Original article

International guidelines for the diagnosis
and management of hereditary
haemorrhagic telangiectasia
M E Faughnan,1,2 V A Palda,3 G Garcia-Tsao,4 U W Geisthoff,5,6 J McDonald,7
D D Proctor,8 J Spears,9 D H Brown,10 E Buscarini,11 M S Chesnutt,12 V Cottin,13
A Ganguly,14 J R Gossage,15 A E Guttmacher,16 R H Hyland,1 S J Kennedy,17
J Korzenik,18 J J Mager,19 A P Ozanne,20 J F Piccirillo,21 D Picus,22 H Plauchu,23
M E M Porteous,24 R E Pyeritz,25 D A Ross,26 C Sabba,27 K Swanson,28 P Terry,29
M C Wallace,30 C J J Westermann,19 R I White,31 L H Young,32 R Zarrabeitia33< Additional tables are

published online only. To view
these files please visit thejournal online (http://jmg.bmj.
com).
For numbered affiliations see
end of article.
Correspondence to
M E Faughnan, St. Michael’s
Hospital, University of Toronto,
St. Michael’s Hospital, 30 Bond
St, Toronto, M5B-1W8, Canada;faughnanm@smh.ca
The HHT Guidelines Working
Group intends to generate
updated clinical guidelines
within approximately 5 years.
Centres with recognised
expertise in the diagnosis andmanagement of HHT can belocated at http://www.hht.org/,
the website for the HHT
Foundation International.
Received 2 May 2009
Revised 22 May 2009
Accepted 30 May 2009
Published Online First
23 June 2009

ABSTRACT
Background HHT is an autosomal dominant disease withan estimated prevalence of at least 1/5000 which canfrequently be complicated by the presence of clinicallysignificant arteriovenous malformations in the brain, lung,gastrointestinal tract and liver. HHT is under-diagnosed
and families may be unaware of the available screening
and treatment, leading to unnecessary stroke andlife-threatening hemorrhage in children and adults.
Objective The goal of this international HHT guidelines
process was to develop evidence-informed consensus
guidelines regarding the diagnosis of HHT and theprevention of HHT-related complications and treatmentof symptomatic disease.
Methods The overall guidelines process was developed
using the AGREE framework, using a systematic searchstrategy and literature retrieval with incorporation ofexpert evidence in a structured consensus process
where published literature was lacking. The Guidelines
Working Group included experts (clinical and genetic)from eleven countries, in all aspects of HHT, guidelines
methodologists, health care workers, health careadministrators, HHT clinic staff, medical trainees, patientadvocacy representatives and patients with HHT. The
Working Group determined clinically relevant questions
during the pre-conference process. The literature search
was conducted using the OVID MEDLINE database, from1966 to October 2006. The Working Group subsequently
convened at the Guidelines Conference to partake ina structured consensus process using the evidence
tables generated from the systematic searches.
Results The outcome of the conference was thegeneration of 33 recommendations for the diagnosis andmanagement of HHT, with at least 80% agreement
amongst the expert panel for 30 of the 33
recommendations.

(AVMs) in the brain, lung, gastrointestinal (GI)tract and liver.
Unfortunately, HHT is often not diagnosed, andentire families therefore remain unaware of available screening and treatment, and children andadults unnecessarily develop stroke or life-threatening haemorrhage. The goal of the international
HHT guidelines process was to develop evidencebased consensus guidelines for the diagnosis of
HHT, the prevention of HHT-related complications,and treatment of symptomatic disease.

METHODS
The overall guidelines process (ﬁgure 1) was developed using the AGREE framework3 with guidelines
methodologists. The structure was that ofa systematic evidence-based process with incorporation of expert evidence in a structured consensus
process where evidence was lacking. We expected
only weak or poor evidence in most areas, but chose
this approach to maximise quality and applicabilityof the guidelines and provide a foundation for
future research and guidelines in HHT.

Determination of need for guidelines
The need for clinical guidelines for HHT was identiﬁed by the HHT Foundation International, aninternational advocacy group for people with
HHT, and the Foundation’s Scientiﬁc and Medical
Advisory Board. This was based on their consistentobservations of care gaps in HHT, speciﬁcallythat HHT is underdiagnosed, that there are often
delays in diagnosis, and that most patients andfamilies with HHT are not receiving appropriate
preventive treatment. No clinical guidelines were inplace for the multisystem manifestations of thedisorder, except for guidelines for liver vascularmalformations (VMs).4

INTRODUCTION
Hereditary haemorrhagic telangiectasia (HHT) isan autosomal dominant disease with an estimatedprevalence of 1/50001 and is thought to be present
in all races and parts of the world. Althoughepistaxis is the most common symptom of HHT
and mucocutaneous telangiectasia the mostcommon sign,2 HHT is also often complicatedby the presence of arteriovenous malformations
J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

Membership of the HHT guidelines working group
An organising committee of clinicians, scientists,
methodologists, patients and Foundation members
selected the members of the HHT Guidelines
Working Group. This included experts (clinical andgenetic) from 11 countries, in all aspects of HHT,
guidelines methodologists, healthcare workers andadministrators, HHT Foundation representatives,73Original article
articles and reviews were also performed for each clinically
relevant question. Bibliographies of retrieved publications werereviewed to identify sources not obtained in our search. Publications in abstract form were included to minimise publication
bias. One author (MEF) and the literature review assistant(J Silver) independently reviewed abstracts, and any relevant
studies were pulled for review. Inclusion and exclusion criteria
for study selection are listed in table AI (see online). Resultsfrom selected studies were extracted into evidence tables, and,along with original papers, were sent to participants for review
and to determine if any relevant literature was missing.

Determination of clinical recommendations
Participants convened at the Guidelines Conference to take partin a structured consensus process using the evidence tables. With
the assistance of professional guidelines facilitators, topic
subgroups prioritised clinically relevant questions and thengenerated recommendations for these. All participants assembled afterwards to vote for all generated recommendations.
Those recommendations achieving less than 80% agreement
were further discussed, revised again with a facilitator, and voted
on again. Wording of recommendations was considered ﬁnal, andthey are presented with the percentage agreement obtained on
the ﬁnal vote. Priorities for future research were also identiﬁed
during the process (see online table AII).

Grading of evidence
Each recommendation was graded to indicate the level ofevidence available using the classiﬁcation system of the CanadianTask Force on the Periodic Health Examination5 (table 1). In
addition, values around recommendations were generated using
the GRADE instrument,6 7 and these were reported as ‘strengthof the recommendation’. The ‘strength of the recommendation’incorporated evidentiary and non-evidentiary factors, including
baseline risks of outcomes, beneﬁts of treatment, potential
harms of treatment, certainty of point estimates, and levels ofevidence. Values were also incorporated, such as the importanceof certain outcomes to stakeholders and other factors such asavailability of certain tests.

General organisation

Figure 1 The adopted process of guideline development. HHT,
hereditary haemorrhagic telangiectasia.
and patients with HHT. Each member was also a member ofa topic subgroup (diagnosis, epistaxis, cerebral vascular malformations (CVMs), pulmonary AVMs (PAVMs), GI bleeding andliver VMs). Patients contributed to the development of theclinically relevant questions and the recommendations, withparticular input regarding values around recommendations.

Determination of clinically relevant questions
During the pre-conference process, the topic subgroups worked
by email to develop clinically relevant questions. The subgroups
circulated and edited these through several iterations. These
formed the basis for the literature review.

Background preparation
A literature search was conducted using the OVID Medline
database from 1966 to October 2006 to identify relevant
English-language publications, using the search strategies as
outlined in table AI (see online). Hand searches of relevant
74

The pre-conference process occurred by email over 6 months
leading up to the 2-day Guidelines Conference near Toronto,
Canada, in November 2006. The Conference was held ina facility with anonymous key pad voting technology. The large
group sessions were recorded (audio) and minuted.

Preparation of report
Topic leaders generated each area of this article, which was thenrevised by MEF, VP and the topic members for each group, andthen reviewed by the other authors. The literature search

Table 1Categorisation of the quality of evidence

Quality ofevidence

Description

I
II-1
II-2
II-3
III

Evidence obtained from at least one properly randomised, controlled trial
Evidence obtained from well-designed controlled trials without
randomisation
Evidence obtained from well-designed cohort or caseecontrol analyticalstudies, preferably from more than one centre or research group
Evidence obtained from comparison between times and places with orwithout the intervention, or dramatic results in uncontrolled experiments
Opinions of respected authorities, based on clinical experience,descriptive studies, or reports of expert committees

J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

Original article
Table 2 Curaçao Criteria for clinical diagnosis of hereditary
haemorrhagic telangiectasia (HHT)
Criteria

Description

Epistaxis
Telangiectases
Visceral lesions

Spontaneous and recurrent
Multiple, at characteristic sites: lips, oral cavity, fingers, nose
Gastrointestinal telangiectasia, pulmonary, hepatic, cerebral or
spinal arteriovenous malformations
A first-degree relative with HHT according to these criteria

Family historyreferenced was that obtained in October 2006. At the time ofﬁnal manuscript review, two steps were taken to ensure that no
generated recommendation needed immediate revision. Firstly,
a literature search for any interim randomised controlled trials in
HHT was performed, which revealed none. Secondly, theWorking Group was polled for knowledge of any recent publications that would lead to a signiﬁcant change in any of therecommendations, and none were identiﬁed.

Role of funding sources
Although the funding organisations were not directly involvedin the generation of the recommendations, some of the participants in the guidelines process were also board members of the
HHT Foundation International and its Scientiﬁc and Medical
Advisory Board. The other funding sources had no role in thedesign, conduct and reporting of the study or in the decision tosubmit the results for publication.

