An unusual cause of hypoxia: Getting to the heart of the matter

Abstract

A 63 year old female presented to hospital with progressive exertional dyspnoea over a 6 month period. In the year preceding her admission, she reported an intercurrent history of abdominal pain, diarrhoea and weight loss. She was found to be hypoxic, the cause for which was initially unclear. A ventilation-perfusion scan identified a right-to-left shunt. Transoesophageal echocardiography (TOE) demonstrated a significant right-to-left intracardiac shunt through a patent foramen ovale (PFO); additionally severe tricuspid regurgitation was noted through a highly abnormal tricuspid valve. The findings were consistent with carcinoid heart disease with a haemodynamically significant shunt, resulting in profound systemic hypoxia. 24 hour urinary 5-Hydroxyindoleacetic acid (5-HIAA) and imaging were consistent with a terminal ileal primary carcinoid cancer with hepatic metastasis. Liver biopsy confirmed a tissue diagnosis. The patient was commenced on medical therapy for carcinoid syndrome. She subsequently passed away while undergoing anaesthetic induction for valvular surgery to treat her carcinoid heart disease and PFO.

Full text

D Hammersley, A Shamsi
etal.
An unusual cause of hypoxia K7–K11
5:1
CASE REPORT
An unusual cause of hypoxia: getting to the
heart of the matter
DanielHammersley1,*, AamirShamsi2,*, MohammadMurtazaZaman3, Philip Berry4 and LydiaSturridge1
1Frimley Park Hospital, Frimley, Surrey, UK
2St George’s Hospital, London, UK
3Royal Brompton Hospital, London, UK
4Guy's & St Thomas’ NHS Foundation Trust, London, UK
*(D Hammersley and A Shamsi contributed equally to this work)
Correspondence should be addressed to D Hammersley: djhammersley@gmail.com
Summary
A 63-year-old female presented to hospital with progressive exertional dyspnoea over
a 6-month period. In the year preceding her admission, she reported an intercurrent
history of abdominal pain, diarrhoea and weight loss. She was found to be hypoxic, the
cause for which was initially unclear. A ventilation–perfusion scan identied a right-to-
left shunt. Transoesophageal echocardiography (TOE) demonstrated a signicant right-
to-left intracardiac shunt through a patent foramen ovale (PFO); additionally severe
tricuspid regurgitation was noted through a highly abnormal tricuspid valve. The ndings
were consistent with carcinoid heart disease with a haemodynamically signicant shunt,
resulting in profound systemic hypoxia. 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA)
and imaging were consistent with a terminal ileal primary carcinoid cancer with hepatic
metastasis. Liver biopsy conrmed a tissue diagnosis. The patient was commenced on
medical therapy for carcinoid syndrome. She subsequently passed away while undergoing
anaesthetic induction for valvular surgery to treat her carcinoid heart disease and PFO.
Learning points:
•Carcinoid syndrome is a rare condition, which presents a signicant diagnostic challenge due to its insidious
presentation and symptoms. This frequently results in a marked delay in diagnosis.
•Carcinoid heart disease is characterised by distortion and xation of right-sided heart valves, which cause valvular
regurgitation, stenosis or both. Valvular abnormalities are often found in association with right ventricular failure.
•In the case described, carcinoid heart disease was found in association with a signicant right-to-left intracardiac
shunt, created through a PFO due to right atrial volume overload. This prevented right ventricular failure at the
expense of creating a state of severe induced systemic hypoxia.
•This physiological adaptation resulted in an unusual presentation of this condition, due to symptoms resulting
from hypoxia, rather than the classical symptoms of carcinoid syndrome or right ventricular failure.
Key Words
fcarcinoid syndrome
fpatent foramen ovale
fshunt
10.1530/ERP-17-0055
ID: 17-0044
51
This work is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0
International License.
https://doi.org/10.1530/ERP-17-0055
www.echorespract.com © 2018 The authors
Published by Bioscientica Ltd

