Batch, J. A.

Conwell, L. S.

Delbridge, R. G.

Gray, L. M.

Thomsett, M. J.

L.S. Conwell

L.M. Gray

R.G. Delbridge

M.J. Thomsett

J.A. Batch

Crossref

Journal of Pediatric Endocrinology and Metabolism

Reversible Cardiomyopathy in Paediatric Addison's Disease - A Cautionary Tale

University of Queensland eSpace

© Freund Publishing House Ltd., London Journal of Pediatric Endocrinology & Metabolism. 16. 1191-1195 (2003) 
Reversible Cardiomyopathy in Paediatric Addison's Disease -
A Cautionary Tale 
L.S. Conwell1, L.M. Gray2, R.G. Delbridge3, M.J. Thomsett1 and J.A. Batch1 
'Department of Endocrinology and Diabetes and 3 Paediatric Intensive Care Unit, 
Royal Children's Hospital Brisbane and2Rockhampton, Queensland, Australia 
ABSTRACT 
A 13 year-old girl with clinical features of 
Addison's disease developed acute cardiac 
failure after initiation of treatment and after 
initial clinical improvement. Large doses of i.v. 
hydrocortisone and oral fludrocortisone, in 
addition to inotropic and ventilatory support, 
were required to achieve cardiovascular stabil-
ity. The cardiomyopathy improved over one 
week and her condition then remained stable on 
oral glucocorticoid and mineralocorticoid 
replacement therapy. Reversible cardiomyo-
pathy is a rare and potentially life-threatening 
complication of Addison's disease. The second 
reported paediatric patient is presented, the only 
one reported to require ventilatory support. 
KEY WORDS 
adrenal failure, Addison's disease, myocardium, 
cardiomyopathy 
INTRODUCTION 
Acquired autoimmune adrenal failure may occur 
alone or as a manifestation of either autoimmune 
polyendocrinopathy type 1 or type 2 syndromes. It 
is the commonest cause of primary adrenal failure 
in developed countries, accounting for 75-90% of 
cases1. 
Reprint address: 
Dr. L.S. Conwell 
Department of Endocrinology and Diabetes 
Royal Children's Hospital 
Herston Road, Herston 
Brisbane, Queensland 
Australia, 4029 
e-mail: louise_conwell@health.qld.gov.au 
VOLUME 16, NO. 8, 2003 
This report describes reversible cardiomyopathy 
in a child with Addison's disease. There is only one 
previous report of such a case. An 11 year-old boy 
developed cardiac failure 24 hours after treatment 
with intravenous fluids and hydrocortisone2. In 
comparison, the patient in this report required 
increased inotropic support and mechanical 
ventilatory support. 
PATIENT REPORT 
A 13 year-old girl presented with 3 weeks of 
weight loss, lethargy, weakness, abdominal cramp-
ing, vomiting and salt-craving. Increasing skin 
pigmentation had been apparent for several months. 
Her past medical and family history was unremark-
able. 
Physical examination revealed a cachectic, weak 
and hyperpigmented girl. Her temperature was 
35.2°C, respiratory rate 20/min, heart rate 105/min, 
blood pressure 65/30 mmHg and peripheral 
perfusion poor. 
Initial investigations demonstrated sodium 121 
mmol/1 (normal 137-147), potassium 7.0 mmol/1 
(3.5-5.0), creatinine 0.14 mmol/1 (0.04-0.10), chlor-
ide 93 mmol/1 (96-109), bicarbonate 14 mmol/1 
(25-33), venous pH 7.3 (7.3-7.4), glucose 4.2 
mmol/1 (3.0-7.7), corrected calcium 3.45 mmol/1 
(2.25-2.65), magnesium 0.4 mmol/1 (0.7-1.1) and 
lactate 1.1 mmol/1 (0.6-2.0). 
A provisional diagnosis of acute adrenal 
insufficiency was made. Early morning Cortisol 
measured on a sample collected 7 days before 
presentation was 27 nmol/1 (1.0 μ§Αϋ) (normal 
200-700 nmol/1 [7-25 Mg/dl]). ACTII could not 
be measured prior to treatment. Adrenal auto-
antibodies were subsequently positive (1:160) 
confirming the diagnosis of autoimmune Addison's 
disease. 
1191 
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1 192 L.S. CONWELL ET AL. 
Intravenous fluids, intravenous hydrocortisone 
(100 mg q 6 h) and oral fludrocortisone (100 ^ig 
bid) were commenced. Despite marked initial 
improvement, respiratory distress and hypotension 
developed 36 hours after admission. Basal respirat-
ory crackles were present without peripheral 
oedema. Despite initial hypovolemia, the patient 
was only in 1.2 1 positive fluid balance. The chest 
X-ray was consistent with extensive pulmonary 
oedema (Fig. 1). 
After initiation of intravenous broad-spectrum 
antibiotics, intravenous magnesium bolus, diuretic 
therapy and inotropic support (dopamine 5 μg/kg/ 
min), the patient was transferred to a tertiary 
paediatric intensive care unit. 
Increasing inotropic support was required (dopa-
mine 7.5 μg/kg/min and dobutamine 10 μg/kg/ 
min). Echocardiography revealed a non-dilated left 
ventricle, mild mitral regurgitation and global 
reduction in left ventricular fractional shortening to 
24% (normal 26-40%). Cardiac troponin I was 