DIAGNOSIS OF HHT
Background
Making the diagnosis of HHT in a patient allows the appropriate
screening and preventive treatment to be undertaken in thepatient and their affected family members. HHT has traditionallybeen diagnosed on the basis of its clinical features, but can now
also be diagnosed using genetic testing. We reviewed the evidence
and expert experience for clinical and genetic diagnosis in HHT.
The clinical diagnostic features of HHT have been identiﬁed
by describing the clinical presentation of patients who have
known or suspected HHT and their close relatives. The averageage of onset for epistaxis is 12 years, with nearly 100% affectedby age 40 years.2 8e10 Most patients report the appearance of
telangiectasia of the mouth, face or hands 5e30 years after the
onset of nose bleeds, most commonly during the third decade.
Unfortunately, there are no longitudinal natural history studies
of HHT clinical manifestations and how these might vary withgenotype.
In 2000, consensus clinical diagnostic criteria known as the
Curaçao Criteria were published11 (table 2). Using these criteria,
a diagnosis of HHT is considered ‘deﬁnite’ if three or morecriteria are present, ‘possible or suspected’ if two criteria arepresent, and ‘unlikely’ if 0 or 1 criterion is present.

There have been no studies reporting sensitivity and speciﬁcity of the Curaçao Criteria, but the expert panel agreed that
the Curaçao Criteria are particularly helpful in two situations:(1) discriminating affected from non-affected older adults and(2) ruling-in the diagnosis in younger adults and children. The
expert panel was speciﬁcally concerned about the risk of missing
diagnoses in children and young adults, who might have no
epistaxis or visible telangiectases, yet have undiagnosed PAVMs
or CVMs.12 It is in these groups that genetic testing should be
most useful.
The goal of genetic testing for HHT is to clarify the speciﬁc
HHT mutation in an HHT family, allowing diagnosis among
those relatives (often children and young adults) who do notmeet clinical diagnostic criteria. Genetic testing is performed
ﬁrst on the index case in the family and involves DNA
sequencing and deletion/duplication analysis of the codingexons of the endoglin gene (ENG, HHT1) and the activin A
receptor type II-like 1 gene (ACVRL1, HHT2). Mutations inthese genes account for the majority of cases of HHT. At least
two other HHT loci have been described, although speciﬁc
genes at these loci are not yet identiﬁed.13 14 Mutations in the
SMAD4 gene can cause a rare syndrome which combines
juvenile polyposis and HHT.15 Genetic testing in HHT iscomplex relative to many other genetic conditions because
a mutation in one of multiple genes can cause the condition,
not all genes that can cause HHT have been discovered, andthere are no ‘common mutations’, with most families having
their own ‘private’ HHT mutation.
Several authors have reported16 17 a clinical sensitivity/
mutation detection rate of w75% for sequence analysis of ENG
and ACVRL1. Use of an additional method to detect large deletion/duplication mutations increases the detection rate by
w10%.16 17 Recent reports suggest that about 1e3% of patientsclinically diagnosed with HHT will have a mutation detected in
the SMAD4 gene, or about 10% of those who test negative for
ENG and ACVRL1 mutations.17e19
There is considerable clinical overlap between patients/families with ENG mutation and those with ACVRL1 mutation,with VMs reported in similar organs in both types.20e22 The
expert panel agreed that ENG versus ACVRL1 genotype should
not signiﬁcantly inﬂuence screening recommendations for VMs.
Most HHT patients/families with SMAD4 mutation reported todate have juvenile polyposis and are therefore at risk of GI
malignancy.15 18
There is currently no evidence about the effect of prenatal
testing for HHT and no consensus among experts about how
fetal diagnosis might alter pregnancy or delivery management.
Expert experience is that prenatal diagnosis is not commonlysought in HHT, and is most often requested as an alternative topostnatal diagnostic testing when there is already anotherreason for performing prenatal testing.

Table 3 Level II study of screening tests for pulmonary arteriovenous malformations (PAVMs) inpatients with hereditary haemorrhagic telangiectasia (HHT), using reference standard
Study

No of
subjects

Prevalenceof PAVMs

Referencestandard

Cottin et al (2004)82

105

45%

CT or PA

Test

Sensitivity

Specificity

TTCE
Chest x-ray
A-a gradient

93%
70%
68%

52%
98%
98%

A-a gradient, alveolarearterial gradient calculated from arterial blood gas on room air; CT, CT of the chest; PA, diagnostic pulmonary
angiography; TTCE, transthoracic contrast echocardiography (using agitated saline).

J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

75Original article
Recommendations

The expert panel recommends that clinicians diagnose HHT using the Curaçao Criteria (see table) or by identification ofa causative mutation.
Clinical considerations: Applying the Curaçao Criteria for clinical diagnosis of HHT requires a targeted, multi-generation family
history for HHT, given that most individuals with HHT will have an affected parent, grandparent and other close relatives. When
applying the Curaçao Criteria, the clinician should consider the patient’s age, given the commonly delayed appearance of the signs
and symptoms of HHT. At least 90% of patients with HHT meet the clinical criteria by age 40, but few do in the first decade of life.
If a patient has clinical features suggestive of HHT, but no family history, it is possible that patient has a new mutation, andtherefore the diagnosis of HHT remains possible.
The expert panel recommends that clinicians consider the diagnosis of HHT in patients with one or more Curaçao Criteria(see table).
Clinical considerations: When applying the Curaçao Criteria for clinical diagnosis, identifying 2 or fewer of the criteria after clinicalexamination and history should not be considered sufficient evidence to rule out the diagnosis, particularly in the first few decadesof life.
The expert panel recommends that asymptomatic children of a parent with HHT be considered to have possible HHT,
unless excluded by genetic testing.
Clinical considerations: Given the expected poor sensitivity of the Curaçao Criteria for clinical diagnosis in children, the clinician
can clarify the diagnosis using genetic testing, if a familial mutation has been identified. If genetic testing is not possible, theclinician should proceed as if the child has HHT and consider appropriate screening for visceral AVMs.
The expert panel recommends that clinicians refer patients for diagnostic genetic testing for HHT
1. To identify the causative mutation in a family with clinically confirmed HHT
2. To establish a diagnosis in relatives of a person with a known causative mutation, including:a. Individuals who are asymptomatic or minimally symptomaticb. Individuals who desire prenatal testing
3. To assist in establishing a diagnosis of HHT in individuals who do not meet clinical diagnostic criteria
Clinical considerations: Genetic testing for HHT is a multi-step process. In an experienced laboratory, the index case is generally
tested by sequence and deletions/duplications analysis of both the ENG and ACVRL1 genes. It is reasonable to perform the deletion/
duplication analysis either simultaneously with the sequence analysis or only in cases in which the sequence analysis is negativeor equivocal.
If an HHT-causing mutation is identified in the index case (test is positive), diagnostic genetic testing for HHT can be offered to all
at-risk relatives. These relatives would have ‘family-specific’ mutation testing by targeted sequencing.
If no mutation is identified (test is negative) in the index case, diagnostic genetic testing cannot be offered to other family
members. Such families should be advised that, in the future, currently undetectable HHT mutations will become detectable as new
genes and testing methods are discovered. In the meantime, diagnosis and medical management of at-risk family members will
rely on clinical findings and knowledge of the natural history of HHT.
If a genetic variant of uncertain significance is identified (test is equivocal) in the index case, additional confirmatory testing may beavailable, or additional interpretive information may become available in the future, to clarify whether the genetic variant in questionis in fact a benign variant or a disease-causing mutation.
The expert panel recommends that for individuals who test negative for ENG and ACVRL1 coding sequence mutations,
SMAD4 testing should be considered to identify the causative mutation.
Clinical considerations: If full gene analysis for the ENG and ACVRL1 genes is negative, the next step is for the clinician to request
similar testing of the SMAD4 gene.
The expert panel recommends that all HHT patients and their families with SMAD4 gene mutations should undergo
gastrointestinal screening for polyposis and gastrointestinal malignancies as per national screening recommendations.
Clinical considerations: Appropriate screening for patients and those with the SMAD4 gene mutations includes colonic screening
for polyposis with colonoscopy, starting at age 15e18 and everyone to 2 years thereafter. The first colonoscopy should be
performed at an age 5 years younger than that at which the youngest family member developed colon cancer. Affected patientsshould also undergo upper GI surveillance with oesophagogastroduodenoscopy/enteroscopy/small bowel series or capsule study
starting at age 25 and everyone to 2 years thereafter in accordance with previously published guidelines.23

EPISTAXIS
Background
Recurrent spontaneous epistaxis is the most common symptomof HHT and often leads to iron-deﬁciency anaemia.24 Epistaxis
appears before the age of 20 years in about 50% of patients, with
78e96% of all HHT patients developing it eventually.2 During
the guidelines development process, patients identiﬁed epistaxis
as a priority HHT-related health concern affecting theireveryday life, and the literature suggests that epistaxis is an
important factor reducing quality of life in HHT.25 We reviewed
the evidence for treatment of HHT-related epistaxis, searchingfor studies regarding treatment of the usual chronic recurrent
epistaxis as well as of acute episodes of epistaxis requiring urgent
medical consultation.
Non-invasive management of chronic recurrent epistaxis in
HHT has focused to date on prevention of epistaxis events
76

Level of evidence: III
Strength of recommendation: weak
Agreement: 82%

Level of evidence: III
Strength of recommendation: weak
Agreement: 91%
Level of evidence: III
Strength of recommendation: weak
Agreement: 87%
Level of evidence: III
Strength of recommendation: weak
Agreement: 80%

