Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: Issues in clinical management and review of pathogenic mechanisms

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Rare diseases c 4
Series editors: A E Tattersfield, R M du Bois
Hereditary haemorrhagic telang iectasia and
pulmonary arteriovenous malformations: issues in
clinical management and review of pathogenic
mechanisms
Claire L Shovlin, Michelle Letarte
Hereditary haemorrhagic telangiectasia (HHT,
Rendu-Osler-Weber syndrome) exemplifies an
important group of diseases which have
catalysed advances in the understanding of
fundamental pathophysiological mechanisms.
In this paper areas of clinical management of
HHT are discussed and the molecular patho-
genesis is reviewed. The first section is aimed at
all clinicians and concentrates on the recogni-
tion of a disorder in which silent cerebral and
pulmonary involvement may be life threatening
if left untreated. Recent data concerning the
diagnostic and treatment modalities for pulmo-
nary arteriovenous malformations (PAVMs)
are also reviewed, and the growing concern that
many patients with HHT may have small or
residual PAVMs is highlighted. The paucity of
good longitudinal data on these patients and
others with diVerent forms of HHT highlights
the need for further clinical studies. In the sec-
ond section the results of molecular research
which suggests a role for receptors and ligands
of the transforming growth factor (TGF)-â
superfamily in the pathogenesis of this vascular
disease are discussed. The means by which
such information may relate to the clinical
heterogeneity observed in HHT are specifically
addressed, and more fundamental questions
such as how reduced cell surface expression of
endoglin predisposes a patient to develop
PAVMs are also discussed.
Hereditary haemorrhagic telangiectasia
The classical patient with the vascular disorder
hereditary haemorrhagic telangiectasia (HHT)
has nose bleeds, dilated blood vessels over the
lips and finger tips, and gastrointestinal bleed-
ing in later life. However, this clinical scenario
represents only one of the presentation pat-
terns of HHT.
12
It is now recognised that, in
addition to microscopic mucocutaneous tel-
angiectases derived from post capillary venules
(fig 1A),
3
HHT leads to the development of
larger abnormal vascular structures at other
sites. Arteriovenous malformations in the
pulmonary, cerebral, and hepatic circulations
account for some of the most devastating clini-
cal complications of the disease.
The autosomal dominant inheritance pat-
tern of HHT has enabled identification of the
underlying genetic defects, prompting in-
creased scientific interest in the disorder.
Mutations in at least two genes have been
shown to be associated with HHT in diVerent
families: endoglin on chromosome 9,
4
and
ALK-1 (activin receptor-like kinase 1) on
chromosome 12.
5
Both genes encode endothe-
lial cell transmembrane proteins that can be
defined as components of the receptor com-
plexes for growth factors of the TGF-â super-
Figure 1 Hereditary haemorrhagic telangiectasia (HHT). (A) Mucocutaneous
telangiectasia on the lips of a patient with HHT. In these simple telangiectases, thin walled
endothelial cell lined vessels resembling dilated post capillary venules connect apparently
normal capillaries and draining venules, with a high frequency of direct arteriovenous
communications.
36
(B) Histology of microscopic PAVMs. Haemotoxylin and eosin stained
slide taken from an open lung biopsy specimen displaying dilated vascular structures in
place of normal corner vessels. These were not visible radiologically, although they caused
hypoxaemia and a right-to-left shunt.
7
As in mucocutaneous telangiectases,
3
it is thought
that larger lesions (see fig 2) may arise from microscopic PAVMs by a process of
remodelling.
Thorax 1999;54:714–729714
Respiratory Medicine,
Imperial College
School of Medicine,
National Heart and
Lung Institute,
Hammersmith
Hospital, Du Cane
Road, London
W12 0NN, UK
C L Shovlin
Cancer and Blood
Programme, The
Hospital for Sick
Children, 555
University Avenue,
Toronto, Ontario,
M5G 1X8, Canada
M Letar te
Correspondence to:
Dr C L Shovlin.

family. This suggests that disease pathogenesis
is likely to result from perturbation of physi-
ological eVect(s) of these growth f actors in vas-
cular development or homeostasis. At the
present time, the factors implicated and the
mechanisms which regulate their action remain
speculative. Relevant data are discussed further
in the final section of this review, to which the
non-clinical reader is referred directly.
CLINICAL ASPECTS OF HHT
HHT is more common than previously appre-
ciated, with prevalence rates exceeding one in
10 000 in some regions.
8–11
The disease dis-
plays age related penetrance, with manifesta-
tions developing throughout life and varying
between aVected individuals, even individuals
from the same family. Heterozygotes account
almost exclusively for the patient population:
there are very few reports of probable homo-
zygous cases.
12–14
The common clinical manifestations of
HHT are summarised in table 1 which also
provides an overview of the presentation
patterns and treatments for the manifestations
that are usually managed by appropriate
specialists (epistaxis, mucocutaneous tel-
angiectasia, and gastrointestinal lesions); fur-
ther information may be found in excellent
recent reviews.
12
A significant proportion of
patients with HHT have pulmonary and
cerebral vascular involvement. These manifes-
tations diVer from other common sites of
involvement since silent lesions may cause
considerable morbidity and mortality if left
untreated.
The key to appropriate management of
patients with HHT is to be alert to the
possibility of additional visceral involvement
and hence the importance of establishing a
diagnosis. This point needs to be considered by
the physician as individuals presenting with
HHT are often unaware that they have a famil-
ial disease. Current clinical diagnostic criteria
require the presence of three out of four key
features for a definitive diagnosis—namely,
spontaneous recurrent epistaxis, telangiectases
at characteristic sites, a visceral manifestation,
and an aVected first degree relative.
40
To reduce
the number of cases overlooked and deprived
of suitable screening regimes, the label of “sus-
pected HHT” should be used if two features
are present, and particularly in the presence of
PAVMs which are rare in patients without
HHT.
40
Since HHT may present to a number
of clinical specialities, the significance of a par-
ticular presentation is often overlooked.
41
CEREBROVASCULAR MALFORMATIONS AND HHT
Cerebral manifestations including tel-
angiectases, venous malformations, and arte-
riovenous malformations (CAVMs) are under-
recognised in patients with HHT. Cerebral
involvement is usually said to aVect 5–10% of
patients with HHT,
18
but a much higher
incidence is seen when asymptomatic patients
are screened.
42
The highest complication rate is observed in
high flow CAVMs which may present with
headache, epilepsy, ischaemia (due to a vascu-
lar steal eVect), or haemorrhage. Symptomatic
lesions may be treated by microsurgical exci-
Table 1 Clinical features of HHT
Site Incidence Type of lesion Presentation pattern Treatment regimes
Nasal mucosa >90% Telangiectasia Nose bleeds are usually the first
manifestation of HHT, frequently
commencing in childhood
1) Routine therapy: packing,
humidification, treatment with iron and
transfusions when needed.
Oestrogen/progesterone therapy
proposed (in view of possible induction
of squamous metaplasia) but no benefit
in only controlled trial.
15
2) Laser
treatment successful. Argon and KTP
lasers which use wavelengths maximally
absorbed by haemoglobin
16 17
often
preferred to Nd-YAG
18
which carries a
higher risk of cartilage absorption and
septal perforation. 3) Surgery, such as
septal dermoplasty to replace thin nasal
mucosa with a tougher skin graft, is
successful in expert hands,
19
though
vessels regrow. 4) Other. Therapeutic
embolisation may be diYcult because
of extensive anastomoses; cauterisation
has only a limited role.
17
Mucocutaneous 50–80% Telangiectasia Increase with age. Main concerns are
cosmetic. May haemorrhage
Generally not indicated, but argon laser
therapy can be used
17
Gastrointestinal tract 11–40% Telangiectasia, aneurysms and
AVMs
20
Onset generally over 30 years: iron
deficiency anaemia, occasionally acute
gastrointestinal haemorrhage
Iron supplementation and transfusion
are the mainstay of treatment.
