Bleeding from the gastrointestinal tract is very common and important problem in clinical practice. There are lots of causes of GI bleeding, but sometimes it is very difficult to locate and treat gastrointestinal bleeding. Here we discuss Heyde’s syndrome, an important cause of gastrointestinal bleeding in an elderly female patient who is also suffering from HCV related decompensated CLD with multiple myeloma. Heyde’s syndrome is now known to be gastrointestinal bleeding from angiodysplasic lesions due to acquired vWD-2A secondary to aortic stenosis, and the diagnosis is made by confirming the presence of those three things. For this, a wide range of investigations and treatment modalities are now available. One should therefore make an aggressive attempt to localize the bleeding site. Newer endoscopic technologies may prove beneficial. Aortic valve replacement is claimed to minimize or even stop the bleeding in such patients. But still there are a few reports showing gastrointestinal bleeding after aortic valve replacement. Old age and co-morbidities may create a hindrance in valve replacement or resection surgery. Some newer treatment options like hormonal and thalidomide therapy look promising but they have inadequate evidence behind them. Here, we discuss this clinical problem, strategies and evidence, areas of uncertainty, available guidelines, and our conclusions about Heyde’s syndrome.
Angiodysplasia is the most common vascular lesion of the gastrointestinal tract, and this condition may be asymptomatic, or it may cause gastrointestinal (GI) bleeding . The vessel walls are thin, with little or no smooth muscle, and the vessels are ectatic and thin. It is a degenerative lesion of previously healthy blood vessels found most commonly in the cecum and proximal ascending colon but bleeding from proximal intestinal angiodysplasias, and nasal bleeding is also reported [2,3]. After diverticulosis, it is the second leading cause of lower GI bleeding in patients older than 60 years. An association between colonic angiodysplasia and aortic stenosis was described by Edward C Heyde et al. . It is caused by the induction of Von Willebrand disease type IIA (vWD-2A) by a depletion of Von Willebrand factor (vWF) in blood flowing through the nARGHowed valvular stenosis. The existence of this syndrome was debated for a considerable period of time when finally it was shown that the gastrointestinal bleeding did actually resolve after aortic valve replacement in many such patients, thereby giving a definite
credence to the existence of this syndrome [2,5]. The bleeding could be severe and the patient usually requires multiple blood transfusions. We describe a case of Heyde’s syndrome with
multiple angiodysplastic lesions throughout the colon, mostly at the distal part and discuss the various challenges in the diagnosis and treatment of such patients.
Mrs. Chaina Chakraborty, 71 year old pleasant lady, known to have multiple myeloma (MULTIPLE MYELOMA-IgG Kappa Myeloma and Beta2 Microglobulin-4.2) chronic liver disease (HCV related) with Esophageal Varices (grade 2), duodenal ulcer and aortic stenosis with IHD was admitted to SHL gastroenterology department through ER with the complaints of passage of black tARGHy stool for last five days and generalized weakness for same duration. She had previous history of hospital admission for several times in the last three months with these same complaints and received 8-10 units of blood and blood products over that period. Now her hemoglobin 5 gm/dl, Haematocrit 20.9%, TC 10.5 K/uL, Platelets 40K/uL, PT, aPTT was normal. Echocardiogram shows nARGHow LVOT with Dynamic subvalvular Aortic Stenosis Gr 78/28mmHg with no AR. Endoscopy shows grade 2 esophageal varix but no
active bleeding from varix. Colonoscopy shows angiodysplastic
lesions through the colon with hamorrhoids.Bleeding occur
most probably from angiodysplastic lesions but we don’t see any
active bleeding from any angiodysplasia. Initially patient was
managed with blood transfusion with fresh frozen plasma and
also platelet aphaeresis (Figure 1).
Our patient is an elderly lady with multiple co-morbidities.
She was treated by thalidomide for multiple myeloma that
was controlled. Two times EVL was done for HCV related
decompensated CLD with feature of hypersplenism with low
platelet count. Her past history of multiple episodes of lifethreatening
blood loss makes it necessary to do something to
prevent gastrointestinal blood loss. The options available are
angiographic intervention, endoscopic intervention, intestinal
resection, aortic valve replacement, and estrogen-progesterone
therapy/thalidomide therapy. The patient herself along with
her relatives were unwilling for any major surgical intervention
due to her advanced age and the multiple comorbidities that she
had, further compromising the likely outcome after the surgery.
There was a high chance of more angiodysplastic lesion in small
gut which is not approachable on colonoscopy and there was no
capsule endoscope in our country.