Level of evidence: III
Strength of recommendation: weak
Agreement: 93%
Level of evidence: III
Strength of recommendation: strong
Agreement: 97%

through measures to maintain integrity of the nasal mucosa,
such as humidiﬁcation. The rationale for humidiﬁcation is that
endonasal crusting and airﬂow lead to damage of endonasal
telangiectasia and secondary bleeding, whereas humidiﬁcation
should help prevent endonasal crusting. There are small caseseries of various topical medications, including lubricants (eg,saline, antibiotic ointments),26 27 as well as topical oestrogencream/ointment28 and antiﬁbrinolytics,29 with variable successin decreasing HHT-related epistaxis. There are insufﬁcientpublished data to recommend one topical therapy over another;
however, expert experience is that there is mild beneﬁt fromhumidiﬁcation and that the risk of topical lubricants and saline
is very low.
Procedural therapies for chronic HHT-related epistaxis
include endonasal laser, electrical or chemical coagulation
techniques, replacement of the fragile endonasal mucosa by
J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

54/306112/296

66/22553/e

45/52(Large PAVMs)

15/e

76/276

7/13
Pregnancy
42/172
PaediatricPrasad et al 200496

Mager et al 200483

Gupta et al 200295

Dutton et al 199593

Lee et al 199797

Chilvers et al 199094

White et al 198892

Gershon et al 200198

86%

100%

88%

73%

87%

79%

83%

96%

94%

95%

Diagnosis
of HHT

12 (4e18)28 (24e34)36 (5e76)41 (13e63)

42 (12e73)

41 (8e70)44 (13e77)

45 (7e85)3845 (7e77)

Mean (range)age (years)

100%

100%

100%

100%

100%

100%

100%

100%

100%

100%

Intervention

90%

100%

95%

100%

100%

100%

98%

100%

100%

100%

% withfollow-up

8430

Minimum 3

356

Minimum 3

27

62

35

96

Mean follow-up(months)

Technical success
Estimated fetal radiation dose
Improved PaO2 preepost
Absence of PAVM complications(FOCAL group)
Absence of PAVM complications(DIFFUSE group)
Reperfusion

Improved SpO2 preepost
Improved shunt(100% O2) preepost
Improved peak work capacity preepost
Technical success
Improved O2 preepost
TIA

Reperfusion

Improved SpO2 preepost
Improved shunt (Tc99 MAA)

Improved SpO2 preepost
Improved shunt (Tc99 MAA)

Improved PaO2 preepost
Improved shunt (100% O2) preepost
Reperfusion
Growth small PAVMs
TIA
Brain abscess

PAVM involution
Reperfusion

PAVM involution
Reperfusion
Growth small PAVMs

Post-embolisation
outcome

DVT, deep vein thrombosis; Tc99 MAA, shunt measurement using Technetium 99-labelled albumin macroaggregates; TIA, transient ischaemic attack.

Faughnan et al 2004

155/415

Pollak et al 200685

87

Subjects/
PAVMs

Study

100%
50e220 mRad
p<0.003100%
83% (2 deaths, 1 frombrain abscess, 1 fromlung transplant)
15%

100%
77%
2%

p<0.05p<0.00160%

15%p<0.0001
p<0.0001

p<0.001p<0.00113% (patients)
8% (PAVMs)
14% (patients)3%2%
p<0.0001
p<0.0001

93%
7%

97%
3%
18%

Frequency postembolisation outcome

Table 4 Level II uncontrolled case series of transcatheter embolisation (detachable coils, balloons, etc) for pulmonary arteriovenous malformations (PAVMs)

Pleurisy
Air embolisation
Paradoxical embolisation
DVT
Pleurisy
Fetal/childhood complications
Long-term
Pleurisy
Other pain
AnginaParadoxical embolisation
Device misplaced
Brachial plexus injury

Long term
Pleurisy
AnginaTIALong term
Pleurisy
Paradoxical embolisation
Device misplaced
PAVM perforation
TIA
Pleurisy
AnginaStrokeTIA
Paradoxical embolisation
Surgical device removal
Pulmonary hypertension
Long term
Pleurisy
AnginaParadoxical embolisation
Haemoptysis
Long term
Pleurisy
AnginaConfusion
StrokeParadoxical embolisation
Myocardial puncture
Pleurisy
Air embolisation
Paradoxical embolisation
DVT
Pulmonary infarct

Procedural
complication

10%
5%
3%
1%
29%
0%
0%
24%
2%
1%
0%
3%
1%

0%
12%
2%
0.5%
0%
12%
<0.5%
1%
1%
1%
13%
2%
1%
2%
2%
1%
1%
0%
3%
5%
1%
1%
0%
9%
3%
2%
1%
2%
1%
31%
2%
4%
8%
8%

Frequency
complication

Original article

77

78

1/10 (10%)
1/10 (10%)
2/10 (20%)
1/19 (5%)

3/93 (3%)
5/93 (5%)
1/41 (2%)
2/41 (4%)

Perforation
Delayed bleeding
Perforation
Reduced or stabilised number 6/9 (67%)
8 (4e42) vs 4 (0e44) Antral narrowingof transfusions
Reduction in mean yearlytransfusions preepost
p<0.002
Death (MI)
Reduced mean transfusions
5/6
Feminising
preepost*
Vaginal bleeding
No further bleeding
Mean haemoglobin preepost 8.6 vs 9.9
DVTp¼0.00180%
Perforation

8/8 (100%)
3/8 (38%)
3/8 (38%)
9/10 (90%)

18100%
23/43 (53%)
Medical therapy
19 ethinylestradiol/norethindrone
2 danacrine
2 aminocaproic acid57 (33e78)*Mean for all 10 patients (HHT and non-HHT).
APC, argon plasma coagulation; DVT, deep vein thrombosis; MI, myocardial infarction; Nd-YAG, neodymium-doped yttrium aluminium garnet laser.

6
100%
100% ethinylestradiol+norethisterone versus placebo
65e89

Van Cutsem et al 1990,106 10, severe GI bleeding from 6/10 (60%)
VMs, transfusion dependent
Placebo-controlled
cross-over trial
Longacre et al 2003,103
43, HHT-related GI bleeding 43/43 (100%)
Case series

51
100%
66 (55e81)
9/41 (22%)

93, severe GI bleeding,transfusion dependent
41, severe GI bleeding,transfusion dependent
Gostout et al 1988,111
Case series
Sargeant et al 1993,110
Case series

63

18, severe GI bleeding,transfusion dependent
Bown et al 1985,109
Case series

10/93 (11%)

100% ND-YAG(repeated sessions)

100%

15

Reduced transfusions
No further transfusions
Recurrence requiring surgery
Reduced transfusions
14
100%

100%
2 APC
6 ND-YAG (mean 7 sessions)
100% ND-YAG (2e6 sessions)
62 (42e74)

Subjects
Study

8/18 (44%)

Procedural
complication
Frequency posttreatment outcome
Meanfollow-up% withfollow-up (months) Post-treatment outcome
Mean (range)
No with HHT age (years)
Intervention

Therapeutic trials for gastrointestinal (GI) bleeding in hereditary haemorrhagic telangiectasia (HHT)
Table 5skin or buccal mucosa (dermoplasty), nasal artery embolisation and closure of the nasal cavity (known as Young’s
procedure). There have been no controlled or well-designed
comparative studies of any of these procedures in HHTrelated epistaxis, for either acute or chronic management.
Case series and expert opinion of endonasal coagulation
for treatment of moderate HHT-related epistaxis suggeststhat most types of endonasal coagulation appear to be lowrisk procedures with subjective improvement in mostpatients.24 26 30e34 Chemical cautery (eg, AgNO3) and CO2
laser coagulation appear to have poorer outcomes in HHT andhigher risk of intraoperative bleeding.26 Septal dermoplasty
has been reported, in one uncontrolled retrospective caseseries of patients with severe epistaxis, to decrease meantransfusion requirements and to improve subjective qualityof life, but follow-up was available in <50% of treatedpatients35 and complications included endonasal crusting anddryness. Young’s procedure has been shown in a few small
case series of patients with severe epistaxis to cause cessationof epistaxis and also to improve quality of life, althoughpatients report side effects of chronic mouth breathing.36e38
Nasal artery embolisation is generally not useful for treatment of chronic epistaxis, since the effect is generally shortterm.39 40 Submucosal or intravascular endonasal injectionsof different substances have been reported,41 42 often with
reduction in epistaxis but also reports of complications suchas severe allergic reactions and blindness.42
The expert panel agreed that, given the learning curve forsurgical management of chronic HHT-related epistaxis,
involvement of surgeons with expertise in HHT-related epistaxis
may increase the likelihood of appropriate choice of treatment
and improve outcomes of therapy. The expert panel also agreed
that this applied to nasal surgery for indications other thanepistaxis, in HHT patients.
Several medical treatments have been reported for HHTrelated epistaxis, but there are no well-designed studies
supporting their effectiveness and most studies have been
limited by the lack of a validated sensitive outcome measure.
There is one negative randomised placebo-controlled doubleblind trial of oestrogen,43 and another of tranexamic acid,44 inwhich investigators were unable to demonstrate signiﬁcant
improvement in haemoglobin (primary outcome) but did
demonstrate signiﬁcant improvement in subjective epistaxis(secondary outcome).44
There are no well-designed studies of the ﬁrst-line management of acute epistaxis, although nasal packing is often used
to control acute bleeding. However, endonasal telangiectasias
are extremely fragile and therefore packing removal can cause
rebleeding. This can be minimised with atraumatic packingdfor example, using lubricated or pneumatic packing, thelatter allowing insertion and removal of the packing ina deﬂated size. Low-pressure pneumatic packing may also
minimise mucosal ischaemic damage. Two uncontrolled caseseries of embolisation,40 45 in patients with severe ongoing
epistaxis despite packing, reported excellent immediate successrates (80e100%), but with early recurrence of epistaxis andrisk of serious procedural complications (stroke, tissue
necrosis).
The panel also discussed management when an HHT patient
has an indication for antiplatelet or anticoagulant therapy. There
are no published studies regarding the use of anticoagulants in
HHT, but expert experience revealed a wide range of outcomes,
with some HHT patients tolerating anticoagulation and others
developing life-threatening bleeding.