Oestrogen-progesterone,
21
and laser
therapy
22
beneficial. The role of
antifibrinolytics is unclear.
23–25
Pulmonar y >20% Discussed in text.
Cerebral 15% Discussed in text.
Hepatic 8–16% Dilated sinusoids and peri-portal
veins; AVMs including hepatic
artery-hepatic vein and portal
vein-hepatic vein communications.
Associated fibrosis
26
Usually silent. Hepatic artery-hepatic
vein AVMs: hyperdynamic circulation.
27
Portasystemic shunts: ascites
28
and
encephalopathy
29
Diagnosis: angiography, CT, MRI or
Doppler sonography.
30
Treatment:
embolisation
27
but not without risk
31 32
;
liver transplantation may be needed
33
Conjunctival Up to 45% Telangiectasia Usually silent. May have “bloody
tears”
34 35
AVM = arteriovenous malformation.
Other sites involved more rarely include spinal, renal,
36
coronar y,
37
bony,
38
urogenital, splenic,
30
and retinal
39
vascular beds.
Incidence data are derived from references 1, 2, and 8 except where stated.
Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations 715

sion, stereotactic radiotherapy for lesions less
than 3 cm in diameter, and embolisation.
12
There are no tr ials comparing embolisation
with other forms of treatment but a recent
review suggests that patients oVered stereotac-
tic radiotherapy fared less well in terms of
immediate mortality, obliteration of the lesion,
and post-intervention neurological deficits
than patients treated by microsurgery.
43
There has been considerable debate about
the optimal therapy for asymptomatic CAVMs.
The natural history of HHT associated
CAVMs is not entirely clear though it is usually
assumed to be equivalent to non-HHT
CAVMs. A risk of haemorrhage of 2% per
annum, varying with certain features of the
lesion,
44 45
is generally used as the basis of care-
ful risk-benefit analyses. These analyses sug-
gest that in asymptomatic patients the risks of
haemorrhage with expectant treatment out-
weigh the risks of intervention, particularly in
young patients.
46
However, the risk assessment
for individual patients must consider the
patient’s age, specific features of the lesion, and
particularly the available therapeutic
expertise.
246
Since intervention may be recommended for
asymptomatic patients, some centres oVer
screening programmes for families with HHT
using intravenous digital subtraction angio-
graphy (DSA).
247
This avoids the morbidity
from conventional cerebral angiography al-
though the limitations of this relatively non-
invasive technique have to be recognised.
Pulmonary arteriovenous malformations
and HHT
OVERVIEW
More than 20% of patients with HHT develop
pulmonary arteriovenous malformations
(PAVMs) which range from diVuse tel-
angiectases (fig 1B)
48–50
to large complex struc-
tures consisting of a bulbous aneurysmal sac
between dilated feeding arteries and draining
veins (fig 2).
51
Around 95% of feeding arteries
come from the pulmonary rather than systemic
circulation.
50
Since approximately 70% of
PAVMs occur in patients with HHT,
52–54
their
detection should prompt a thorough review of
the patient and his or her family. Multiple
lesions are particularly suggestive of an associ-
ation with HHT.
52 53 55
PAVMs tend to increase in size,
50 56 57
espe-
cially if multiple,
56
and rarely regress
spontaneously.
57
The mortality rate in histori-
cal reviews of untreated but usually sympto-
matic patients with PAVMs over periods of 15
years or less ranges from 4% to 22%
52 55 56 58 59
and, in severe cases, up to 40%.
60
Complica-
tions are more common when HHT is
present.
61
The abnormal vessels may bleed into
a bronchus or the pleural cavity, sometimes
with a fatal outcome.
60 62 63
However, it is the
functional consequences of the direct commu-
nications between pulmonary and systemic cir-
culations, bypassing the capillary bed, that
most commonly cause problems. Such right-
to-left shunts cause hypoxaemia and the
absence of a filtering capillary bed allows para-
doxical embolism of particulate matter which
can reach the systemic arteries, causing clinical
sequelae, particularly in the cerebral circula-
tion.
These processes account for the clinical fea-
tures on presentation (table 2). It should be
noted that dyspnoea was common (47%),
though many patients tolerate hypoxaemia—
even exercise aggravated hypoxaemia—well,
reflecting their low pulmonary vascular resist-
ance and ability to generate supranormal
cardiac outputs
64–66
which may increase further
on exercise.
67
Haemoptysis was seen in 11%.
Up to 50% of patients had no respiratory com-
plaints on presentation despite physical signs
(such as cyanosis, clubbing, or a vascular bruit)
or an abnormal chest radiograph. Most impor-
tantly, many patients had minimal respiratory
symptoms when presenting with neurolog ical
complications of PAVMs (transient ischaemic
attacks, strokes and cerebral abscesses).
52 55
PAVMs accounted for two thirds of HHT-
related neurological presentations in one
series
68
and they carry a significant mortality.
69
It is recommended that patients with PAVMs
should receive antibiotic prophylaxis prior to
dental and surgical interventions to reduce
embolic abscesses,
83−85
although there is no
direct evidence of benefit. Formal treatment of
PAVMs by periangiographic embolisation
techniques or surgery is required to alter radi-
cally the long term prognosis for patients with
PAVMs.
DIAGNOSIS OF PAVM
Pulmonary angiography is required for thera-
peutic embolisation and is also mandatory to
determine the position and structure of abnor-
mal vascular lesions prior to surgical treatment.
Angiography is labour, cost and radiation
intensive and its use should be limited to indi-
viduals in whom non-invasive diagnostic tests
strongly suggest the presence of PAVMs. The
methods used depend upon local experience
but several recently published studies are worth
reviewing.
Initial investigations
Chest radiographs—Moderate sized PAVMs
appear as rounded, well circumscribed lesions
(fig 2), often with associated band shaped
shadows resulting from dilated feeding and
draining vessels. The intensity of shadowing
may be diminished or enhanced respectively by
the Valsalva and Muller manoeuvres.
86
Patients
with PAVMs often present with an abnormality
on the chest radiograph,
55 57
and this may have
led to an overestimate of the frequency of
radiographic abnormalities at presentation; it is
now recognised that a normal posterior-
anterior and lateral chest radiograph does not
rule out PAVMs (table 3),
42 56 87
particularly in
patients with small or diVuse malformations.
Assessment of hypoxaemia—Unexplained and
often profound hypoxaemia is the hallmark of
large PAVMs, but there are additional features
that may help to establish more specific
diagnostic tests. Further desaturation on as-
suming the upright posture, orthodeoxia, is
common in patients with PAVMs,
91
due prima-
716 Shovlin, Letarte

rily to a gravity induced increase in flow
through basally situated shunts (approximately
70% of PAVMs),
50 52 53 58 71 75
which increases
the right-to-left shunt.
92
Data on the eVect of
exercise on shunt flow and hypoxaemia are
contradictory.
73 93
The detection of hypoxaemia lacks specifi-
city as a diagnostic test (table 3)
42
butitcan
identify patients worthy of further investiga-
tion. In 66 patients who had undergone
embolisation, the presence and extent of
residual PAVM disease was related to oxygen
saturation (despite the imprecision of pulse
oximetry
94 95
) with the patients erect and supine
and on maximal exercise, and to the change in
oxygen saturation between being erect and
Figure 2 A PAVM from diagnosis to treatment. A 42 year old woman presented with lethargy and a history of previous
nose bleeds. A chest radiograph (A) and CT scan (B) suggested the presence of a PAVM. She was marginally hypoxaemic
(Pa
O
2
11.4 kPa on air) with no orthodeoxia. Her right-to-left shunt measured by 100% oxygen was 6–8%. Angiography
confirmed a single lesion in the right mid zone (C). Selective angiography (D) revealed a complex structure with three
feeding arteries and a single draining vein. The feeding vessels were embolised with five metallic coils (E). Two months after
embolisation there was significant improvement in oxygenation (Pa
O
2
13.5 kPa).
Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations 717

supine.
