Skip to main content
main-content

01.12.2016 | Case report | Ausgabe 1/2016 Open Access

Journal of Medical Case Reports 1/2016

Takotsubo-like syndrome triggered by fludrocortisone overdose for Addison’s disease: a case report

Zeitschrift:
Journal of Medical Case Reports > Ausgabe 1/2016
Autoren:
Radu Campean, Matthias Hasun, Claudia Stöllberger, Johannes Bucher, Josef Finsterer, Christoph Schnack, Franz Weidinger
Abbreviations
BNP
Brain natriuretic peptide
cMRI
Cardiac magnetic resonance imaging
ECG
Electrocardiogram
EF
Ejection fraction
MRI
Magnetic resonance imaging
NYHA
New York Heart Association
PGA II
Polyglandular autoimmune type II syndrome
QTc
Corrected QT interval
TTC
Takotsubo cardiomyopathy

Background

Heart failure in Addison’s disease has been described mainly in older patients with ischemic, valvular, or hypertensive heart disease [ 1]. Reversible left ventricular dysfunction after initiation of hormone therapy has been reported in only nine patients with Addison’s disease, as listed in Table  1 [ 29]. We present a patient with suspected polyglandular autoimmune type II syndrome (PGA II), in whom transient left ventricular dysfunction with heart failure was documented by echocardiography, electrocardiogram (ECG), serum brain natriuretic peptide (BNP) levels, and cardiac magnetic resonance imaging (cMRI).
Table 1
Heart failure occurring after initiation of hormone replacement therapy for Addison’s disease
Reference
Age/Sex
Comorbidity
Therapy
Onset of heart failure after
Left ventricular function
Left ventricular function normal after
Acute electrocardiogram
Follow-up electrocardiogram
Heart failure therapy
Outcome
2
47/f
None
HC, FC
20 days
Normal, pericardial effusion
4 months
Normal
NR
Furosemide
R
3
11/m
None
HC
1 day
Severely reduced
6 months
VT
NR
Catecholamines, furosemide
R
4
68/m
Mitral valve prosthesis, hepatopathy
Cortone (cortisone)
4 years
NR
NR
NR
NR
Furosemide, nitrates
R
5
71/f
None
HC
Shortly
Apical ballooning
9 months
ST↑
NR
ß-Blocker, ACE-inhibitor
R
6
69/f
Pyelonephritis
HC
3 days
Severely reduced
3 weeks
T-Inv, QT→, VT
Regression of T-Inv
Cardioversion
NR
7
6/m
None
HC, FC
20 days
Severely reduced
7 days
NR
NR
Furosemide, spironolactone
R
8
42/f
None
HC
2 days
Severely reduced
7 days
ST↑
Normal after 1 week
Catecholamines, mech vent
R
9
53/f
Thyroiditis
HC
Several days
Apical ballooning
2 weeks
ST↑, T-Inv, QT→
NR
NR
R
Present case
41/f
Thyroiditis
HC, FC
3 weeks
Severely reduced
3 months
T-Inv, QT→
ST abnormality
ß-Blocker, ACE-inhibitor, furosemide
R
ACE angiotensin-converting enzyme, f female , FC fludrocortisone, HC hydrocortisone, m male, mech vent mechanical ventilation, NR not reported, QT→ QT prolongation, R recovered, ST↑ ST segment elevation, T-Inv T-wave inversion, VT ventricular tachycardia