Frequency
complication

Original article

J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

Original article
Recommendations
The expert panel recommends that physicians advise patients with HHT-related epistaxis to use agents that humidify thenasal mucosa to prevent epistaxis.
The expert panel recommends that for HHT-related epistaxis requiring surgical intervention, clinicians consider endonasal
coagulation as a first-line treatment option.
Clinical considerations: Endonasal coagulation should be applied carefully and with experience to avoid complications such as
septal perforation (which often leads to worse epistaxis), even if it means repeating the intervention several times. If recurrent
endonasal coagulation has not been effective and epistaxis is severe, then more invasive procedures, such as septal dermoplasty
or Young’s procedure, can be considered.
The expert panel recommends that clinicians refer HHT patients with epistaxis and who desire treatment tootorhinolaryngologists with HHT expertise for evaluation and treatment.
Clinical considerations: Primary physicians are key players in the care of HHT patients, especially in the emergency situation. In
the patient with epistaxis problematic enough to warrant consideration of treatment, consultation with an otorhinolaryngologist
with HHT expertise should help guide the intervention choice, to maximise effectiveness and reduce risk, in this life-long rare
disorder.
The expert panel recommends that, when considering nasal surgery for reasons other than epistaxis, the patient andclinician obtain consultation from an otorhinolaryngologist with expertise in HHT-related epistaxis.
Clinical considerations: In the patient with HHT and an unrelated ENT problem requiring surgery, consultation with anotorhinolaryngologist with HHT expertise should help guide the procedural interventions to minimise risk of worsening epistaxis.
The expert panel recommends that the treatment for acute epistaxis requiring intervention include packing with material or
products that have a low likelihood of causing rebleeding on removal (eg, lubricated low-pressure pneumatic packing).
Clinical considerations: In order to perform atraumatic packing, the clinician can lubricate the packing or use pneumatic packing
which allows insertion and removal of the packing in a deflated size. When pneumatic packing is used, low-pressure packing ispreferable. This recommendation specifically addresses nasal packing performed by physicians, although the expert panel is awarethat patients often choose to self-pack the nose.
The expert panel recommends that HHT-related epistaxis is not an absolute contraindication to anticoagulant/antiplatelet
therapy. Anticoagulant/antiplatelet therapy can increase the risk of epistaxis, and the decision to use these agents should
be based on the individual patient risk and benefits.
Clinical considerations: HHT-related epistaxis will seldom, if ever, lead to sudden death, while the use of anticoagulants/
antiplatelets may prevent catastrophic or life-threatening events. In most HHT patients in whom visceral sources for life-threatening
haemorrhage (ie, significant PAVMs and CVMs) have been ruled out, a trial of anticoagulation can be considered if indicated.
Referral to an otorhinolaryngologist with expertise in HHT should be considered, before the start of anticoagulation therapy, tocreate a prior treatment plan in the event of a catastrophic bleeding event and to consider preventive surgical procedures.

Level of evidence: III
Strength of recommendation: weak
Agreement: 87%

Level of evidence: III
Strength of recommendation: weak
Agreement: 100%Level of evidence: III
Strength of recommendation: weak
Agreement: 93%

Level of evidence: III
Strength of recommendation: strong
Agreement: 100%

Background

CEREBRAL VASCULAR MALFORMATIONSDefinition

Approximately 23% of HHT patients will harbour a CVM.48e50
The rationale for screening for CVMs in HHT is that screening
will detect a treatable CVM before the development of a lifethreatening or debilitating complication. We therefore reviewed
the evidence regarding complications of CVMs, the performanceof screening tests, and the effectiveness of treatment for CVMs.
Given the rarity of HHT-related CVMs, most of the evidence
reviewed relates to the more common sporadic CVMs.
The bleeding risk of CVMs in HHT has been estimatedretrospectively at w0.5% per year,51 although there are noprospective natural history studies. In larger series of sporadic

The term CVM refers to a variety of vascular abnormalities,classiﬁed on the basis of morphology, including: (1) arteriovenous
malformations (CAVMs) (including microAVMs measuring<1 cm in size); (2) cavernous malformations; (3) venous angiomas/developmental venous anomalies (DVAs); (4) capillarytelangiectasias, enlarged capillary-sized vessels; (5) vein of Galenmalformations; (6) high-ﬂow pial ﬁstulae (arterivenous ﬁstulae(AVFs)); and (7) mixed malformations.46 All of these types of
CVMs can be found in HHT patients, although typically HHT is
associated with CAVMs, AVFs, microAVMs and telangiectasias.47
Table 6

Level of evidence: III
Strength of recommendation: weak
Agreement: 94%
Level of evidence: III
Strength of recommendation: weak
Agreement: 93%

Screening studies for liver vascular malformations (VMs) in hereditary haemorrhagic telangiectasia (HHT)Study% withHHTType ofstudy

NumberPopulation

112

105

HHT, consecutive
patients

100%

Screening
DescriptiveCT

Telangiectasia CVMs
AV shunt
AP shunt
AV & AP shunt
Perfusion abN PHT

Ravard et al 2004113

24
24

HHT, consecutive
patients controls

100%

Screening
Descriptive
comparativeCT

Buscarini et al 2004114

346

HHT, members of
HHT families

221 (64%)

Screening
Descriptive

Doppler US

Buscarini et al 1997115

73

HHT, one family

40 (55%)

Screening
Descriptive

Doppler US

Ocran et al 2004116

22

HHT consecutive
patients

100%

Screening
Descriptive

Doppler US

Dilated HA
Telangiectasia
AV shunt
AP shunt
Mild
Moderate
SevereMild
Moderate
SevereDilated HA
Dilated intra HA
AV shunts

Memeo et al 2005

Test

Findings forliver VMs

Frequency ofabnormality
in liver VMs

Prevalenceof liver VMs
detected

Gold standard

50/78 (64%)
20/78 (26%)
40/78 (51%)
16/78 (21%)
22/78 (28%)
46/78 (59%)
46/78 (59%)
16/16 (100%)
12/16 (75%)
5/16 (31%)
3/16 (19%)
11/92 (12%)
70/92 (76%)
11/92 (12%)
3/13 (23%)
3/13 (23%)
7/13 (46%)
14/16 (88%)
15/16 (94%)
16/16 (100%)

78/100 (78%)

No

16/24 (67%)

No

92/221(41%)

No

13/40 (32%)

Angio12/13

16/22 (73%)

No

Clinical liver VMs, patients with clinical signs or symptoms of liver VMs.
abN, abnormal; AP, arterioportal; AV, arteriovenous; CVM, confluent vascular malformations; HA, hepatic artery; PHT, portal hypertension; PV, portovenous; US, ultrasonography.

J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

79Original article
Table 7

Case series of treatment for liver vascular malformations (VMs) in hereditary haemorrhagic telangiectasia (HHT)
Treatment

Medianfollow-up(months)

14 HF
12 BIL
5 PHT
6 HF+BIL
2 HF+PHT
1 HF+PHT+BIL

Trans

15

11 HF
5 Steal
4 PHT

6

3 BIL
2 PHT
1 HF+BIL

Study

No

Lerut et al 2006127

40

Chavan et al 2004125

Azoulay et al 2002126

Clinicaltypes

Outcomesof treatment

Frequencyof outcomes

58

5-year survival
HF improved
HF Stable
HF alone Death
BIL+/ HF Death
PHT +/ HF Death83%
18/24 (75%)
5/24 (21%)
1/24 (4%)
4/18 (22%)
3/8 (38%)

Staged HAembolisation

28

Transplant

57

Alive
HF alive
HF improved
Steal alive
Steal improved
PHT alive
PHT improved
Alive
BIL alive
PHT alive
HF+BIL alive

11/15 (73%)
10/11 (91%)
10/11 (91%)
5/5 (100%)
5/5 (100%)
2/4 (50%)
2/4 (50%)
4/6 (67%)
3/3 (100%)
1/2 (50%)
0/1 (0%)Complications

Frequency ofcomplications

Intraoperative bleed*GI bleed*
CHF*
Acute rejection*
Chronic rejection*
Graft failure*
Cerebral bleed*
PAVM bleed*
Non-fatal complications
Hepatic necrosis*
Cholangitis/cholecystitis*

1/40 (3%)
1/40 (3%)
1/40 (3%)
1/40 (3%)
1/40 (3%)
1/40 (3%)
1/40 (3%)
1/40 (3%)
24/40 (60%)
1/15 (7%)
3/15 (20%)

GI bleeding*
Peritonitis*

1/6 (17%)
1/6 (17%)*Causing death.
CHF, congestive heart failure; GI, gastrointestinal; HA, hepatic artery; HF, high-output heart failure; PAVM, pulmonary arteriovenous malformation; PHT, portal hypertension; BIL¼biliary.