89
Oxygen saturation with the patient
erect was the best predictor of the presence or
absence of disease, though sensitivity and spe-
cificity were again too low to recommend it as
the sole diagnostic screening test (table 3).
Confirmatory studies
Abnormal architecture—Helical CT scanning
with three-dimensional reconstructions con-
veniently identifies small, multiple lesions; it
can also identify thrombosed
88 96
and, with
contrast, recanalised structures.
77
It exposes
patients at risk of recurrent disease to a signifi-
cant dose of radiation, and misdiagnoses have
been reported.
97
At present NMR screening is
less eVective than computed tomographic
(CT) scanning or pulmonary angiog raphy as
small PAVMs with rapid blood flow are not
visualised,
98
but methodology is improving.
Intravenous digital subtraction angiography
(DSA) of pulmonary arteries is performed
prior to formal catheter pulmonary ang io-
graphy in some centres to visualise the pulmo-
nary vasculature, particularly as part of an out-
patient screening programme.
42
However, this
method is less likely to detect certain lesions
than formal angiographic studies.
42
Detection of right-to-left shunts—In normal indi-
viduals the right-to-left shunt is less than 2% of
the cardiac output
99 100
and ascribed to “post-
pulmonary” shunting due to the mixing of pul-
monary venous blood with deoxygenated blood
from bronchial, mediastinal, and thebesian
veins. The flow through right-to-left shunts is
usually expressed as a fraction of total flow
(Q~ s/Q~ T) and may be calculated from the
reduction in arterial oxygenation or by ana-
tomical methods using particles 7–11 mm in
diameter which normally impact in pulmonary
capillaries but pass through large calibre shunt
vessels.
100% inspired oxygen breathing method:
Calculating the shunt from the arterial oxygen
tension after breathing 100% oxygen for 20
minutes has been considered the gold standard
for non-invasive methods of estimating the size
of the shunt.
99
EVects of ventilation-perfusion
inequalities should be overcome since blood
derived from poorly ventilated alveoli will be
fully saturated, though it should be noted that
this method will also detect post-pulmonary
shunting. The anatomical intrapulmonary
shunt may be underestimated if microscopic
arteriovenous malformations are participating
in gas exchange,
101
although such shunts may
not be treatable. Disadvantages include the
requirements for a mask and bag to give 100%
oxygen, arterial blood gas sampling and
diYculties in calibrating the oxygen electrode
for high oxygen tensions using blood tono-
Table 2 Symptoms and signs of PAVMs at presentation in major series. Many patients will have symptoms, stigmata or a family history of HHT
Incidence
(%)
Mean
(%) No. of patients References Comments
Respiratory
Dyspnoea on exertion 27–71 47 427 52, 53, 55, 56™, 57, 70, 71*, 72–76™, 77
Chest pain 6–17 12 132 52, 70, 73
Haemoptysis 4–18 11 413 52, 53, 55, 56™, 57, 59, 70, 71*, 74–76™,
78
Particularly if systemic rather than
pulmonary arterial supply
79 80
Haemothorax 0–2 <1 129 53, 74, 76™ Probably increased in pregnancy
62 63 81
Asymptomatic 25–58 49 197 52, 56™, 71*, 72–74, 76™, 82
Cyanosis 9–73 30 209 52, 56™, 71*, 72, 74, 76™, 82
Clubbing 6–68 36 201 52, 55, 56™, 57, 73, 74, 76™,
Bruit 25–58 49 197 52, 55, 56™, 70, 73, 82
Neurological
Cerebral abscesses 0–25 9 302 52, 53, 58, 71*, 74–76™, 77
Clinical TIA/stroke 11–55 24 335 52–54, 70, 71*, 73–76™, 77 Asymptomatic incidence possibly double
78
Migraine 4–38 28 150 53, 74, 75
TIA = transient ischaemic attack.
™: The 32 cases reported in reference 76 and 27 cases in reference 56 include a high proportion of individuals diagnosed by screening of asymptomatic HHT family
members; *indicates a childhood series of 31 patients.
71
In view of overlapping series, data from reference 59 were not presented as all cases were reported in refer-
ence 52, and data in reference 82 were reported only where not stated in reference 75.
Table 3 Comparison of findings from diVerent methods used to detect PAVMs
Patient population
Sensitivity Specificity
No. of PAVMs
missed compared
with angiography
No. where PAVMs not
detected at
angiography ReferenceTotal
PAVM
present
No
PAVM Unknown
Radiology
Chest radiography 98 12 84 2 83% (52–98) 92% (84–97) 2 (2% of pts) 7 (7% of pts)† 42
CT scans 40™ 40 0 0 2/109 PAVMs
(2%)
42/109 PAVMs
(39%)
88
Hypoxaemia
Pa
O
2
98 12 84 2 67% (35–90) 61% (50–71) 4 (4% of pts) 33 (34% of pts)† 42
Sa
O
2
erect <96% 66 66 0 0 73% 35% 0* 89
R-L shunts
100% oxygen
shunt >5% 37 8 28 1 88% (47–100) 72% (51–87) 1 (2.7% of pts) 8/15 (53% of pts)† 42
Contrast
echocardiography
21 15 6 0 6 (28% of pts) 90
99m
Tc scan
shunt >5% 66 66 0 0 68% 72% 0* 89
shunt >3.5% 66 66 0 0 87% 61% 0* 89
Pa
O
2
= arterial oxygen tension; SaO
2
= arterial oxygen saturation.
*Method of patient ascertainment in reference 89.
†The ang iographic data were obtained by intravenous rather than pulmonary artery catheter DSA: the number of “overdiagnosed” PAVMs may therefore include some
PAVMs missed by this less sensitive angiog raphic method. Data obtained from HHT family screening programmes
42 90
or known PAVM patients.
88 89
718 Shovlin, Letarte

metry or commercially available sealed buVer
solutions. In the absence of right heart
catheterisation mixed venous oxygen content is
usually estimated. The normal arteriovenous
oxygen content (A–V
O
2
)diVerence is 5 ml/
100 ml. Recognising that patients with an A–V
shunt are likely to have an increased cardiac
output, and that a lower A–V
O
2
diVerence of
3.5/100 ml may be more appropriate for this
situation, some centres calculate the shunt for
both normal and high cardiac outputs (using
A–V
O
2
diVerences of 5 ml/100 ml and 3.5/
100 ml, respectively), with the final shunt frac-
tion given as a range between the two values (as
in fig 2). Using 100% inspired oxygen, a right-
to-left shunt of more than 5% is considered
abnormal.
Radionuclide scanning: following intra-
venous injection of technetium-99m (
99m
Tc)-
labelled albumin microspheres or macroaggre-
gates, the right-to-left shunt can be calculated
by comparing the quantity reaching the
systemic circulation with the total quantity
received.
102 103
Shunts of up to 3.5% are
detected in normal subjects.
102
Recent data
from one institution with extensive experience
using this method indicated that, in patients
who had undergone embolisation of PAVMs, a
shunt measurement of >3.5% had 87%
sensitivity and 61% specificity for the presence
of residual disease.
89
However, suitable facili-
ties are not always available.
Contrast echocardiography can be used to
assess the presence of right-to-left shunting,
although currently the shunt cannot be quanti-
fied by this method. Microbubbles generated
by intravenously injected echocontrast should
be lost on passage through the normal pulmo-
nary capillary bed; the appearance of echoes in
the left ventricle indicates the presence of a
right-to-left shunt, a delay of 2–5 seconds indi-
cating an intrapulmonary shunt rather than an
intracardiac shunt in which left ventricular
echoes appear almost instantly.
104
Contrast
echocardiography may be too sensitive for
clinical use, however (see below).
Comparisons of non-invasive screening procedures
and correlation with angiographic confirmation of
PAVMs
Non-invasive methods have rarely been com-
pared, although an excellent correlation was
obtained for right-to-left shunt measurements
obtained by the 100% inspired oxygen and
radioisotope methods in one centre,
103
and
between 100% oxygen and the multiple inert
gas elimination technique (MIGET) in an-
other, though only when right heart catheter
data allowed appropriately high mixed venous
oxygen content values to be used in the shunt
equation for 100% oxygen.