D Hammersley, A Shamsi
etal.
An unusual cause of hypoxia K8
5:1
This work is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0
International License.
https://doi.org/10.1530/ERP-17-0055
www.echorespract.com © 2018 The authors
Published by Bioscientica Ltd
Background
Exertional breathlessness is a common presenting
complaint in acute medicine. Hypoxia is a common
clinical finding in these patients. This case demonstrates
an unusual cause of hypoxia. Standard first-line
investigations would not have reached the underlying
diagnosis in this case and as such it demonstrates the
complex investigative strategy required to reach this
diagnosis. The case illustrates the challenges of diagnosing
carcinoid syndrome. It was only through investigation
of the exertional breathlessness that the underlying
diagnosis of carcinoid syndrome with carcinoid heart
disease was made.
Case presentation
A 63-year-old female presented acutely to hospital with
progressive dyspnoea over the previous 6 months. She
had no other significant medical co-morbidities, but
2 months previously had been investigated for chronic
lower abdominal pain, weight loss and diarrhoea,
which had started 1year beforehand. Recent outpatient
investigations into her gastrointestinal symptoms,
including a pelvic ultrasound scan and a colonoscopy, had
been unremarkable and consequently these symptoms
had been attributed to irritable bowel syndrome.
On admission to hospital, she was cachectic with a
body mass index (BMI) of 19. Observations identified
resting hypoxia, with oxygen saturation of 91% on room
air; other observations were within normal parameters.
Cardiovascular examination revealed a pansystolic
murmur at the left sternal edge, there was no peripheral
oedema and her venous jugular pressure was not elevated.
Respiratory system examination was unremarkable with
no peripheral or central cyanosis and vesicular breath
sounds bilaterally throughout the lung fields.
Investigation
Arterial blood gas on room air confirmed type I respiratory
failure with pO2 7.64 kPa. Blood tests (including full blood
count, renal function, liver function and C-reactive
protein) were all unremarkable. 12-lead electrocardiogram
showed normal sinus rhythm with a normal cardiac axis.
Chest radiograph was unremarkable and did not identify
any parenchymal, interstitial or pleural abnormalities
that could account for the hypoxia.
A computed tomography (CT) pulmonary angio-
gram demonstrated no evidence of a pulmonary
embolism, but an ill-defined hypodense lesion in the
liver was noted that was suspicious for a metastatic
deposit. Persistent hypoxia was further investigated
with a ventilation–perfusion (VQ) nuclear scan, which
showed no evidence of perfusion defect to suggest
thromboembolic disease, but did confirm the presence
of a large right-to-left shunt.
Echocardiography was performed to assess for
the presence of an intracardiac shunt. Transthoracic
echocardiography (TTE) was limited by suboptimal
windows, but identified an abnormal tricuspid valve
appearance with restriction and splinting of the valve
leaflets with loss of coaptation causing severe regurgitation
and mild stenosis (Figs1, 2 and Video1). Right ventricular
Figure1
TTE apical 4-chamber view, demonstrating abnormal tricuspid valve
appearance.
Figure2
Colour Doppler showing severe tricuspid regurgitation.