CAVMs,52 the annual rate of rupture is 2e4%/year.52 On thebasis of case series, CAVMs and AVFs appear to have a moreaggressive natural history, while cavernous malformations (CM),capillary telangiectasias and DVAs, also reported to occur in
HHT,49 appear to have a more benign natural history.12 48 51 53 54
There are several case series and reports of catastrophic haemorrhagic sequelae of CVMs and spinal AVFs occurring duringchildhood.50 55e58 Rarely, spontaneous resolution of CVMs has
been reported.59 60
The typical imaging features of HHT CVMs include the presence of either multiple, cortical, micro AVMs or AVFs harbouring
single feeding arteries and single draining veins.12 53 54 Catheter
angiography remains the ‘gold standard’ for diagnosis of mosttypes of CVMs, but carries a 0.5% risk of permanent stroke.61
MRI is considered to be a safe, non-invasive modality to screen for
CVMs, but unfortunately there are no screening studies assessing
its performance in HHT. MRI screening studies for non-HHT
CVMs have been limited by small size, retrospective design andlack of blinding to clinical status, but suggest sensitivity of
80e95% for medium to large sized CVMs.62e64 MRI is lesssensitive for the detection of micro AVMs,64 but the addition ofcontrast enhancement (gadolinium for patients >2 years of age)to MRI sequences increases the sensitivity for microAVMs. The
inclusion of sequences designed to detect blood products(currently gradient echo sequences) also increases the sensitivityof MRI for microAVMs and signs of asymptomatic haemorrhage.55 ‘False-positive’ results may occur when other types of
CVMs are encountered including telangiectasias which havea favourable natural history49 and for which no further invasive
imaging is required. Transcranial Doppler ultrasonography (US)
has also been used to screen for CVMs,65 66 with reported sensitivity of w80% for medium to large-sized CVMs, but studies arelimited by sample size and design. No evidence exists for followup screening after an initial negative study, as there is no evidence
to suggest that adult patients with HHT develop new CVMs.
MRI provides a relatively safe, sensitive testing modality toidentify CVMs in children.67 While MRI itself poses little risk,
the expert panel acknowledges the risk related to sedation/anaesthesia of children for diagnostic procedures. Of greatest
concern is the risk of respiratory depression, but this should be
minimised with appropriate cardiorespiratory monitoring. No
80evidence exists at this time to recommend follow-up screening
after an initial negative study during childhood, but consideration should be given to one adulthood MRI following initial
negative childhood MRI.
The expert panel agreed that CVM obliteration is required toeffectively eliminate the future risk of haemorrhage. Althoughtreatment may provide a large relative risk (RR) reduction for
cerebral bleeding, procedural risks are signiﬁcant. There are no
published studies of the efﬁcacy or safety of any form of treatment of CVMs in HHT patients. However, several large caseseries (>200 patients, mostly single-centre) of embolisation,
microsurgery and stereotactic radiation in non-HHT CAVMs
show widely ranging effectiveness for each modality.49 54 56 68e78
On the basis of this, as well as expert experience, the expert panel
agreed that effective treatment strategies include embolisation,
microsurgery and stereotactic radiation, or combinations of these.
With the rarity of CVMs and the associated risks of treatment,
the expert panel agreed that each case should be managed in an
individualised manner and decisions about invasive testing andtherapy should occur at centres with signiﬁcant experience andexpertise in all treatment modalities. Although there is noevidence regarding differences in outcomes according to expertisein management of these cases, the expert panel agreed
that centres with experience in HHT-related CVMs will be
more aware of important issues related to the care of HHT
patients and likely to have better outcomes of surgical and otherprocedures.
CVMs occur in infants and children with HHT.12 47 50 57 79 80
Before the age of 6 these malformations tend to be high-ﬂow pialﬁstulae (cerebral or spinal cord AVFs).47 Expert opinion is thatthese malformations have a more aggressive natural history thannidus-type CAVMs, including presenting events such as intracerebral haemorrhage, cognitive deﬁcit, cardiac insufﬁciency,
epilepsy and hydrocephalus.12 47 79 80 Embolisation or microsurgical obliteration of these high-ﬂow pial ﬁstulae in children may
therefore be of signiﬁcant beneﬁt when performed by a neurovascular centre with expertise in these techniques in children.
There is no evidence to guide the management of CVMs
during pregnancy and delivery, as there is no good evidence
regarding the risk of CVM complications or treatment during
pregnancy and delivery.
J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

Original article
Recommendations
The expert panel recommends that the clinician screen adult patients with possible or definite HHT for CVMs.
Clinical considerations: Dissension resulted primarily from the lack of evidence of treatment effectiveness for asymptomatic
CVMs in HHT and therefore the lack of evidence for benefit of screening.
The specifics regarding screening method are detailed in the next recommendation. There is no evidence for any role for repeat MRI
screening in adults, after an initial negative study. The likelihood of detecting a CVM will be less in patients with only a ‘possible’
diagnosis of HHT, but screening in these patients may be reasonable if the diagnosis of HHT cannot be ruled out genetically.
The expert panel could not generate a recommendation regarding screening for spinal AVFs, given their rarity and the absence ofevidence. However, if screening for spinal AVFs is being considered in children with HHT, a sagittal T2 MRI scan of the spine would
be appropriate.
The expert panel recommends the use of MRI for CVM screening in adults with possible or definite HHT using a protocol
with and without contrast administration and using sequences that detect blood products, to maximise sensitivity.
Clinical considerations: If patients have received previous embolisation, coil compatibility with MRI must be confirmed before MR
examination. The expert panel acknowledges that the optimum age for adult screening remains unknown, but felt that age 18 wasappropriate as patients enter adulthood. In the presence of a negative MRI result in adulthood, no further screening tests aresuggested. There may be additional benefits to performing an MRI at initial assessment, in the detection of infarcts and othercentral nervous system complications of HHT.
The expert panel recommends that the clinician screen children with possible or definite HHT for CVMs in the first
6 months of life (or at time of diagnosis) with an unenhanced MRI, and refer all patients with an MRI positive for theselesions to a centre with neurovascular expertise for consideration of invasive testing and further management.
Clinical considerations: Dissension resulted primarily from the lack of evidence of treatment effectiveness for asymptomatic
CVMs in HHT and therefore the lack of evidence for benefit of screening, as well as greater risk of screening in children.
When MR screening is performed with the use of sedation and anaesthesia in young children, it is necessary to monitor
cardiorespiratory parameters during the procedure and to provide an equivalent standard of care to that provided in an operatingroom. The technique used to sedate/anaesthetise infants for MRI should be performed in accordance with local expertise and noundue risk taken to obtain such a screening test. The MRI would generally be planned at the time of HHT diagnosis, preferably
before 6 months of age when the risk/benefit ratio would be optimal.
The expert panel recommends that adults presenting with an acute haemorrhage secondary to a CVM be considered for
definitive treatment in a centre with neurovascular expertise.
The expert panel recommends that all other adults with CVMs be referred to a centre with neurovascular expertise to beconsidered for invasive testing and individualised management.
Clinical considerations: The expert panel recognises that asymptomatic CVMs discovered during screening of HHT patients may
carry a more favourable natural history. These patients should be managed on an individualised basis. Since some CVMs may carrya favourable natural history, referral to a centre with neurovascular expertise before invasive imaging (catheter angiography) is
performed may minimise unnecessary testing.
The expert panel recommends that pregnant women with suspected or confirmed HHT harbouring an asymptomatic CAVM
during pregnancy have definitive treatment of their CAVM deferred until after delivery of the fetus. The expert panel
recommends that the delivery of the fetus follow obstetrical principles.

PULMONARY ARTERIOVENOUS MALFORMATIONS
Background
PAVMs are present in 15e50% of people with HHT and havebeen associated with life-threatening complications, as previously reviewed.81 82 The rationale for screening HHT patientsfor PAVMs is that screening will detect a treatable PAVM before
the development of a life-threatening or debilitating complication. We therefore reviewed the evidence regarding complications of PAVMs, the performance of screening tests, and theeffectiveness of treatment for PAVMs.
PAVMs have been shown to be associated with disabling andlife-threatening complications, such as stroke, transientischaemic attack (TIA), cerebral abscess, massive haemoptysis
and spontaneous haemothorax81 83e86 in retrospective series.
The neurological complications are presumed to occur via
paradoxical embolisation through PAVMs, whereas the
haemorrhagic complications occur due to spontaneous PAVM
rupture. These complications have been demonstrated in largely
adult series of HHT patients, although they have also been
demonstrated in a paediatric HHT series,87 albeit smaller in size.
There have also been small series reporting these same complications during pregnancy,88 89and the expert panel agreed thatthe complication risk appears to be greater during pregnancy.
Since clinical symptoms and signs of PAVMs are often
absent before the development of complications, a number ofscreening tests have been studied, including physiological methodsof measurement of intrapulmonary shunt as well as
multiple different imaging modalities. In the one comparative
study (table 3), transthoracic contrast echocardiography withagitated saline (TTCE) has been demonstrated to have the best
combination of high sensitivity82 and low risk90 91 among
J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

Level of evidence: III
Strength of recommendation: weak
Agreement: 77%

Level of evidence: III
Strength of recommendation: weak
Agreement: 100%Level of evidence: III
Strength of recommendation: weak
Agreement: 64%

Level of evidence: III
Strength of recommendation: strong
Agreement: 94%
Level of evidence: III
Strength of recommendation: strong
Agreement: 84%