65
Contrast echo-
cardiography was more sensitive than measure-
ment of arterial blood gas tensions and chest
radiography.
105
Indirect comparisons between
PAVM screens in neighbouring European
HHT populations indicate that contrast echo-
cardiography is also more sensitive than 100%
inspired oxygen methods; contrast echocardio-
graphy generated a high diagnostic yield of
51% (many of whom did not have angiographi-
cally detectable AVMs
90
) compared with 33%
in a separate HHT population screened by
100% oxygen methods.
42
It has therefore been
suggested that contrast echocardiography may
be an excessively sensitive technique, and this
needs to be determined.
All non-invasive methods occasionally fail to
detect PAVMs which are subsequently diag-
nosed by angiography (see table 3). More
commonly the inverse is seen; an abnormally
high shunt is detected by non-invasive methods
but no shunt is seen at formal pulmonary
artery catheter angiography. Nearly 40% of a
total of 109 PAVMs identified by CT scanning
were not detected at angiography
88
and an
abnormal transfer factor for carbon monoxide
(T
LCO), observed in a proportion of patients
with PAVMs, often persists following appar-
ently successful embolisation therapy.
73 75
It is
presumed that lesions missed by formal
pulmonary angiography (or responsible for the
reduced transfer factors) were too small for
detection (as in fig 1B) and will not be amena-
ble to embolisation. When widespread they
cause profound hypoxaemia,
7484954
but the
clinical significance of smaller numbers of such
PAVMs is unknown.
Conclusions and recommendations
Patients considered at risk of PAVMs because
of suspicious symptoms, signs or radiological
appearances should be investigated with at
least measurement of arterial blood gas ten-
sions and/or supine and erect oximetry, to-
gether with posterior-anterior and lateral chest
radiographs. If there is still concern, at least
one non-invasive method to assess the presence
of PAVMs or degree of right-to-left shunting
should be undertaken before formal pulmo-
nary angiography is warranted; the choice of
procedure is still likely to depend upon local
experience. Shunt measurements are likely to
be performed by 100% oxygen methods in res-
piratory units, nucleotide scanning in centres
where facilities are available, and elsewhere by
contrast echocardiography noting that this
technique is likely to overestimate the number
of patients with treatable lesions. When a shunt
is detected but pulmonary angiography proves
negative, the possibility of intracardiac shunt-
ing may need to be excluded by echocardio-
graphy.
Screening programmes to detect PAVMs in
patients with HHT deserve separate considera-
tion as these will often take place outside a
hospital and can involve a large number of
individuals. There is continuing debate regard-
ing which screening methods should be used. It
may therefore be worth selecting robust, easy
to perform techniques. For example, the use of
initial oximetry avoids the discomfort of
arterial blood gas sampling and may be
justified, particularly in children. The optimal
screening intervals are unknown. Current
recommendations to screen every 5–10
years,
1 106
or more frequently if the patient is
approaching a period known to be associated
with PAVM enlargement and rupture such as
puberty
2 107
or pregnancy,
163
are rarely
achieved. Lesions can develop over 2–3 years
76
Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations 719

so even these regimes may be insuYciently fre-
quent. The risks of PAVMs increase during
pregnancy so it is particularly important to
screen prior to or, if necessary, during
pregnancy
62 63
since safe embolisation proce-
dures can be carried out even in the third
trimester,
62
but it should be noted that desatu-
ration due to right-to-left shunting may be
masked by physiological factors during
pregnancy.
108
Although some authors have sug-
gested that screening for PAVMs can be limited
to individuals with particular genotypes,
1
the
current genetic data do not allow the risk of
PAVMs to be confidently excluded and suggest
that all HHT families should be oVered
screening
106 109
(see below).
TREATMENT OF PAVMS
Surgical resection was the only treatment
available for PAVMs until recently and it
caused significant morbidity.
50 71
The advent of
pulmonary artery embolisation
110 111
altered the
risk-benefit ratio of intervention markedly and
coincided with a wider recognition of the risks
of leaving asymptomatic PAVMs untreated
(although such concerns were first raised
nearly 50 years ago
86
). The hazards of interven-
tion relate predominantly to the procedure,
though removal of a low resistance shunt may
rarely aggravate coincidental pre-existing pul-
monary hypertension resulting from non-
HHT pulmonary vascular pathogenic
events.
73 76 112 113
Embolisation
The embolisation techniques used to occlude
the feeding vessels to PAVMs with thrombus
are described elsewhere.
73 82 114–116
The throm-
bus organises on thrombogenic fibres associ-
ated with carefully positioned metallic coils, or
as a result of blood stasis due to an occluding
balloon. In one CT scan follow up series 96%
of PAVMs regressed including 57% within four
weeks of embolisation.
88
The coil or balloon
needs to be small enough to be sited distally to
prevent occlusion of a feeder vessel which also
supplies a normal capillary bed, but not too
small to r isk systemic embolisation through the
PAVM
82 115
or the development of collateral
flow between the bronchial artery and distal
pulmonary artery resulting in recanalisation of
the PAVM.
77
As a result, detachable coils and
balloons have been developed. The choice of
specific agent to initiate thrombus formation is
a result of personal preference and experience
of the operator. Balloons may be better for
more distal placement
77 115
but they carry the
risk of deflation prior to permanent occlusion
of the vessel.
74 76 117
Embolisation of PAVMs is generally safe (see
table 4) and both safety and eYcacy improve
with experience
75 78 116
as illustrated by the
reduction in episodes of air embolism causing
transient angina over recent years. All reports
document dramatic improvements in the
physiological extent of the shunt (table 4).
65
Exercise capacity may improve even in patients
who had not developed hypoxaemia on
exertion.
73
Lung volumes are generally pre-
served and there may be improved forced vital
capacity if PAVMs had been acting as space
occupying lesions.
93
The reduction in TLCO
often does not improve,
73 75
presumably be-
cause it reflects the involvement of smaller ves-
sels. Once embolised, the feeding artery to the
PAVM usually remains occluded according to
most series. A particular result in a recent series
with a surprisingly high rate of recanalisation
(and unusually half of the new feeder arteries
being of bronchial artery supply
77
)mayhave
been due to technical issues, alternative
diagnostic methods, or a diVerent patient
population. However, it is well recognised that
removal of a low resistance shunt may unmask
or provoke the development of new PAVMs or
new pulmonary artery feeder vessels to the
treated lesion. As a result, a series of treatments
several months apart may be required, and it is
generally recommended that patients should
remain under regular review.
75 76 78
Unfortunately, the firm clinical impression
of a reduction in the occurrence of cerebral
events following embolisation therapy has not
yet been supported by adequate numerical
data. Between 19% and 60% of patients with
PAVMs treated by embolisation have residual
shunts as measured directly or suggested by
persistent hypoxaemia,
75 76 78 89
the figure rising
to 73% when contrast echocardiography was
used.
87
Cerebrovascular complications have
occurred in treated patients, including one cer-
ebral abscess in the Hammersmith series,
75
and
two cerebrovascular accidents occurred
amongst the seven patients with persistent
PAVMs in the “large PAVM” Baltimore/Yale
series (45 patients were initially treated).
78
Embolisation of progressively smaller vessels
has been adopted to reduce these risks, though
technical issues limit the feasibility of embolisa-
tion, particularly with smaller vessels and
diVuse disease.
Surgery
Surgical procedures have largely been sup-
planted by the embolisation techniques de-
scribed above.
119
In addition to the peri-
operative risks, there were concerns regarding
loss of functioning lung in patients at risk of
recurrent disease in non-resected lobes. Some
reports demonstrated improved haemodynam-
ics and oxygenation
66
following surgery but
physiological studies showed significant re-
sidual right-to-left shunts in many patients
(table 4).
Surgical intervention may be appropriate in
some situations since morbidity has been
reduced with improved surgical techniques
including the use of video assisted
thoracoscopy
120
which is helped by the subpleu-
ral location of many PAVMs.
