, Hatron PY, Kaminsky P, Carette MF, Lacombe P, Simon AC, Rivière S, Harlé JR, Fraisse A, Lavigne C, Leguy-Seguin V, Chaouat A, Khouatra C, Dupuis-Girod S, Hachulla E. PLoS One. 2017 Oct 5;12(10):e0184227. doi: 10.1371/journal.pone.0184227. eCollection 2017.PMID: 28981519
Oct-17 SMAD4 gene mutation increases the risk of aortic dilation in patients with hereditary haemorrhagic telangiectasia.Vorselaars VMM, Diederik A, Prabhudesai V, Velthuis S, Vos JA, Snijder RJ, Westermann CJJ, Mulder BJ, Ploos van Amstel JK, Mager JJ, Faughnan ME, Post MC. Int J Cardiol. 2017 Oct 15;245:114-118. doi: 10.1016/j.ijcard.2017.06.059.PMID:28874282
Sep-17 Screening children for pulmonary arteriovenous malformations: Evaluation of 18 years of experience. Hosman AE, de Gussem EM, Balemans WAF, Gauthier A, Westermann CJJ, Snijder RJ, Post MC, Mager JJ.Pediatr Pulmonol. 2017 Sep;52(9):1206-1211. doi: 10.1002/ppul.23704. Epub 2017 Apr 13.  PMID:28407366
Aug-17 The Lung in Hereditary Hemorrhagic Telangiectasia.Dupuis-Girod S, Cottin V, Shovlin CL. Respiration. 2017;94(4):315-330. doi: 10.1159/000479632. Epub 2017 Aug 30. PMID: 28850955
Aug-17 Cerebral Abscess Associated With Odontogenic  Bacteremias, Hypoxemia, and Iron Loading in Immunocompetent Patients With Right-to-Left Shunting Through Pulmonary Arteriovenous Malformations.Boother EJ, Brownlow S, Tighe HC, Bamford KB, Jackson JE, Shovlin CL. Clin Infect Dis. 2017 Aug 15;65(4):595-603. doi: 10.1093/cid/cix373. PMID: 28430880
Jun-17 Response to Bevacizumab for the treatment of Rendu-Osler disease-A note of caution.Dupuis-Girod S, Buscarini E.Liver Int. 2017 Jun;37(6):928. doi: 10.1111/liv.13385. No abstract available. PMID: 28544692
Jun-17 Hemoglobin Is a Vital Determinant of Arterial Oxygen Content in Hypoxemic Patients with Pulmonary Arteriovenous Malformations.Rizvi A, Macedo P, Babawale L, Tighe HC, Hughes JMB, Jackson JE, Shovlin CL. Ann Am Thorac Soc. 2017 Jun;14(6):903-911. doi: 10.1513/AnnalsATS.201611-872OC. PMID: 28267932
Jun-17 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 ClinMicrobiol Infect Dis. 2017 Oct;36(10):1975-1980. doi: 10.1007/s10096-017-3023-7. Epub 2017 Jun 3. PMID: 28578477
May-17 Hepatic angiodynamic profile in paediatric patients with hereditary haemorrhagic telangiectasia type 1 and type 2.Giordano P, Francavilla M, Buonamico P, Suppressa P, Lastella P, Sangerardi M, MinielloVL, Scardapane A, Lenato GM, Sabbà C. Vasa. 2017 May;46(3):195-202. doi: 10.1024/0301-1526/a000616. Epub 2017 Mar 1. PMID: 28248153
Apr-17 Pulmonary arteriovenous malformations: evidence of physician under-education.Shovlin CL, Gossage JR.ERJ Open Res. 2017 Apr 12;3(2). pii: 00104-2016. doi: 10.1183/23120541.00104-2016. eCollection 2017 Apr. PMID: 28421188
Apr-17 Familial cerebral abscesses caused by hereditary hemorrhagic telangiectasia.Tørring PM, Lauridsen MF, I Dali C, Andersen PE, Ousager LB, Brusgaard K, Kjeldsen A.Clin Case Rep. 2017 Apr 13;5(6):805-808. doi: 10.1002/ccr3.785. eCollection 2017 Jun. PMID: 28588815
Mar-17 7-day weighed food diaries suggest patients with hereditary hemorrhagic telangiectasia may spontaneously modify their diet to avoid nosebleed precipitants.Finnamore H, Silva BM, Hickson BM, Whelan K, Shovlin CL. Orphanet J Rare Dis. 2017 Mar 28;12(1):60. doi: 10.1186/s13023-017-0576-6. PMID: 28347346

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