mildly elevated at 2.2 ng/1 (<0.4 ng/1). Ventilation 
Fig. 1: Chest X-ray. Bilateral mid and lower zone alveolar 
shadowing consistent with extensive pulmonary 
oedema. 
was supported with mask continuous positive 
airway pressure (CPAP) for 2 days. Intubation and 
ventilation were then required due to intolerance of 
mask CPAP and the ongoing requirement for 
respiratory support. The patient did not develop 
acidosis during this period. Intravenous hydro-
cortisone and oral fludrocortisone doses were 
increased to achieve cardiovascular stability 
(maximal doses of 100 mg q 3 h and 300 μg tid, 
respectively). Extubation was achieved on day 8, 
with cessation of inotropic support on day 9. 
Nasopharyngeal aspirates were negative for 
respiratory viruses. Blood cultures were negative. 
Initial thyroid function tests at presentation showed 
an elevated TSH level of 8 mU/1 (normal 0.4-5 
mU/1) with normal f IV The TSH had normalised 
on repeat testing and thyroid autoantibodies were 
negative. 
Left ventricular fractional shortening had in-
creased to 32% by day 12. Trivial mitral regurgita-
tion persisted. ECG on day 21 showed T-wave 
inversion in leads 1, AVL and V6. Hypomagnes-
aemia persisted, requiring oral supplementation for 
3 weeks. The patient's condition then remained 
stable on oral glucocorticoid and mineralocorticoid 
replacement therapy, and was weaned to expected 
physiological doses by day 17. Echocardiography 
5 months later demonstrated stable myocardial 
contractility with low-normal left ventricular 
fractional shortening and improved mitral valve 
function. 
DISCUSSION 
Potential factors contributing to myocardial 
dysfunction in this patient with Addison's disease 
include chronic glucocorticoid deficiency, mineralo-
corticoid deficiency, ischaemia and hypomagnes-
aemia. 
Other examples of reversible cardiomyopathy in 
the context of glucocorticoid deficiency have been 
described, including a neonate with congenital 
adrenal hyperplasia and a 36 year-old man with 
Addison's disease3'4. A 6 year-old boy, subsequent-
ly diagnosed with adrenoleukodystrophy, died due 
to primary myocardial pump failure5. In contrast to 
these patients, the reported patient's cardiac func-
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CARD IOMYOPATHY IN ADD I SON ' S D I SEASE 1193 
tion deteriorated after the commencement of 
treatment and after initial clinical improvement. 
Hypovolaemia and/or electrolyte imbalance are 
not essential in the pathogenesis of circulatory 
collapse observed in adrenal insufficiency. Cortico-
steroids play a key role in the regulation of 
circulatory function6. Glucocorticoids are important 
for intrinsic myocardial contractility and regulation 
of the sympathetic nervous system. Adrenalectom-
ised animals demonstrate diminished myocardial 
function with impaired adenosine triphosphatase 
activity7, calcium transport8, and compartment-
alisation of Phosphorylase in heart muscle9. 
Glucocorticoid deficiency downregulates adrenerg-
ic receptors, and decreases epinephrine synthesis, 
tissue sensitivity to catecholamines and epinephrine 
activation of glycogenolysis in the myocardium''. 
Sympathectomy and a - and ß-blockade protect 
stressed adrenalectomised animals from circulatory 
failure. It has been proposed that catecholamines 
may have a detrimental effect on the heart in the 
absence of a corresponding increase in gluco-
corticoid, due to an increase in intracellular lactate 
and impaired contractility10. Aldosterone exerts a 
positive inotropic action; therefore mineralocortic-
oid deficiency may also contribute to myocardial 
dysfunction". 
Cardiac troponin I is a very sensitive and 
specific marker for myocardial cell necrosis, with 
levels remaining elevated for 7-10 days after an 
episode of myocardial necrosis12. Although there 
were no acute ischaemic ECG features, inverted Τ 
waves were apparent at Day 21. In this case, 
ischaemic injury may have been a secondary effect 
rather than the primary causative insult. Gluco-
corticoid deficiency may lower the threshold for 
ischaemic injury. 
In addition to impaired cardiac output, hypo-
tension in Addison's disease is due to hypo-
volaemia secondary to renal salt loss and vomiting; 
and increased production of the vasodilator 
bradykinin and decreased vascular reactivity, both 
due to glucocorticoid deficiency". Lower levels of 
α ι-adrenergic receptors and angiotensin-1 receptors 
have been described. Although plasma angiotensin 
II levels are high and contribute to the maintenance 
of peripheral resistance, the effectiveness of 
angiotensin II is blunted". 
Although congestive cardiac failure associated 