50
A strong case for
surgical intervention by choice was proposed
relatively recently
74
based on poor embolisation
data from a single institution, but the findings
in this series are not representative of the
results elsewhere.
78
Surgical resection might be
indicated for patients in whom a persistent
right-to-left shunt (and embolic risk) persists
following embolisation of all feasible vessels.
88
Lung transplantation has been proposed for
patients with diVuse disease,
54
though for most
720 Shovlin, Letarte

patients the untreated prognosis is unlikely to
justify exposure to transplantation associated
morbidity.
Conclusions and perspective
Retrospective series of patients with PAVMs
that are generally symptomatic indicate that
the risks associated with non-treatment
52 55 59
exceed those of any interventional regime
(table 4). The overwhelming benefit of emboli-
sation therapy compared with surgical resec-
tion is that it spares functioning lung in patients
who are at risk of developing new lesions.
Nevertheless, it is important to determine
whether embolisation is able to prevent para-
doxical emboli as satisfactorily as complete
surgical excision in individuals where this
would have been feasible. Further long term
follow up data are required for all treated
patients, probably stratified according to the
degree of residual shunt, and distinguishing
between individuals with and without HHT
(the development of new PAVMs is less likely
in the latter group).
Embolisation is currently recommended for
all PAVMs with feeding arteries greater than
3 mm in diameter.
54 76 121
This is based on tech-
nical issues and the diameter s of feeding arter-
ies associated with clinical strokes which in
four patients ranged from 2.9 mm to
4.6 mm.
121
Some centres routinely treat feeding
vessels between 2 mm and 3 mm in
diameter.
116
While feeding vessels of larger calibre will
obviously pose the highest risk of embolic
events, it has not been established that smaller
vessels pose no risk. Such vessels would include
those in angiography negative, shunt positive
patients, particularly those detected by contrast
echocardiography, and may concern a large
proportion of patients with PAVMs as 13 of 31
feeding arteries were less than 3 mm in
diameter in one survey of CT scans.
96
It will be
important to follow the clinical progress of
these and equivalent cohorts to assess whether
the screening methods are too sensitive for
clinical use, or are defining a group of patients
in whom particularly rigorous follow up is
indicated. At present it seems reasonable to
extend the recommendations for prophylactic
antibiotic therapy from all patients in whom
PAVMs are suspected to include patients in
whom PAVMs have been treated, unless careful
post-embolisation investigations indicate that
the residual shunts have been abolished.
In view of the number of situations in which
there is a lack of good longitudinal data on the
outcome of patients with HHT, it is hoped that
current national and international collabora-
tive eVorts will be extended to include such
studies with agreed protocols, particularly in
the areas highlighted in this section.
Current understandings of mechanisms
The identification of mutations in two genes
which encode components of the receptor
complexes for ligands of the TGF-â super-
family indicates a role for these growth factors
in HHT. In this section we present the
Table 4 Treatment of PAVM in diVerent series of patients. Series completion dates are given as the year of publication if not specified
Series years (reference)
No of
patients
No of
PAVMS Mortality
Complications
Mean
R-L shunt
pre-post Rx
Residual
R-L shunt
Follow up
(years)
Complications
during follow upPleurisy
Paradoxical
embolism
Balloon
deflation Other
Embolisation
Baltimore-Yale series
1978–1980 (118) 5 16 0 15% 15% 15% — — — <2 40% recur
pre 1983 (72) 10 58 0 20% — several 10% ang 44 to 24% — — —
1978–1987 (53) 76 276 0 10% 3% 0% 5% ang — — — —
1991–1992 (117) 35 96 0 7% 1% 6% 6% ang — — 1–10 1.3% recur
1978–1995 (78)† 45 52 0 31% 4% — 2% ang — 53%Ä — 15% recur,
4% CVA
Hammersmith series
1984–1990 (82) 16 79 0 13% — — 1DVT 28 to 13% — — —
1990–1995 (114) 6 28 0 7% 0% — 1DVT — — — 12% recur
1987–1994 (75) 53 >200 0 9% 2% 3% 3% ang 23 to 9% 60%© <4 2% cerebral
abscess
Other series
pre 1991 (116) 19 58 0 26% 2% — nil — — 10% recur
1986–1991 (73) 8 22 0 25% 0% — 12%
arryth
25 to 13% 100% <2 —
1990–1995 (76) 32 92 0 9% 4% 2% 2% arryth 17 to 7% 19%® mean 2 6% recur
1989–1994 (77) 12 20 0 36% — — nil — 73%™ — —
1994–1998 (87) 7 14 0 — — — — — — 57% recur
Surgery
1897–1953 (58) 140 — 5% — — 1 out of 3 recur
1952–1967 (56) 16 — — — 1–15 —
pre 1958 (50) 239 212 5% Minimal data reported — — prog SOB
pre 1963 (71)* 31 40 3% 1 out of 3 — —
1964–1992 (74) ? 12 0 1 out of 1 — —
Mayo Clinic
1952–1966 (59) 28 — 0 — 1–12 1 prog SOB,
1CVA
1952–1972 (52) 36 — 0 3 out of 3 1–12 4 prog SOB,
1CVA
1973–1984 (55) 18 — 0 5 out of 10 1–12 —
DVT = deep venous thrombosis; ang = angina; arryth = arrhythmia; recur = recurrence; prog = progressive; SOB = shortness of breath; CVA = cerebrovascular acci-
dent.
*Childhood series.
†All lesions had feeding artery diameters of 8 mm or more.
Mean values for R-L shunt stated; residual shunt measured or indicated by ©
99m
Tc scanning, ®100% inspired oxygen, ™contrast echocardiography and Äpersistent
hypoxaemia as defined in reference 42.
Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations 721

currently available data that are directing
future research into the understanding of the
pathogenesis of this vascular disease. There
remain considerable gaps in the mechanistic
links between genomic mutations and the gen-
eration of the diseased blood vessels.
There are good clinical as well as scientific
reasons for pursuing the study of the underly-
ing molecular defects in HHT. Performing
mutation analysis of endoglin (HHT1) and
ALK-1 (HHT2) on a large number of patients
should indicate whether specific mutations are
related to particular phenotypes or complica-
tions, and further advance our understanding
of the structure and function of these proteins
and their contribution to the pathology of
HHT. A molecular diagnostic test is currently
under development and, once such a test is
shown to be reliable, it will facilitate the identi-
fication of patients with HHT and the classifi-
cation of families.
MOLECULAR GENETICS OF HHT
Linkage studies first identified a locus for HHT
on chromosome 9
122 123
and suggested that a
further gene existed.
122
Additional families
were used to map a second HHT locus to
chromosome 12
124 125
and it is likely that there is
at least one more locus.
126
A locus on 3p22 was
suggested
4
but was subsequently shown not to
be the case.
125
The mutated genes were identi-
fied as endoglin on chromosome 9
4
and ALK-1
on chromosome 12.
5
Endoglin (HHT1)
The gene for endoglin lies on the long arm of
chromosome 9 in the interval predicted by
linkage analyses. A number of mutations have
now been characterised and are summarised in
fig 3.
4 109 127–130
The mutations include deletions
and insertions, missense mutations, and point
mutations generating premature stop codons.
Additional mutations are predicted in pro-
moter or intronic regions.
109
These considera-
tions, and the fact that almost all mutations
have been unique to a particular family,
highlight the diYculties facing mutational
screening programmes.
Not all mutations result in stable mRNA
transcripts.
109 130
Mutant proteins are rarely
detectable and, if expressed at all, exist
transiently within the cell and do not reach the
cell surface (fig 3
128
and unpublished observa-
tions). This leads to a decrease in the level of
functional endoglin expressed on peripheral
blood activated monocytes and umbilical vein
endothelial cells in patients with HHT1.