Level of evidence: III
Strength of recommendation: weak
Agreement: 80%

screening tests for PAVMs in adults with HHT, when comparedwith the reference standard tests (CT and pulmonary angiography). There have been no comparative screening studies for
PAVMs in children with HHT.
Embolisation has been shown in several non-controlled
series83 85 92e96 to be efﬁcacious and to have a good safety
proﬁle, with only rare PAVM-related complications during
5e10 year follow-up (table 4) . In the short term, these studies
showed very high rates of immediate technical success andsigniﬁcant improvement in oxygenation (table 4). Longer term
after embolisation, reperfusion did occur in up to 15%, andgrowth of small PAVMs in up to 18% (table 4), but clinicalcomplications were very rare. These series primarily reported
outcomes for treatment of PAVMs with feeding artery diameterof 3 mm or greater, although expert experience suggests thatembolisation of smaller PAVMs (2e3 mm) has similar outcomes.
The safety and efﬁcacy were similar for large PAVMs in adults97
as well as for PAVMs in children,87 although there is little
experience with embolisation of PAVMs in children under theage of 4 years. There is only one small case series of embolisation
during pregnancy,98 suggesting reasonable safety. Although there
is no evidence regarding differences in outcomes according toexpertise in embolisation of PAVMs, the expert panel agreed that
centres with experience in this procedure are more likely to havebetter outcomes than inexperienced centres.
The long-term follow-up of PAVMs is described using CTof thethorax. This allows detection of reperfusion by non-involution of
the aneurysmal sac w1 year after embolisation and also detectionof growth of small residual PAVMs, which are common in HHT.85
TTCE has been shown to be not useful after embolisation, giventhat it remains positive in w90% of patients after embolisation.99
81Original article
Recommendations
The expert panel recommends that clinicians screen all patients with possible or confirmed HHT for PAVMs.
Clinical considerations: Screening should be performed at the time of initial clinical evaluation for HHT. Although less evidence
exists in children, the expert panel included children in the screening recommendation, since they are also at risk of life-threatening
complications, and treatment appears to be similarly effective.
In patients with negative initial screening, repeat screening should be considered after puberty, after pregnancy, within 5 years
preceding planned pregnancy, and otherwise every 5e10 years.
The expert panel recommends that clinicians use TTCE as the initial screening test for PAVMs.
Clinical considerations: Screening should be performed by clinicians with significant expertise in HHT, usually in an HHT centre of
excellence, to achieve the accuracy and low risks reported in the literature. TTCE is considered positive if there is detection of any
bubbles in the left atrium. Positive screening should be confirmed with unenhanced multidetector thoracic CT with thin-cut (eg,
1e2 mm) reconstructions. CT was not recommended as a screening test because of the associated radiation exposure, but could
be considered for screening in centres without expertise in TTCE for PAVM screening.
In children, the choice of screening tests should be decided on a case-by-case basis, but may include clinical evaluation (forcyanosis, dyspnoea, clubbing), supine and upright pulse oximetry, chest radiography and/or TTCE.
The expert panel recommends that clinicians treat PAVMs with transcatheter embolotherapy.
Clinical considerations: The recommendation applies to all adults with PAVMs and children with symptomatic PAVMs. The decision
to treat in asymptomatic children (no dyspnoea, no exercise intolerance, no growth delay, no cyanosis or clubbing, no previous
complication) should be made on a case-by-case basis. The selection of PAVMs for embolisation is based on feeding artery diameter,
generally 3 mm or greater, although targeting PAVMs with feeding artery diameter as low as 2 mm may be appropriate.
This procedure should be performed by clinicians with significant expertise in embolising PAVMs, usually in an HHT centre of
excellence, to achieve the effectiveness and low risks reported in the literature. This is particularly relevant when considering
embolisation in rare or higher risk situations, such as during pregnancy and in patients with mildemoderate pulmonary
hypertension. The panel agrees there is no role for surgical management of PAVMs, other than in the management of lifethreatening bleeding in a centre where embolisation expertise is unavailable.
The expert panel recommends that clinicians provide the following long-term advice to patients with documented PAVMs(treated or untreated):
1. Antibiotic prophylaxis for procedures with risk of bacteraemia
2. When intravenous access is in place, take extra care to avoid intravenous air
3. Avoidance of SCUBA diving
Clinical considerations: The rationale for recommending prophylactic antibiotics for bacteraemic procedures in people with
PAVMs is based on expert opinion that cerebral abscess is common in these patients (w10% before PAVM diagnosis), that
cerebral abscess in these patients occurs primarily as a complication of bacteraemic procedures, the fact that cerebral abscess is
associated with considerable morbidity and mortality, and that this precaution is low risk. The American Heart Association
guidelines for prevention of bacterial endocarditis should be followed for choice of antibiotics.
Similarly, careful avoidance of intravenous air bubbles is recommended to prevent cerebral air embolism, and this could include an
in-line filter. There are only theoretical arguments for avoidance of SCUBA diving suggesting that there may be an increased risk ofcomplications of decompression in patients with PAVMs.
These precautions should be followed life-long, regardless of size of PAVMs, even once PAVMs are treated. These precautions
should also be considered in HHT patients in whom PAVMs have not been excluded or in whom microscopic PAVMs are suspected(eg, detected on TTCE but not detectable on CT).
The expert panel recommends that clinicians provide long-term follow-up for patients who have PAVMs, in order to detect
growth of untreated PAVMs and also reperfusion of treated AVMs.
Clinical considerations: Follow-up allows the identification of embolised PAVMs that have reperfused and other PAVMs that havegrown large enough to be considered for embolisation. Multidetector thoracic CT with thin-section reconstruction (1e2 mm) should
be undertaken within 6e12 months after embolisation and then approximately every 3 years after embolisation.
For patients with only small untreated PAVMs and in patients with suspected microscopic PAVMs (eg, detected on TTCE but notdetectable on CT), the follow-up period should be determined on a case-by-case basis (approximately every 1e5 years) with CT(as above), with consideration for limiting radiation exposure.

GASTROINTESTINAL BLEEDING
Background
Although 80% of patients with HHT have gastric or small
intestinal telangiectasia100 on endoscopy or capsule examination,
only 25e30% of patients will develop symptomatic GI
bleeding,1 2 101 102 which usually does not present until the 5th or
6th decades of life. Patients rarely develop signiﬁcant GI bleeding
before 40 years of age.1 2 101 102 Women are affected with GI
bleeding in a ratio of 2e3:1.103 104
Patients with HHT and GI bleeding may or may not be
symptomatic, as the bleeding is usually in a slow, chronic andintermittent fashion, often without notable melaena. Patients
often have few symptoms until they become anaemic. In severecases, HHT GI bleeding causes morbidity, dependency on bloodtransfusions, and increased mortality.103 Severity of GI bleedingin HHT is generally based on severity of the anaemia. Gastricand duodenal telangiectasias are more common than colonictelangiectasias and contribute more to overall GI bleeding andchronic anaemia in HHT patients.105
At present, endoscopic evaluation is considered the gold standard
test for evaluation of GI bleeding in HHT patients. Although the
majority of patients with HHT will have GI telangiectasias, theutility of endoscopic evaluation is in the anaemic or iron-deﬁcientpatient. The presence and number of gastric and duodenal telan82

Level of evidence: III
Strength of recommendation: strong
Agreement: 96%

Level of evidence: II
Strength of recommendation: weak
Agreement: 96%

Level of evidence: II
Strength of recommendation: strong
Agreement: 96%

Level of evidence: III
Strength of recommendation: weak
Agreement: 87%

Level of evidence: II
Strength of recommendation: strong
Agreement: 100%

giectasias have been shown to predict the presence and number ofjejunal telangiectasias,104 and therefore, for diagnostic purposes, anoesophagogastroduodenoscopy is sufﬁcient in most cases.
Management of GI bleeding in HHT involves treatment of theiron-deﬁciency/anaemia and therapies to reduce GI bleeding. Treatment of anaemia and iron deﬁciency includes aggressive ironreplacement and blood transfusions as necessary. There are no studiesof iron replacement in HHT, but experts agree that oral iron supplementation may be sufﬁcient in some patients, although considerationof intravenous iron supplementation may be necessary in more severecases. There have been no studies of erythropoietin therapy in HHT,
but it is sometimes considered in severe cases, in combination withiron, in an attempt to accelerate treatment of the anaemia.
Current treatment options to reduce chronic GI bleeding in
HHT include hormonal therapy (oestrogen/progesterone preparations or danacrine), antiﬁbrinolytics (aminocaproic acid ortranexamic acid), other medications reported only as isolatedcase reports (tamoxifen, interferon, thalidomide and sirolimus)
and endoscopic therapy. There is one small double-blind placebocontrolled cross-over trial106 (table 5) of combination hormonal
therapy (ethinylestradiol 0.05 mg plus norethisterone 1 mg)
versus placebo, each for 6 months, in 10 patients with transfusion-dependent severe GI bleeding. Five of the six HHT
patients had no further GI bleeding while receiving treatment,
J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

Original article
and, in the overall group, there was a signiﬁcant decline intransfusion requirements. In a retrospective case series103 of 43
HHT patients with GI bleeding, median haemoglobin improved
signiﬁcantly (8.6 to 9.8 mg/dL, p¼0.0018) for the 23 patientstreated with medical therapy (ethinylestradiol/norethindrone in
19, danacrine in two, and aminocaproic acid in two). Although
there are only other individual case reports107 of danacrine in
HHT GI bleeding, it may be a reasonable alternative tooestrogen/progesterone therapy in male patients, as it does nothave feminising effects. There is only individual case report
evidence for antiﬁbrinolytics for HHT-related GI bleeding,108 but
there is expert experience suggesting beneﬁt in these patients.
Overall, there is insufﬁcient evidence to recommend any medical
treatment as ﬁrst-line therapy in these patients, given thepotential side effects; however, there may be a role for theseagents when iron replacement is insufﬁcient to control anaemia.
There are small case series (table 5) and expert experiencesuggesting that local endoscopic therapy, using argon plasma
coagulation (APC) or ND-YAG laser, may be beneﬁcial in reduction of HHT-related GI bleeding. In three small case series109e111
of repeated ND-YAG therapy, transfusion requirements declined
in more than 50% of patients. The expert panel agreed that,
although the reported series were primarily of the use of ND-YAG

laser, APC is the most effective method of endoscopic therapy
currently available. Overall, there is insufﬁcient evidence torecommend endoscopic therapy as ﬁrst-line therapy in HHTrelated GI bleeding; however, there may be a role for endoscopic
therapy when iron replacement is insufﬁcient to control anaemia.
There is no evidence or experience supporting cauterisation ofcolonic telangiectasia, or for surgery or transcatheter embolotherapy in the routine management of HHT-related GI bleeding.
Although there is no evidence regarding differences in outcomesaccording to expertise in endoscopic management of GI bleedingin HHT, the expert panel agreed that clinicians with experience in
HHT-related GI bleeding will better prepared to make decisions
about when to treat GI telangiectasia in HHT and are likely toachieve better outcomes for these procedures.
There is no evidence of any beneﬁt from altering nutrition or
lifestyle, or screening for Helicobacter pylori in patients with
HHT-related GI bleeding. HHT patients with GI bleeding should
avoid anticoagulants and drugs that alter platelet function.
However, when other comorbidities require use of these drugs,
expert experience is that these can often be tolerated, especiallywhen doses are kept as low as possible.