Angiographic intervention is also not preferable as there is
a possibility of existence of multiple unnoticed angiodysplasias,
possibility of gut infarction after angiography, and the deranged
renal function of the patient would be a contraindication for
angiography. All these problems make it difficult to choose the
best and acceptable solution for this patient like aortic valve
replacement (Figure 2&3).
We do argon plasma coagulation (APC) of angiodysplastic
lesion in colon as far as possible in 2 sessions with injection of
octreotide. In this measure she was recovered well and there was
no bleeding at least 1 year follow-up. After that again melaena
started on/off. She was also treated by desmopressin nasal
spray with cap.danazol to increase vWF with inj octreotide. This
measure decreases her incidence of melaena. We offer her to do
aortic valvae replacement for further management but she was
Angiodysplasia is the most common vascular lesion of the
gastrointestinal tract, and this condition may be asymptomatic,
or it may cause gastrointestinal (GI) bleeding . Seventyseven
percent of angiodysplasias are located in the cecum and
ascending colon, 15% are located in the jejunum and ileum, and
the remainder is distributed throughout the alimentary tract.
Nasal bleeding is also reported [2,3]. These lesions typically are
nonpalpable and small (< 5 mm). Angiodysplasia may account
for approximately 6% of cases of lower GI bleeding. It may be
observed incidentally at colonoscopy in as many as 0.8% of
patients older than 50 years. The prevalence for upper GI lesions
is approximately 1-2%.Clinical presentation in patients with
angiodysplasia is usually characterized by maroon-colored stool,
melena, or hematochezia. Bleeding is usually low grade, but it
can be massive in approximately 15% of patients. In 20-25% of
bleeding episodes, only tARGHy stools are passed. Iron deficiency
anemia and stools that are intermittently positive for occult
blood can be the only manifestations of angiodysplasia in 10-
15% of patients. Bleeding stops spontaneously in greater than
90% of cases but is often recurrent. An association between
colonic angiodysplasia and aortic stenosis was described by
Edward C Heyde et al. .
The exact mechanism of development of angiodysplasia
is not known, but chronic venous obstruction may play a role
[6,7]. Increased expression of angiogenic factors, like basic
fibroblast growth factor (bFGF) and vascular endothelial growth
factor (VEGF), is also believed to play a role in the pathogenesis
of colonic angiodysplasia . In Heyde’s syndrome; it seems
that bleeding occurs from pre-existing angiodysplasias in the
gut. This bleeding is due to an acquired haematological defect
caused by aortic stenosis [5,9]. Age-related senile tissue changes
may predispose to angiodysplasia and the link between the
angiodysplasia and aortic stenosis is controversial [10-12].
Various studies have described the acquired von Willebrand
factor deficiency as being a reason for bleeding in Heyde’s
syndrome [5,13]. The haematological defect is identified as
deficiency of high molecular weight (HMW) multimers of von
Willebrand factor (vWF) . The high shearing force caused
by blood jet in aortic stenosis uncoils the HMW multimers of
vWF exposing the vWF cleavage site for ADAMST . This leads
to selective loss of HMW multimers of vWF due to increased
proteolysis. Acquired vWF deficiency state is thus created (von
Willebrand syndrome type 2A). There is an evidence showing normalisation of HMW multimers of VWF after aortic valve
replacement surgery [15-18]. Heydes syndrome consists of a
triad of aortic stenosis, acquired vWF deficiency and anaemia
due to bleeding angiodysplasia or idiopathic bleeding .
The main challenge is localisation of bleeding source in these
patients . The bleeding source could be hidden and out of
reach for conventional endoscopies.Wireless capsule endoscopy
is a useful invention that helps us to visualise the small intestine.
It also guides us about the route for enteroscope insertion. It
is a painless and noninvasive procedure. The disadvantages of
capsule endoscopy include the inability to detect all the lesions,
especially in presence of active bleeding, and the inability
to intervene [17,19]. The double balloon and single balloon
endoscopies are described to be useful to overcome these
disadvantages of capsule endoscopy [14,15]. It is claimed that
double balloon and single balloon endoscopies can visualise
most of the small bowel and thus enable diagnostic manoeuvres
and therapeutic techniques like achieving haemostasis,
performing polypectomies, stricture dilatation, and stenting.
This technique produces superior quality images than capsule
endoscopy. However, the cost and availability of these techniques
could limit their use in developing countries. Therapeutic
options for Heyde’s syndrome include aortic valve replacement,
surgery, angiographic intervention, double or single balloon
endoscopy,Argon plasma coagulation(APC) and medical therapy
including hormonal and thalidomide therapy, octreotide [5,19].