128
Quantification of the level of mature endoglin
expressed using metabolic labelling and immu-
noprecipitation is being used to screen poten-
tial patients with HHT1 prior to mutation
identification (unpublished data, presented in
table 5). AVected members in 57 of 95 HHT
families tested had a mean endoglin level of
48% of normal (range 8–72%) while non-
aVected siblings in these families had a mean
level of 105% (range 73–140%). The nor mal
levels of endoglin predicted in patients with
HHT2 were confirmed in families in which
ALK-1 mutations were identified; their levels
were indistinguishable from normal individu-
als. Peripheral blood mononuclear cells (lym-
phocytes and monocytes) do not express
significant levels of endoglin when first isolated
but induction occurs if the monocyte fraction is
activated by adherence and cell culture for
16–24 hours.
128 131
Levels are, however, 5–20
times lower than on human umbilical vein
endothelial cells (HUVEC) where endoglin
expression is abundant and constitutive. This
Figure 3 Summary of endoglin mutations. Intracellular refers to detection when transfected into COS cells. FS =
frameshift; UTR = untranslated region; Ä indicates deletion.
Exon 1
Deletions
#
1()
#
24
Insertion
Splice site
Nonsense
Missense
Type #
#1
Deletion
Exon
Introns I–II
DNA
>250 bp
cDNA
Exon 2 skip,
Protein Mutant protein
Intracellullar
Not detected
Intracellular
Reference
FS, truncated 109.......
#13
Insertion 8 +G 1111 FS at 371, truncated 127,128
#14
Splice site Intron III a to g Exon 3 skip 109.......
#2
521bp∆576–596 ∆193/199 109.......
#3
739bp∆882–920 ∆295/307 4.......
#4
Introns VII–VIII 1.5 kb Exon 8 skip ∆332/378
∆74/120
#19
Nonsense 4 C512T, no cDNA detected 109.......
Absent
#24
Missense 1 (ATG codon) T2C 130.......
Absent
#25
2 G155T 130.......
Gly52Val
#26
2 T157C 130.......
Cys53Arg
#27
4 G447C 130.......
Trp149Cys
#28
4 C479A 129.......
Ala160Asp
#29
7 T917C 130.......
Leu306Pro
#15
Intron III g to a Exon 3 skip 128
∆74/120, 70 kDa mutant*
Intracellular
#21
7 C831G 4,128
∆276 (truncated)
Not detected
#22
8 T1050A 127,128
∆349 (truncated)
Not detected
#23
10 C1414T 127,128
∆471 (truncated)
#16
Intron IV a to g Not stated 130..............
#17
Intron VIII g to a ∆1111–1134 109.......
∆371/378
#20
5 G587A 127.......
∆195 (truncated)
#18
9B G1311C, intron 9B retained 130.......
FS at 437, truncated
109.......
#5
84bp∆1078–1081, FS at 360, truncated 130.......
#6
Intron VIII–3 UTR
'
>4 kp No cDNA detected Absent 109.......
#7
9A 1 bp ∆G1206 FS at 402, truncated
FS at 423, truncated
FS at 478, truncated
FS at 517, truncated
FS at 518, truncated
FS at 552, truncated
130.......
#8
9A 1 bp ∆A1267 130.......
#9
11 2 bp ∆AG1432–1433 130.......
#10
11 2 bp ∆TG1550–1551 127.......
#11
11 2 bp ∆GC1553–1554 4,128
#12
11 1 bp
1bp
∆C1655 127.......
#
4
#
2
#
3
#
5
#
13
()
#
6()
2356789A 9B 1210 13 14114
#
27
#
19
#
16
#
17
#
18
#
20
#
21
#
28
#
29
#
23
#
22
#
25
#
26
#
14
#
15
#
7
#
8
#
9
#
10
#
11
#
12
722 Shovlin, Letarte

explains the smaller range of values observed
for HUVEC from patients with HHT1 (26–
61%) and HHT2 or normal neonates (83–
128%) than for the activated monocytes (table
5).
These data also indicate that endoglin muta-
tions are not aVecting the normal allele,
contrary to a previous proposal that the muta-
tions were behaving as dominant negative
alleles.
127
We have also shown that vessels that
appear to be nor mal in patients with HHT1
express reduced levels of endoglin in situ
(50%) compared with values seen in normal
individuals and when compared with the
endothelial cell marker PECAM-1.
132
The next mechanistic question is whether
the development of an arteriovenous malfor-
mation requires a “second hit” to inactivate the
normal copy of endoglin, analogous to the
situation proposed for tumour suppressor
genes.
4
This appears not to be the case as the
ratio of endoglin to PECAM-1 was similar in
the vascular lesions (cerebral and pulmonary
AVMs) as in the other vessels in these
patients.
132
This suggests that the endoglin
mutations are operating as null alleles causing
haploinsuYciency.
ALK-1 (HHT2)
The HHT gene on chromosome 12 encodes a
receptor for the TGF-â superfamily, the activin
receptor-like kinase 1 (ALK-1; also known as
TSR1).
5
The mutations described in this gene
are found in sequences encoding the extracel-
lular, transmembrane, and kinase domains (fig
4).
5 133 134
Their distribution, and the fact that
some mutant alleles appeared to result in low
to undetectable levels of transcript, indicate
that this group of mutations may also result in
functionally null alleles.
133
GENOTYPE-PHENOTYPE CORRELATIONS
Locus heterogeneity: diVerences between endoglin
and ALK-1 families
Prior to the molecular studies the fact that
HHT was a heterogeneous disorder had not
been fully appreciated. Occasional familial
clustering of cerebral
135 136
and pulmonary
119
involvement had been described but it was not
clear whether this represented chance occur-
rences in a disease in which only some
members of an aVected family developed any
particular complication.
Even before mutations in endoglin on chro-
mosome 9 and ALK-1 on chromosome 12 were
Table 5 Analysis of endoglin levels in HHT families in relation to mutations detected
Endoglin level
Cases
tested Predicted outcome
Mutations detected
Mean Range Endoglin ALK-1
Non-aVected siblings 105% 73–140% 36 Normal 0 0
Clinically diagnosed HHT patients
Group A 48% 8–72% 92 HHT1 19 0
Group B 101% 72–137% 38 Non-HHT1 0 3
Newborns from HHT families
Group A 47% 26–61% 15 HHT1 9 0
Group B 99% 83–128% 38 Normal (if HHT1 family, n = 19) 5* 0
Normal or HHT2 (if non-HHT1
family, n = 19)
02
*Mutation present in aVected parent and absent from newborn.
Endoglin levels were measured on peripheral blood activated monocytes in patients and siblings and umbilical vein endothelial cells
in neonates by metabolic labelling and immunoprecipitation. Levels are expressed relative to controls (spouses or age matched
unrelated blood or umbilical cord samples) and, in the HHT family members, fell into two distinct groups as illustrated.
Figure 4 Overview of ALK-1 mutations. Ä indicates deletion.
Exon 1
Deletion
Insertion
Nonsense
Missense
Type #
#1 4 Transmembrane
Deletions
Exon cDNA
∆G400 (1 bp)
ProteinProtein region Reference
Truncated 134
#2 4 Transmembrane
∆G406–409 (4 bp) Truncated 134
#3 6 Intracellular; ATP binding site
∆694–696 (3 bp) ∆Ser 5
#4 3 Extracellular domain
140 (1 bp) Truncated 134
#5 7 Intracellular, kinase domain
Intracellular, kinase domain
865 (1 bp) Truncated 133
#6 4 Intracellular
Intracellular
G423A Truncated 133
#7 4
G475T Truncated 133
#8 7
C924A Truncated 133
#9 3 Extracellular
Extracellular
Extracellular
Extracellular
Extracellular
G150T 133
#10 3
G152A Cys Tyr 134
#11 3
G200A 133
#12 3
C231G 134
#13 3
A286G 134
#14 7
G998T 133
#15 8
Intracellular, kinase domain
Intracellular, kinase domain
Intracellular, kinase domain
Intracellular, kinase domain
Intracellular, kinase domain
C1120T 133
#16 8
T1126G 5
#17 8
G1232A 5
#18 9
C1270A 133
Insertions
Missense
Nonsense
#
2
#
1
#
4
#
3
#
5
#
14
#
8
2 3 5 6 7 8 9 104
#
16
#
15
#
17
#
18
#
9
#
10
#
11
#
12
#
13
#
6
#
7
Arg Gln
Arg Trp
Arg Gln
Met Arg
Pro Thr
Ser IIe
Cys Trp
Asp Asn
Trp Cys
Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations 723

described, a flurry of reports signalled that
there might be diVerences between families
according to whether they were linked to the
chromosome 9 locus or not.