Recommendations

The expert panel recommends that all patients over 35 years should have annual measurements of haemoglobin or haematocrit
levels because of the increased risk of significant GI bleeding with age. Directed endoscopic evaluation should be undertaken inpatients with anaemia disproportionate to epistaxis. The expert panel advises against GI endoscopic investigations in patientswith HHT and no evidence of anaemia.
Clinical considerations: A blood test for haemoglobin and ferritin should be drawn as part of the annual physical examination with the family
physician. The age of 35 is preferred, as few people begin having problems with GI bleeding before 40 and this allows measurement ofbaseline haemoglobin to track GI losses. Patients over 50 years of age, particularly women, are considered at higher risk of HHT-related GI
bleeding. Of note, fecal occult blood testing can be falsely positive due to GI transit of swallowed epistaxis and therefore this test is not useful.
In HHT patients with suspected GI bleeding, the expert panel recommends that an upper endoscopy be the first diagnostic test.
The diagnosis of HHT-related GI bleeding is made in the presence of anaemia and endoscopic visualisation of characteristic GI
telangiectasia in combination with clinical judgement.
Clinical considerations: HHT patients with anaemia should be referred to clinicians with HHT expertise for endoscopic visualisation to
identify the source of their GI bleeding. Since the majority of the bleeding occurs in the stomach and proximal small intestine, an upper
endoscopy is usually sufficient to diagnose upper GI telangiectasias. The clinician must be aware that the presence of characteristic GI
telangiectasias does not necessarily indicate that they are the source of anaemia or GI bleeding and does not preclude other sources of
bleeding. Wireless capsule endoscopy may be considered when direct endoscopic visualisation of the GI tract with upper and lower
endoscopies does not adequately explain the anaemia.
It is not common for the GI telangiectasias in HHT to cause massive, acute GI bleeding. In HHT patients with acute GI bleeding therefore
other causes should be considered first as in non-HHT patients.
The expert panel recommends oral and/or intravenous iron supplementation as first-line therapy for mild anaemia and chronic
bleeding secondary to HHT-related telangiectasia.
Clinical considerations: For replenishment of iron stores, the clinician can select the oral iron formulation that is best tolerated by thepatient, as long as the dosing is adequate. Often patients will require 6e12 months of, for example, ferrous fumarate 300 mg once daily,
but the dose and duration are adjusted according to the patient’s haemoglobin and ferritin response. If one oral iron preparation is nottolerated, then a trial of another should be considered. If oral iron replacement is insufficient or not tolerated, then intravenous iron,
preferably iron sucrose, should next be considered. Haemoglobin and ferritin levels should be monitored regularly, with the frequency
depending on the severity of the anaemia, until both the anaemia and iron deficiency are resolved. Some patients may require long-termor life-long iron supplementation. If additional therapy with erythropoietin is considered, patients should be screened and treated for
PAVMs before therapy is initiated, because of the thrombogenic risk of erythropoietin.
The expert panel recommends against the use of multiple attempts at local endoscopic therapy because of the additive risk ofadverse events without corresponding benefits.
Clinical considerations: The HHT patient with anaemia not responding to iron supplementation should be referred to a clinician withexpertise in endoscopic treatment of HHT patients, for consideration of one or two attempts to locally cauterise visible telangiectasias.
This is most likely to be beneficial when performed with APC and by an endoscopist with related experience. Since the majority of the
bleeding occurs in the stomach and proximal small intestine, cauterisation during upper endoscopy is most likely to be beneficial. If initialendoscopic cauterisation is not beneficial in a given patient, further multiple attempts at endoscopic cauterisation of GI telangiectasias areunlikely to be beneficial and yet will expose the patient to unwarranted risk. Specialised endoscopy, such as enteroscopy, or performing
endoscopy during surgery is not routinely used for treatment of HHT-related bleeding, but may be considered in cases where treatment of
more distal lesions is being considered (distal to the duodenum and proximal to the terminal ileum).
The expert panel recommends that the clinician consider systemic hormonal or antifibrinolytic therapy in selected HHT patients
to limit ongoing GI blood loss.
Clinical considerations: When unable to maintain the haemoglobin at an acceptable level, that is, 9e10 g/dl or higher, with oral and/or
intravenous iron, then the clinician should consider hormonal therapy or antifibrinolytic therapy, in patients without contraindications. The
usual dosing for hormonal therapy in HHT, based on the one study,106 is daily ethinylestradiol 0.050 mg and norethisterone 1 mg.
Danacrine 200 mg orally twice a day for 6 weeks followed by 200 mg daily in responders may be a beneficial alternative in men, withfewer side effects. Another alternative is antifibrinolytic therapy, with aminocaproic acid or tranexamic acid. Aminocaproic acid is usually
started at 500 mg orally four times a day and increased to a maximum of 2500 mg orally four times a day (10 g/day). Tranexamic acid is
usually started at 500 mg orally every 8e12 h and increased to 1e1.5 g orally every 8e12 h. Patients should be screened and treated for
PAVMs before initiation of either of these systemic therapies, given the thrombogenic risk.

J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

Level of evidence: III
Strength of recommendation: strong
Agreement: 89%

Level of evidence: III
Strength of recommendation: strong
Agreement: 90%

Level of evidence: III
Strength of recommendation: weak
Agreement: 97%

Level of evidence: III
Strength of recommendation: weak
Agreement: 90%

Level of evidence: III
Strength of recommendation: weak
Agreement: 100%83

Original article
LIVER VASCULAR MALFORMATIONS
Background
Although a consensus guideline had been recently published forthe diagnosis and management of liver VMs in HHT,4 to beconsistent, we elected to include this topic in the present
guidelines. As such, we followed the same guidelines process forliver VMs as for other aspects of HHT and reviewed the evidence
regarding diagnosis and treatment of liver VMs in HHT. The
liver VMs recommendations reported in the present guidelines
do not differ signiﬁcantly from the previous guidelines.4
Liver VMs are present in 32e78% of HHT patients112e116(table 6). Although there are no published natural history data
regarding liver VMs in HHT, it appears that symptoms occur inonly about 8% of the patients with HHT and liver VMs.114 117
The clinical presentations of liver VMs include high-output
heart failure, portal hypertension and biliary necrosis.118
In patients who have symptoms suggestive of liver VMs,118 it
is important to establish the diagnosis of liver VMs for therapeutic and prognostic purposes. The diagnosis of liver VMs may
also assist in the clinical diagnosis of HHT, since visceral
involvement is one of the clinical diagnostic criteria.11 Several
different imaging modalities have been reported and studied forthe screening and diagnosis of liver VMs in HHT. From the least
invasive to the most invasive, these tests are Doppler ultrasonography, MRI, triphasic spiral CT and mesenteric angiography.
Doppler US is the least invasive test, requiring no contrast andbeing associated with no procedural complications. There is little
experience with MRI, which does require MR-contrast administration, but involves no radiation exposure. CT is associated withradiation exposure and risk of contrast allergy. Mesenteric catheter angiography has traditionally been considered the diagnostic
gold standard, but is the most invasive, and is rarely used.
Typical angiographic ﬁndings have been described in several
small case series of HHT patients,119e121 including telangiectasias,
conﬂuent VMs, hepatic artery dilatation and shunting (arterioportal, arteriovenous and/or portovenous). Triphasic CT
ﬁndings have been similarly described.112 113 117 Several caseseries of Doppler US in HHT patients have demonstrated
hepatic artery dilatation, elevated hepatic artery ﬂow, andintrahepatic hypervascularity.113 114 116 122 123 There have been
no well-designed studies reporting sensitivity and speciﬁcity of
any of these tests, although the positive predictive value of
Doppler US appears to be near 100%.115 123 Screening studies
of HHT patients (table 6) have reported a prevalence of liver
VMs of 32e72% with Doppler US114e116 and 67e78% withtriphasic CT.112 113 In none of these studies was a diagnostic
gold standard (angiography) uniformly performed; however,these prevalences are all much higher than the symptomatic
rate (8%), suggesting that these tests are sensitive. There areno screening studies in children.
Histological diagnosis from liver biopsy tissue, although quitecharacteristic,118 is unnecessary, given typical imaging ﬁndings,
and risky in patients with liver VMs. Focal nodular hyperplasia
occurs more often in HHT than in the general population,124 but
can be diagnosed through imaging, without biopsy.
There are three uncontrolled case series (table 7) of treatmentsof liver VMs, speciﬁcally hepatic artery embolisation and livertransplantation. Hepatic artery embolisation has the objective of
reducing arteriovenous or arterioportal shunting by embolisingbranches of the hepatic artery. Embolisation appears to be effective in improving symptoms related to high-output heart failure
and mesenteric steal syndrome125; however, the effect is transientand symptoms generally recur. More importantly, ischaemic
complications (ischaemic cholangitis, ischaemic cholecystitis
and/or hepatic necrosis) leading to transplant or death occur in
w30% of the treated cases, including 50% of treated portal
hypertension cases.125 The 2-year survival with embolisation was
w73%. The expert panel agreed that the risk of post-embolisationischaemia would probably be greatest in patients with biliary
presentation of liver VMs. With liver transplantation, symptoms
resolved in the majority of patients.126 127 Liver transplantation isassociated with high blood transfusion requirements, prolonged
hospital stay, and a relatively high rate of postoperative complications. However, the reported 5-year survival rate of 83% in thelarger series127 compared favourably with overall survival rates forliver transplantation.