D Hammersley, A Shamsi
etal.
An unusual cause of hypoxia K9
5:1
This work is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0
International License.
https://doi.org/10.1530/ERP-17-0055
www.echorespract.com © 2018 The authors
Published by Bioscientica Ltd
dimensions (Fig. 3) and systolic function were within
normal limits (Fig.4).
Transoesophageal echocardiography (TOE)
demonstrated a highly mobile aneurysmal ‘skipping rope’
interatrial septum (Video 2). Colour Doppler confirmed
flow across the interatrial septum (Fig. 5). Bubble saline
contrast injection identified a significant right-to-left
shunt through a PFO (Videos3 and 4). Aortic and mitral
valves were mildly thickened and only mildly regurgitant.
The mechanism of the shunt was therefore identified
as an acquired intracardiac circuit occurring as a result
of a severely regurgitant tricuspid valve with the jet of
regurgitation being directed across a PFO into the left
atrium due to right atrial volume overload.
In view of the patient’s symptoms of weight loss,
abdominal pain and diarrhoea, 24-h urinary collection
for 5-hydroxyindoleacetic acid (5-HIAA) was performed.
This was significantly elevated at 717 μmol/24 h (normal
range <42 μmol/24 h) and therefore strongly suggestive
of carcinoid syndrome as the underlying pathology.
Serum chromogranin A and B levels were elevated. ACT
abdomen and pelvis identified a 1 cm hypervascular
lesion in the terminal ileum in addition to mesenteric
lymphadenopathy and a hypervascular hepatic lesion,
in keeping with a primary carcinoid lesion with hepatic
metastasis. MRI liver confirmed an 8 cm right liver lobe
Figure3
TTE apical 4-chamber view demonstrating normal right ventricular
dimensions.
Figure4
M-mode demonstrating normal RV systolic function, as indicated by
TAPSE 2.1 cm.
Figure5
TOE mid-oesophageal aortic valve short axis view with colour Doppler,
demonstrating signicant ow across the interatrial septum.
Video 4
TOE bubble saline contrast injection demonstrating
signicant right-to-left shunt. View Video 4 at http://
movie-usa.glencoesoftware.com/video/10.1530/ERP-17-
0055/video-4.
Video 1
TTE apical 4-chamber view, demonstrating restriction and
splinting of the tricuspid valve leaets. View Video 1 at
http://movie-usa.glencoesoftware.com/video/10.1530/
ERP-17-0055/video-1.
Video 2
TOE mid-oesophageal aortic valve short axis view,
demonstrating highly mobile aneurysmal ‘skipping rope’
interatrial septum. View Video 2 at http://movie-usa.
glencoesoftware.com/video/10.1530/ERP-17-0055/video-2.
Video 3
TTE bubble saline contrast injection demonstrating
signicant right-to-left shunt. View Video 3 at http://
movie-usa.glencoesoftware.com/video/10.1530/ERP-17-
0055/video-3.