137–139
Once mu-
tated genes were identified the search for
phenotype-genotype correlations intensified.
In essence, however, only two distinctions can
be made at present—namely, that PAVMs are
significantly more common in endoglin than
non-endoglin HHT families
1 140
and that
ALK-1 families tend to have milder disease
with more cases of non-penetrance.
5
PAVMs
do not occur exclusively in endoglin families,
however,
109 122
and the phenotype of endoglin
families can be mild for several generations
before an aVected family member presents with
PAVMs.
106 109
Thus, it is dangerous to apply
these population statistics to individual cases.
There are anecdotal suggestions that
CAVMs may also be more common in f amilies
with endoglin mutations but no evidence has
been published. Finally, an HHT family
unlinked to either endoglin or ALK-1 may have
a predisposition towards hepatic involve-
ment,
126
but interpretation needs to be cautious
since systematic hepatic screening of asympto-
matic family members has not been repeated in
other HHT populations.
Specific mutations
Phenotypic data are only available for 30 indi-
viduals with seven endoglin mutations (#1, 2,
4, 6, 14, 17, 19, fig 3). No significant
diVerences between mutations or mutational
types with respect to age of presentation, sever-
ity of nose bleeds, telangiectasia, or PAVMs
have been identified.
109
This would be pre-
dicted from a haploinsuYciency model. Each
mutation accounted for a spectrum of disease
severity in aVected family members not entirely
accounted for by age-related penetrance,
109
highlighting the importance of additional
modifiers of the HHT phenotype.
Genetic and environmental modifiers of the HHT
phenotype
Clinical observations provide clues to several
factors that may potentially influence the
development of HHT lesions in patients,
though undoubtedly more will be described.
Defects in the coagulation cascade which could
exacerbate a haemorrhagic tendency are often
cited and are discussed in detail elsewhere,
141
but they are rare and have not influenced clini-
cal practice. Var iations in fibrinolysis may also
contribute to a haemor rhagic tendency:
quenching excessive fibrinolysis using amino-
caproic acid had beneficial eVects in some
23 24
but not all
25
of a handful of patients tested.
Less obvious at first sight is the importance
of the patient’s sex in a condition inherited as
an autosomal dominant trait. Excluding neo-
nates, women are more at risk of developing
PAVMs
52 53 55 63 75 76
and possibly hepatic
involvement
33 142
and cerebral haemorrhage.
143
This may reflect a fundamental modification of
the HHT vasculature by female hormones, or
relate to haemodynamic changes during
pregnancy.
63
A role for direct hormonal influ-
ences is supported by the successful treatment
of HHT related gastrointestinal bleeding using
combined oestrogen-progesterone therapy,
21
a
report of progesterone receptors in vessels of
patients with HHT,
144
and variations in
epistaxis during the menstrual cycle and
menopause.
63
Haemodynamic changes can also
exacerbate PAVMs, including the development
of pulmonary hypertension as a result of mitral
stenosis
145
or left ventricular dysfunction.
146
Furthermore, cutaneous telangiectasia (known
to be in a dynamic state in HHT
147
) have been
observed to regress following successful pneu-
monectomy for PAVMs,
80 148
possibly due to a
predicted fall in cardiac output though this was
not documented.
MECHANICS: HOW TO GENERATE AN HHT
VESSEL
—THE EXAMPLE OF PAVMS
The question as to whether any of the
abnormal blood vessels in patients with HHT
(telangiectases or larger arteriovenous malfor-
mations) represent true congenital malforma-
tions rather than an acquired lesion in intrinsi-
cally abnormal vessels has not been resolved.
The majority of PAVMs present during teenage
and adult life, suggesting that vascular remod-
elling is occurring. However, the presentation
of PAVMs in childhood is well
recognised
50 52 53 55 58 59 71 75 78
and, although se-
vere disease in two infants may have been due
to homozygous HHT, the possibility of PAVMs
arising dur ing development cannot be ruled
out.
As vascular lesions are associated with both
HHT1 and HHT2, the potential role of both
endoglin and ALK-1 needs to be considered.
Both mutated genes encode proteins that are
expressed predominantly in endothelial cells,
which might explain why aVected individuals
are generally well apart from their vascular
pathology. As there is only limited information
available on ALK-1 we will discuss it first
before concentrating on endoglin and the
lesions with which it is particularly
associated—namely, PAVMs.
ALK-1: a serine/threonine kinase type I receptor
in search of a function
Members of the TGF-â superfamily bind and
signal through a heteromeric receptor complex
composed of serine/threonine kinases in which
the type II receptor generally binds ligand and
phosphorylates the type I receptor which in
turn signals through the recently identified
cascade of Smad proteins.
149 150
ALK-1 is a
serine/threonine kinase type I receptor that can
associate with either TGF-â-RII or activin-RII
when co-transfected into COS cells (a trans-
formed primate cell line), and can bind
TGF-â1 or activin, respectively, although with
low aYnity.
151–153
Since this has not been
demonstrated with endogenous receptors,
ALK-1 is referred to as an orphan receptor as
its physiological ligand has yet to be identified.
The potential ligand might belong to another
subgroup of the TGF-â superfamily—namely,
the bone morphogenetic proteins (BMPs), as
activation of ALK-1 has recently been shown
to trigger an intracellular Smad-1 pathway
associated with signalling by BMPs.
154
724 Shovlin, Letarte

High levels of ALK-1 are found on human
endothelial cells and in lung and placenta, both
of which are highly vascular.
151 152
Rat ALK-1
was found to be most abundant in pulmonary
blood vessel endothelium (all types) as well as
on aorta, vena cava, and certain blood vessels of
kidney, spleen, heart, and intestine.
155
Lung
expression increased fivefold in the early post-
natal period, most probably reflecting an
increase in the pulmonary vasculature.
155
ALK-1 was also found on rat splenic macro-
phages and a murine bone marrow stromal cell
line.
156
This distribution has many parallels to
that of endoglin. A more recent study in a
murine model found that the distribution of
ALK-1 was highest around eight days after
conception at sites of vasculogenesis in both
embryonic and extra-embryonic tissues, in
giant trophoblast cells, and in the endothelial
lining of blood vessels in the decidua. From
days 9–12 ALK-1 was highest in blood vessels,
lung mesenchyme, the submucosa of the intes-
tine and stomach, and at sites of epithelial-
mesenchymal interactions.
157
This pattern of
expression of ALK-1 is very close to that of
TGF-â1,
158
in keeping with a potential role in
vascular development which may be confirmed
in the ALK-1 null mice currently in develop-
ment.
Endoglin: an accessory protein of the TGF-â
receptor superfamily
Endoglin was first identified in childhood
leukaemia with a pre-B lymphocytic
phenotype
159
and was soon recognised as an
endothelial cell marker (CD105) which is
expressed on all types of vascular
endothelium.
160 161
It is also present on bone
marrow mononuclear cells of the pre-
erythroblast lineage
162
and on activated
macrophages.
131
The expression of endoglin is
transiently increased in mesenchymal cells
during embryonic development in association
with cardiac valve formation, for example.
163
Endoglin expression is also increased in
mesenchymal cells in the human lung starting
at eight weeks gestation and remains high at 20
weeks (unpublished observations), in keeping
with a potential role in vascularisation of lining
mesenchyme. In the adult endoglin is ex-
pressed on endothelium
160
and placenta,
164
with
smooth muscle cell expression also
described.