Recommendations

The expert panel recommends that in patients with HHT and abnormal liver enzymes and/or a clinical picture suggestive ofcomplications of liver VMs:
< High output heart failure (exertional dyspnoea, orthopnoea, oedema)< Portal hypertension (variceal haemorrhage, ascites)< Biliary (jaundice, fever, abdominal pain)< Portosystemic encephalopathy< Steal syndrome (intestinal ischaemia)< Doppler US or CT should be offered as a baseline test to confirm liver VMs
Clinical considerations: The confirmation of the diagnosis of liver VMs in symptomatic patients will help prevent misdiagnosis and allow
the clinician to provide appropriate therapy and follow-up. Either Doppler US or CT scan can be used to confirm the diagnosis, although
Doppler US is lower risk. In centres where expertise in the interpretation of Doppler US for diagnosis of liver VMs is lacking, triphasic
helical CT may be appropriate. Further, more invasive, testing may be performed depending on severity of symptoms and type of clinicalpresentation. For example, in patients with related heart failure, right heart catheterisation with measurement of cardiac index andpulmonary pressures can help guide therapy and establish baseline values. In those with symptoms of heart failure versus portal
hypertension, hepatic vein catheterisation with measurement of hepatic venous pressure gradient can guide therapy. For patients withabdominal pain suggestive of mesenteric ischaemia, angiography might clarify the diagnosis.
To clarify the diagnosis of HHT, the expert panel recommends screening for liver VMs, using Doppler US, in patients with 1 or 2
HHT diagnostic criteria and in whom genetic testing is either inconclusive or unavailable
Clinical considerations: The rationale for recommending screening for liver VMs to clarify the diagnosis of HHT is based on the fact thatvisceral involvement is one of the diagnostic criteria for HHT, and therefore finding liver VMs in a patient with probable HHT can help
further clarify the diagnosis of HHT. When screening is undertaken, it is advisable to screen with the least invasive test, such as Doppler
US. Where expertise in Doppler US for liver VMs is lacking, a diagnosis of liver VMs can be made with triphasic CT.
The expert panel recommends that liver biopsy be avoided in any patient with proven or suspected HHT.
Clinical considerations: The rationale for recommending against liver biopsy for diagnosis of liver VMs is that the diagnosis isestablished with imaging studies, whereas biopsy exposes the patient to an unnecessary risk of haemorrhage.

Level of evidence: III
Strength of recommendation: strong
Agreement: 83%

Level of evidence: III
Strength of recommendation: strong
Agreement: 78%

Level of evidence: III
Strength of recommendation: strong
Agreement: 97%

Continued
84

J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

Original article
Continued
The expert panel recommends that hepatic artery embolisation be avoided in patients with liver VMs as it is only a temporisingprocedure associated with significant morbidity and mortality
Clinical considerations: Given the elevated risk of post-embolisation necrosis and death, this procedure should not be considered asa first-line therapeutic option. It may be reasonable for the clinician to consider hepatic artery embolisation in certain patients, such asa patient with heart failure who has failed to respond to optimal medical therapy and who does not have biliary ischaemia or portovenous
shunting and who is not a transplant candidate. The risks and benefits of embolisation and transplant should be considered on an
individualised basis, based on type of shunting, clinical syndrome, patient characteristics and patient preference.
The expert panel recommends that referral for liver transplantation be considered in patients with liver VMs that develop:< Ischaemic biliary necrosis< Intractable heart failure< Intractable portal hypertension
Clinical considerations: Since liver transplantation for liver VMs has a good survival rate, it is a reasonable option for patients withsevere complications of liver VMs refractory to medical therapy. Patients who develop biliary necrosis have the highest mortality,
particularly those who develop it in the setting of heart failure, and therefore should be prioritised for liver transplant, analogous to posttransplant patients who develop bile duct necrosis.

Author affiliations
1
Division of Respirology, Department of Medicine, St Michael’s Hospital, University ofToronto, Toronto, Ontario, Canada
2
Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto,
Toronto, Ontario, Canada
3
Departments of Medicine, Health Policy, Management and Evaluation, University ofToronto, Toronto, Ontario, Canada
4
Section of Digestive Diseases, Department of Internal Medicine, Yale University
School of Medicine, New Haven, Connecticut, USA
5
University of the Saarland, Medical Faculty, Homburg/Saar, Germany
6
Department of Otorhinolaryngology, Holweide Hospital, Hospitals of the City of
Cologne, Cologne, Germany
7
Department of Radiology, University of Utah, Salt lake City, Utah
8
Section of Digestive Diseases, Yale University School of Medicine, New Haven,
Connecticut, USA
9
Department of Surgery, St Michael’s Hospital, University of Toronto, Toronto, Ontario,
Canada10
Dept of Otolaryngology/Head & Neck Surgery, University of Toronto, Toronto,
Ontario, Canada
11
UO di Gastroenterologia ed Endoscopia Digestiva, Ospedale Maggiore, Crema, Italy
12
Portland VA Medical Center, HHT Center of Excellence, Dotter Interventional
Institute, Oregon Health & Science University, Portland, Oregon, USA
13
University of Lyon, Hospices Civils de Lyon, National reference center for rarepulmonary diseases, Lyon, France
14
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania, USA
15
Medical College of Georgia, Augusta, Georgia, USA
16
National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
17
Ontario Newborn Screening Program and Regional Genetics Program, Children’s
Hospital of Eastern Ontario, Ottawa, ON, Canada
18
Massachusetts General Hospital Gastrointestinal Unit, Boston, Massachusetts, USA
19
St Antonius Hospital, Nieuwegein, The Netherlands
20Interventional Neuroradiology, Hopital de Bicetre, Paris, France
21
Department of Otolaryngology-Head & Neck Surgery, Washington University Schoolof Medicine, St Louis, Missouri, USA
22
Department of Radiology, Washington University School of Medicine, St Louis,
Missouri, USA
23
National Reference Center for HHT Disease, Hotel Dieu Hospital, Hospices Civils de
Lyon, Lyon, France
24
SE Scotland Genetic Service, Western General Hospital, Edinburgh, Scotland
25
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
26
Department of Surgery, St Vincent’s Medical Center, Bridgeport, Connecticut, USA
27
Department of Internal Medicine and Public Health, University of Bari, Bari, Italy
28
Mayo Clinic Division of Pulmonary & Critical Care Medicine, Rochester, MN, USA
29
Division of Pulmonary & Critical Care Medicine, Johns Hopkins University, Baltimore,
Maryland, USA
30
Division of Neurosurgery, Krembil Neuroscience Centre, University Health Network,
Toronto, Ontario, Canada
31
Yale Vascular Malformation Center, Yale University School of Medicine, New Haven,
Connecticut, USA
32
Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven,
Connecticut, USA
33
Servicio de Medicina Interna, Unidad HHT, Hospital Sierrallana (Servicio Cántabro de
Salud), Torrelavega (Cantabria), Spain
Acknowledgements Many thanks to the following people who contributed at
different stages to the HHT Guidelines: Marianne Clancy MPA, Justine Cohen-Silver
MD MSc, Sharon Straus MD MSc, Dave Davis MD, Mary Ellyn Parker RN, Ana
Carvalho, Joyce Fenuta RN BScN MHS, Beth Plahn RN MHA, David Stoner BS RPh,
J Med Genet 2011;48:73e87. doi:10.1136/jmg.2009.069013

Level of evidence: III
Strength of recommendation: strong
Agreement: 94%

Level of evidence: III
Strength of recommendation: strong
Agreement: 94%

Keith Williams, Cheryl Wilson MA MS, Jane E Tumpson MAT MBA, Samir Gupta
MD MSc, Kevin Sanders MD MSc, Anna R. Gagliardi PhD, Andrew Worster MD and
Denice Feig MD MSc.
Funding John Abele on behalf of the Argosy Foundation, HHT Foundation International
Inc, Canadian Institutes of Health Research, St Michael’s Hospital Department ofMedicine. Financial support for MEF: Nelson Arthur Hyland Foundation, Li Ka Shing
Knowledge Institute of St Michael’s Hospital.
Competing interests VP received an honorarium for attending the HHT Guidelines
Conference. DP received a grant (completed) from the Ethek F Donahue Foundation to
study hormonal therapy in HHT.
Contributors All of the authors contributed to the guidelines development and theresulting manuscript.
Provenance and peer review Not commissioned; externally peer reviewed.

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87International guidelines for the diagnosis
and management of hereditary
haemorrhagic telangiectasia
M E Faughnan, V A Palda, G Garcia-Tsao, et al.
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