It is claimed that aortic valve replacement reduces or even stops
gastrointestinal blood loss5. Cessation of bleeding after aortic
valve replacement was found to be associated with improved
levels of HMW multimers of vWF after replacement. This finding
strengthened the hypothesis of acquired vWF deficiency in
Heyde’s syndrome. However, advanced age and co-morbidities
can make this an unsuitable choice in some patients. A few case
reports describe massive gastrointestinal bleeding after aortic
valve replacement .
Thus aortic valve replacement might not be the ideal
treatment in every patient of Heyde’s syndrome. Surgery and
endoscopic therapy especially argon plasma coagulation are not
useful in patients with diffuse angiodysplasia. Aortic stenosis
and associated cardiac diseases often make patients of Heyde‘s
syndrome unfit for surgery. Though double balloon endoscopy
is mentioned to be able to visualise the small intestine and
intervene, their cost and availability may limit their use.
Angiographic intervention like embolisation of A-V malformation
can lead to arterial occlusion and gangrene. It is also difficult to
locate and embolise all the lesions in diffuse angiodysplasias.
A few case reports, one uncontrolled trial, and recently a small
double-blind, placebo-controlled, cross-over trial indicate
that oestrogen-progesterone therapy may be effective in
controlling severe recurrent bleeding from gastrointestinal
vascular malformations . Octreotide and estroprogestative
treatments are the best evaluated drugs; however, no appropriate
comparison on cost-effectiveness and tolerance has been performed . Submucosal injection of a saline epinephrine
solution followed by the application of APC has been reported
 New endoscopic techniques such as the Olympus EVIS
LUCERA variable indices of hemoglobin chart function have been
developed to assess completeness of vascular mucosal ablation
. Super selective embolization of visceral arterial branches
is central to the management of patients with lower GI bleeding,
including bleeding from colonic angiodysplasia  Partial or
complete gastrectomy for management of gastric angiodysplasia
has been reported to be followed by bleeding in as many as 50%
of patients. Rebleeding was attributed to other angiodysplastic
lesions.Right hemicolectomy for angiodysplasia is secondline
therapy after endoscopic ablation, if repeated endoscopic
coagulation has failed, if endoscopic therapies are not available,
and for life-threatening hemorrhage.
The mortality rate associated with surgical resection ranges
from 10% to 50%. This is based on the view that surgery cARGHies
a much higher risk in elderly patients, who often have multiple
coexisting medical problems, including coronary artery disease,
coagulopathy, and renal and pulmonary dysfunction. In a study
by Meyer et al, right hemicolectomy resulted in 63% of the
subjects remaining free of intestinal bleeding (mean follow-up,
3.6 y), and 37% had some degree of recurrent bleeding .
The Heyde’s syndrome is supposed to be one of the acquired
von Willebrand factor deficiency states. The recommended
guidelines for the diagnosis and management involve detection
of vW factor levels, detection of antibodies against the same,
and treatment with desmopressin or factor viii/vWF. These
diagnostic modalities are not readily available across our
country and are costly, e.g., in Bangladesh, assessment of vW
factor levels may cost more than hormonal therapy for a month.
There are no recommended guidelines for the management
and treatment of Heyde’s syndrome. One should seek help from
guidelines for management of occult gastrointestinal blood loss.
Also, there should be a consideration for cardiovascular issues
and haematological issues of the patient. Various treatment
options are available for Heyde’s syndrome but most of them
have inadequate evidence behind them. As of now, there is
no universally accepted unified treatment protocol available.
Recurrence of acute hemorrhage from GI angiodysplasia after
hospital discharge occurred in 30% of patients after a mean
follow-up (33±40 mo). In a multivariate analysis, earlier history
of bleeding with a high bleeding rate, over anticoagulation,
and the presence of multiple lesions were predictive factors
of recurrence. Surprisingly endoscopic APC therapy was not
associated with lower rates of recurrent bleeding .
Potentially life-threatening nature, age and co-morbidities,
and poorly understood pathophysiology make Heyde’s
syndrome a tough illness to treat. High index of suspicion
should be kept in mind while treating aortic stenosis and
gastrointestinal hemorrhage in elderly patients.Involvement of a gastroenterologist and a hematologist in treatment of
such patients helps in resolving various issues pertaining
to their respective fields. An aggressive attempt should be
made to visualise the bleeding source. Capsule endoscopy and
double balloon endoscopy may be very useful in diagnosis and
treatment. Though aortic valve replacement is thought to be
corrective in most of the cases, it might not be practical in all
the cases. In spite of lack of strong evidence and the possibility
of side-effects, hormonal therapy could prove to be an effective
treatment modality in such patients. Incidentally, our patient has
done well after inj octreotide & hormonal therapy with Argon
plasma coagulation and her hemoglobin has been raised.