165
Endoglin is upregulated on vascu-
lar endothelial cells in tumours,
166
pathological
skin lesions including psoriasis, and in response
to UV irradiation.
167 168
Endoglin is a homodimeric membrane
glycoprotein of apparent Mr = 180 000
169 170
and has been shown first by chemical crosslink-
ing in HUVECs and subsequently in fibro-
blasts to bind TGF-â1 and TGF-â3 but not
TGF-â2.
170–172
It can associate with TGFâ-RII
and TGFâ-RI (ALK-5)
173 174
as indicated by
immunoprecipitation of the TGF-â1aYnity
crosslinked complexes with antibodies to either
endoglin or TGFâ-RII. However, we have
recently demonstrated that endoglin by itself
does not bind TGF-â1/â3 and therefore
cannot be referred to as a receptor; it only
behaves as such when associated with
TGFâ-RII.
175
We have also observed that endoglin can
bind other growth factors of the TGF-â super-
family when associated with the diVerent
ligand binding receptors. For example, endo-
glin can bind activin or BMP-7 when co-
transfected with activin RII; it will not bind
BMP-7 via BMP-RII, however, indicating that
these interactions are specific. It will also bind
BMP-2 when associated with the ligand
binding type I receptors, ALK-3 and ALK-6.
175
These results suggest that endoglin might serve
as an accessory protein for multiple kinase
receptor complexes of the TGF-â superfamily
and that it could perform a diVerent regulatory
role in diverse cell types, according to the
kinase receptors, ligands, and Smad mediators
present.
When transfected into U937 monocytes or
rat myoblasts, endoglin can modify certain
TGF-â1 (but not TGF-â2) responses such as
the inhibition of cell proliferation by down-
regulation of c-myc, the increase in homotypic
adhesion mediated by increased fibronectin
production, and modulation of the fibrinolytic
system by synthesis of plasminogen activator
inhibitor-1.
176 177
Conversely, antibodies and
antisense oligonucleotides to endoglin added
to first trimester trophoblast explants in culture
stimulated the diVerentiation of trophoblasts
into invasive cells, a process necessary for
establishing fetal-maternal interactions and
known to be inhibited by TGF-â1/â3.
178
Although a potential role for endoglin in
regulating responses to ligands other than
TGF-â1 must be kept in mind while trying to
elucidate the underlying mechanisms of HHT,
it is clear that TGF-â1 is an important regula-
tor of vascular development. TGF-â1 null mice
showed a primary defect in yolk sac vasculo-
genesis and haematopoiesis which led to death
at around day 10 in 50% of homozygous and
25% of heterozygous mice.
179
The diVerentia-
tion of endothelial cells was aVected (rather
than their initial appearance or outgrowth from
yolk sac mesoderm), causing inadequate capil-
lary formation and weak vessels with reduced
cellular adhesiveness. Furthermore, TGF-â3
null mice died soon after birth with extensive
pleural haemorrhage and dilated and fragile
pulmonary veins and capillaries.
180 181
This
suggests that TGF-â1 and TGF-â3 are both
implicated in the development of lung vascula-
ture and impairment of their usual function
might contribute to the pathology of PAVMs.
With this information is it possible to
propose why PAVMs develop? Endoglin is
present from the earliest stages of pulmonary
vascular development, and TGF-â1 and
TGF-â3 are implicated in vasculogenesis
180 181
and angiogenesis,
182
both processes being criti-
cal in vessel development and maturation.
183
In
patients with HHT and reduced endoglin
expression, vascular development is sufficiently
normal for most individuals to have apparently
normal pulmonary vasculature. The careful
regulation of endoglin expression (and ALK-1)
during development suggests, however, that
their complete absence could be lethal, as seen
Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations 725

in the potential homozygotes.
12 13
Current
studies in null mice should resolve this issue.
If most vessels with 50% expression of endo-
glin develop normally, what additional factors
cause some vessels to develop into PAVMs?
Certain physiological or pathological condi-
tions, including altered blood flow
184–186
and
hormonal changes, could be important. This
would provide a partial explanation for why
only a small proportion of endothelial cells
expressing a mutant allele are involved in mor-
phologically abnormal HHT vessels.
We would like to propose that reduced levels
of functional endoglin results in blood vessels
that are more susceptible to dilatation and
remodelling. We have shown that the endothe-
lium in a CAVM was partially disrupted and
stretched out so that the density of important
surface molecules was reduced.
132
In addition,
it may be recalled that TGF-â1 plays a major
role in wound repair. It is abundantly released
by platelets and macrophages at sites of
inflammation and injury,
187–189
is upregulated by
shear stress,
190
and has been implicated in vas-
cular repair processes.
191
In tissue repair as well
as in development, TGF-â1 stimulates the
growth of cells of mesenchymal origin. Fur-
thermore, TGF-â1 induces the synthesis of
extracellular matrix proteins, their integrin
receptors on the cell surface, and the protease
inhibitors implicated in their degradation such
as plasminogen activator inhibitor and tissue
inhibitor of metalloproteases; it also downregu-
lates the expression of matrix degrading
enzymes such as collagenase.
192 193
The net
eVect of TGF-â1 is thus to stimulate matrix
production and enhance interactions between
cells and matrix and between endothelium,
smooth muscle cells, and mesenchymal cells in
the vessel wall. Vasodilatation, intravascular
pressure, or shear stress can aVect endothelial
cell shape in vivo and could initiate remodel-
ling in vessels with reduced levels of endoglin.
Perspectives
The abnormal vascular structures in HHT
appear to develop because mutations in endo-
glin, ALK-1, and possibly other genes result in
a dysregulated response to ligands of the
TGF-â superfamily which play complex and
important roles in vascular development and
repair. At present we cannot pinpoint the exact
ligand(s) or manner in which normal vascular
development or homeostasis is perturbed by
these mutations. Potential ligands of the
TGF-â superfamily have diverse and often
multiple eVects that may influence the vascula-
ture, eVects which may be diVerentially regu-
lated and fine tuned according to the exact
amount of endoglin or ALK-1 present. Future
developments are likely to include the identifi-
cation of the precise TGF-â family members
involved in the disease, and of additional com-
ponents of the pathogenic pathway which may
be identified from finding mutations in new
genes in other HHT families. In addition,
clarification of the roles of normal and mutated
endoglin and ALK-1 through cellular and ani-
mal models is expected.
The identification of a gene defect in an
inherited disease leads to expectations of
molecular therapies, particularly when the
molecular mechanism appears to be stoichio-
metric insuYciency, amenable to replacement
therapy. However, there are hazards in attempt-
ing to restore functional levels of a deficient
protein in complex regulatory networks such as
those in which ligands of the TGF-â family are
involved. It may be some time therefore before
molecular manipulations of HHT can be
applied to patients and, for the foreseeable
future, conventional therapies are likely to be
required.
Claire Shovlin has b een supported by a Wellcome Trust
Advanced Fellowship; Michelle Letarte is a Tery Fox Research
Scientist of the National Institute of Canada, and is supported
by research grants from the Heart and Stroke Foundation and
the Medical Research Council of Canada.
The cases illustrated in fig 2B and fig 3 were investigated at the
Royal Infirmary of Edinburgh. The authors thank Dr David
Lamb and Professor Bill MacNee for fig 2B. For fig 3, Dr Kieran
McBride performed the angiography, Dr Patricia Tweedale the
shunt measurements, and Dr Micheal Sudlow gave permission
to report the case. The authors are grateful to Dr Patricia
Tweedale, Dr Kees Westermann, and Dr Bob White for helpful
discussions, and to Dr Gillian Wallace and Dr Patricia Tweed-
ale for manuscript review. They also thank the staV of the Ersk-
ine Medical Library, University of Edinburgh and colleagues
who provided them with manuscripts prior to their publication.
Most countries have self-help groups for patients with HHT:
UK: Telangiectasia Self-Help Group, 39 Sunny Croft,
Downley, High Wycombe, Bucks. HP13 5UQ, UK.
USA: HHT Foundation International, PO Box 8087, New
Haven, CT 06530, USA.
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