with fludrocortisone treatment has been described 
in patients with Addison's disease13, the patient 
reported here had only received two 100 μg doses 
of oral fludrocortisone. 
Acute viral myocarditis is a common cause of 
reversible myocardial dysfunction in children and 
adolescents14. Viruses such as cytomegalovirus 
have been implicated in the pathogenesis of adrenal 
insufficiency in immunocompromised states, e.g. 
AIDS15. However the patient was immunocompet-
ent and did not have a history of fever or respiratory 
symptoms in the 10-14 days prior to presentation. 
Symptoms and signs of primary adrenal insuffici-
ency had been present for months preceding the 
myocardial compromise, suggesting that a viral 
agent was not simultaneously contributing to acute 
myocarditis and adrenalitis. 
Hypomagnesaemia may contribute to cardiac 
dysfunction. Low magnesium levels are common in 
seriously ill patients, including those with acute 
myocardial infarction or heart failure16. Magnesium 
modulates mechanical and electrical functions of 
cardiac and vascular cells16, and animals fed on a 
low magnesium diet have developed cardiomyo-
pathy17. Hypercalcaemia, as evident in this reported 
patient, has been previously associated with 
Addison's disease, with resolution after correction 
of Cortisol deficiency18. Although glucocorticoid 
receptors are present in bone cells19'20, the 
mechanism is poorly understood. A PTH effect is 
discounted due to hypercalcaemia in an Addisonian 
patient with co-existent idiopathic hypoparathyroid-
ism21. Documented persistence despite intravenous 
rehydration suggests haemoconcentration is not a 
major mechanism. Elevated urinary calcium excre-
tion has been documented indicating increased 
calcium input into the extracellular fluid. Bone 
biopsies in three patients with hypercalcaemia and 
Addison's disease demonstrated depressed osteo-
blastic and osteoclastic activities at the trabecular 
surfaces18. However, calcium levels are mostly 
regulated by active transport of calcium out of 
interstitial bone fluid into the blood by the 
osteocyte 'lining cells'18. 
Cardiac contractile function is diminished by 
acidosis. Mechanisms include altered intracellular 
calcium mobilisation and decreased myofibrillar 
V O L U M E 16. NO. 8. 2003 
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1194 L.S. CONWELL ET AL. 
calcium sensitivity22. However the pH of the 
reported patient was 7.3 at presentation and was in 
the range 7.35-7.45 during the period of 
deteriorating cardiac function in the intensive care 
unit. 
Mitochondrial disorders can be a cause of both 
cardiomyopathy and autoimmune adrenal disease23. 
Our patient did not demonstrate associated clinical 
features, such as ptosis, ophthalmoparesis, peri-
pheral myopathy or pigmentary retinopathy. 
This report describes the onset of congestive 
cardiac failure more than 24 hours after institution 
of treatment and after initial improvement. Chronic 
myocardial glucocorticoid deficiency was likely the 
predominant pathogenetic mechanism causing the 
deterioration in cardiac function. Hydration therapy 
partially corrected the hypovolaemic state, with 
water and sodium retention due to commencement 
of glucocorticoid and mineralocorticoid therapy. 
However recovery of cardiac functioning was 
slower. Hence there was likely diminished func-
tional reserve of the myocardium to cope with the 
increased intravascular volume due to partial 
correction of hypovolaemia. There may be a role 
for increased initial glucocorticoid replacement or 
slower rehydration. Due to the mechanisms stated 
previously, inotropic agents may be poorly effective 
until large doses of glucocorticoid have been 
administered. 
This report highlights the importance of evalu-
ating myocardial function in patients with long-
standing glucocorticoid deficiency and being alert 
to the potential complication of cardiomyopathy as 
treatment is commenced. High doses of gluco-
corticoids may be required in this context. Cardio-
myopathy should also be remembered as a possible 
presentation of glucocorticoid deficiency. 
A C K N O W L E D G E M E N T S 
Dr. Louise Conwell's Clinical Research 
Scholarship was supported by the Royal Children's 
Hospital Foundation, Brisbane. 
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CARDIOMYOPATHY IN ADDISON'S DISEASE 1195 
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Reversible Cardiomyopathy in Paediatric Addison’s Disease - A Cautionary Tale

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Reversible Cardiomyopathy in Paediatric Addison’s Disease - A Cautionary Tale

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