D Hammersley, A Shamsi
etal.
An unusual cause of hypoxia K10
5:1
This work is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0
International License.
https://doi.org/10.1530/ERP-17-0055
www.echorespract.com © 2018 The authors
Published by Bioscientica Ltd
mass. Octreotide scan confirmed a solitary hepatic deposit
with further uptake in the terminal ileum. Percutaneous
biopsy of the liver lesion confirmed a well-differentiated
metastatic carcinoid tumour.
Treatment and outcome
Sandostatin, an analogue of the hypothalamic release-
inhibiting hormone somatostatin, was commenced which
resulted in temporary relief of gastrointestinal symptoms.
The patient’s care was transferred to a tertiary centre
experienced in the management of carcinoid syndrome
and carcinoid heart disease (CHD). A multi-disciplinary
decision was taken to proceed to valvular surgery with PFO
closure. During induction for the operation, the patient
developed severe hypotension with fulminant circulatory
collapse and died before surgery could be undertaken.
Discussion
Carcinoid syndrome is a clinical manifestation of a well-
differentiated neuroendocrine tumour (NET). The NET
arises from enterochromaffin cells, located in either the
gastrointestinal tract or the lungs, which are responsible
for the release of vasoactive substances such as serotonin.
Carcinoid syndrome usually occurs in patients with
metastatic lesions to the liver, which results in failure
of hepatic inactivation of the vasoactive substances
or their release directly into the systemic circulation.
The characteristic symptoms are diarrhoea, cutaneous
flushing and bronchoconstriction. Carcinoid tumours are
rare, with an estimated incidence of 1–2 per 100,000 in
the United States of America (1, 2).
Carcinoid syndrome can present a diagnostic
challenge to physicians, due to its indolent presentation,
in association with an unusual constellation of symptoms.
The typical time from onset of symptoms to diagnosis is
24–28 months, but is sometimes as long as 5 years (3).
Diagnosis can be reached using a combination of 24-h
HIAA urinary excretion levels, blood tests for 5-HIAA
and chromogranin and imaging modalities. Imaging
techniques used include CT, MRI, OctreoScan scintigraphy
and positron emission tomography integrated with CT
(PET CT). Biopsies allow tissue diagnosis and confirm the
degree of differentiation of the tumour.
CHD is a known complication of carcinoid syndrome. It is
estimated to occur in over 50% of patients with this condition
(4). The pathophysiology is via a paraneoplastic effect of the
high levels of secreted vasoactive substances on the right
heart, without inactivation of these substances by the liver.
This results in fibrous plaque deposition and endocardial
thickening, which can cause retraction, distortion and
fixation of the right-sided heart valves. This results in valvular
regurgitation, stenosis or both. The vasoactive substances are
degraded within the lungs, therefore, relatively protecting
the left heart from the disease (3, 4).
Patients with CHD typically present with signs of
severe tricuspid regurgitation and right heart failure in
association with classical systemic carcinoid syndrome
symptoms. Valvular surgery is the only definitive
treatment of CHD, with prosthetic valvular replacement
usually preferred when patients are considered suitable
operative candidates (3). Other strategies address symptom
control though treatment of right ventricular failure with
diuretics. Somatostatin analogues can relieve carcinoid
symptoms and slow tumour growth (5).
In the case described, the patient had symptoms of
carcinoid syndrome with echocardiographic evidence
of CHD. However, in spite of severe tricuspid valvular
disease, there were no clinical features of right heart
failure due to the unique haemodynamic adaptation
created by the shunt. The right heart was effectively
offloading through the PFO, causing a right-to-left shunt.
Although this had prevented fulminant features of right
heart failure, this came at the expense of an induced state
of profound hypoxia created by the shunt. As such, this is
a unique presentation of this condition as it came to light
from symptoms relating to the hypoxia, rather than those
typically described in this condition.
PFO, in its own right, is a common phenomenon,
present in 25% of the population. It is usually benign and
not associated with a significant shunt as left atrial pressure
is higher than right atrial pressure in the physiologically
normal heart (6). In the case described, the torrential
tricuspid regurgitation caused by CHD resulted in raised
right atrial pressure; this in turn caused the continuous right-
to-left shunt across the PFO creating a haemodynamically
significant lesion. A single small study has identified a
higher incidence of significant PFO in patients with CHD
compared with age-matched controls and suggests that in
some cases there may be a role for percutaneous closure
of haemodynamically significant lesions (7). Symptoms of
platypnea–orthodeoxia syndrome have been reported in
patients with a PFO and an additional predisposing feature,
which results in significant shunting of blood from the right
atrium to left atrium (8). Although physiologically feasible
in the case described, the symptoms of this syndrome were
not specifically described by the patient.

D Hammersley, A Shamsi
etal.
An unusual cause of hypoxia K11
5:1
This work is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0
International License.
https://doi.org/10.1530/ERP-17-0055
www.echorespract.com © 2018 The authors
Published by Bioscientica Ltd
The presence of a PFO in a patient with carcinoid
syndrome also creates a conduit for passage of the
vasoactive substances released in carcinoid syndrome
from the right heart to the left heart. This can, in theory,
result in the involvement of left-sided heart valves in
addition to the right-sided heart valves and has been
described elsewhere in the literature (9).
Declaration of interest
The authors declare that there is no conict of interest that could be
perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specic grant from any funding agency in
the public, commercial or not-for-prot sector.
Patient consent
The patient is deceased. Written consent for publication of the submitted
article and accompanying images and videos has been given from the
patient’s next-of-kin.
Author contribution statement
D H and A S drafted the manuscript and contributed equally as rst author.
M M Z contributed to the manuscript. P B was involved in the patient’s care
and reviewed the manuscript. L S was involved in the patient’s care and
reviewed the manuscript.
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Received in nal form 8 November 2017
Accepted 8 November 2017