Case presentation

A 41-year-old white woman presented in December 2014 to our cardiology department with new onset of heart failure New York Heart Association (NYHA) class IV. She reported that she had gained 8 kg weight in the last 4 weeks.
She had a history of a surgically removed uncomplicated ovarian cyst 17 years ago. In 2011, autoimmune Hashimoto thyroiditis was diagnosed and substitution therapy with levothyroxine was started. In November 2014, she was hospitalized in another hospital because of generalized weakness, weight loss of 19 kg, and abdominal pain. Adrenal insufficiency was suspected and confirmed by a positive Synacthen test (Table  2). In view of her autoimmune thyroid disease, the diagnosis of PGA II was suspected. Therapy with levothyroxine 50 μg/day was continued and steroid replacement therapy with Hydrocortone (hydrocortisone) 20 mg/day and fludrocortisone 0.3 mg/day was initiated on 21 November 2014. She was discharged 2 weeks later in a stable clinical condition. Nine days before her actual admission she collapsed because of dizziness and had a cerebral concussion and open fracture of her nasal bone. The cause for the collapse was not further investigated, and neither blood tests, nor cardiac, nor neurological investigations were carried out. As an out-patient she received paracetamol against pain, local therapy with vitamins A and E, and antibiotic therapy with amoxicillin and clavulanate potassium for 7 days. Her family history disclosed that one of her three children, who is now 7-years old, was diagnosed with trisomy 21 and hypothyroidism.
Table 2
Results of blood and urine tests
Day
Normal range
18.11. 2014
21.11. 2014
09.12. 2014
17.12. 2014
18.12. 2014
22.12. 2014
19.03. 2015
07.04. 2015
Leukocytes (G/l)
4.0–9.0
7.2
8.3
18.08
11.8
8.7
NM
11.5
11.5
Hemoglobin (g/dl)
12.0–16.0
11.7
9.7
9.0
9.1
9.1
NM
12.4
12.2
Potassium (mmol/L)
3.3–5.1
4.3
3.8
2.99
3.5
4.7
3.8
3.4
3.9
Sodium (mmol/L)
135–150
134
139
144
136
140
141
138
140
Creatinine (mg/dl)
0.50–1.00
0.7
0.8
0.48
0.6
0.55
0.60
0.64
0.66
C-reactive protein (mg/l)
0.0–5.0
0.5
0.2
0.13
0.2
1.5
NM
NM
0.5
NT pro BNP (ng/l)
<116
NM
NM
NM
18.349
NM
14.100
129
NM
Iron (mg/dl)
33–193
57
NM
27
NM
NM
18
86
222
Ferritin (μg/l)
15–150
134
NM
NM
NM
NM
18
39
38
CK (U/l)
26–145
NM
NM
NM
72
41
NM
NM
69
Troponin T (ng/ml)
0.000–0.009
NM
NM
NM
0.014
NM
0.007
NM
NM
TSH (μU/ml)
0.200–3.700
1.14
1.84
NM
9.06
5.94
NM
NM
5.31
Serum cortisol (μg/dl)
1–18
0.2
NM
NM
23.7
NM
NM
NM
25.08
ACTH (pg/ml)
<46
1310
NM
NM
NM
NM
NM
NM
NM
PTH (pg/ml)
14.9–56.9
NM
NM
NM
NM
NM
62.3
NM
43.0
Cortisol excretion (nmol/24 hours)
57.7–806.8
NM
NM
NM
NM
NM
1492.66
NM
NM
Serum renin (pg/ml)
2.90–27.60
NM
0.73
NM
0.36
NM
NM
NM
NM
ACTH adrenocorticotropic hormone, CK creatine kinase, NT pro BNP N-terminal prohormone of brain natriuretic peptide, NM not measured, PTH parathyroid hormone, TSH thyroid-stimulating hormone
On admission, a physical examination showed orthopnea, blood pressure 110/70 mmHg, tachycardia of 102 beats per minute (bpm), tachypnea of 30 breaths/minute, bilateral basal crepitations, and leg edema. Her oxygen saturation was 90 % at rest, without oxygen. An ECG revealed a sinus tachycardia, low voltage, negative T-waves in V 5 and V 6 and a c corrected QT interval (QTc) of 590 ms (Fig.  1). Her serum troponin T levels were only slightly elevated. The results of blood and urine tests are listed in Table  2. Echocardiography showed septal, apical, and anterior wall akinesia and a severely reduced left ventricular systolic function with a left ventricular ejection fraction (EF) of 30 %. CMRI confirmed her highly reduced systolic function with a left ventricular EF of 28 % and showed a relative enhancement, indicating hyperemia and capillary leakage (Fig.  2). Neither ischemic areas, nor myocardial scars, nor fibrotic changes were detected. Sellar and renal magnetic resonance imaging (MRI) investigations were normal.
Therapy with bisoprolol and ramipril, and furosemide administered intravenously was initiated. Her fludrocortisone dose was reduced to 0.05 mg/day. Under that therapy, her clinical condition improved, her BNP levels regressed (Table  2), echocardiography showed an improvement of systolic function, and ECG abnormalities regressed (Fig.  1). Because of the improvement in her cardiac function, lack of cardiovascular risk factors, and lack of signs for ischemia on MRI, no coronary angiography was carried out. She was discharged as heart failure NYHA class I after 2 weeks with a pharmacotherapy comprising Hydrocortone (hydrocortisone) 20 mg/day, fludrocortisone 0.05 mg/day, levothyroxine 50 μg/day, pantoprazole 40 mg/day, bisoprolol 5 mg/day, and ramipril 10 mg/day. Follow-up investigations 6 months later showed normalization of her ECG and systolic function, documented by echocardiography (Fig.  1) and cMRI (Fig.  2).

Discussion

In our case, heart failure occurred 3 years after the diagnosis of thyroiditis, 3 weeks after the diagnosis of Addison’s disease and initiation of the hormonal therapy, and 9 days after her collapse, when her condition was slowly normalizing. According to previous reports and her history, there were no indications for preexisting cardiovascular disorders.
The pathogenesis of reversible systolic dysfunction in Addison’s disease, resembling Takotsubo cardiomyopathy (TTC), is unknown. There are several speculations about the pathophysiologic mechanism of heart failure after initiation of hormone therapy in Addison’s disease. One speculation assumes that once mineralocorticoid replacement therapy is commenced, renal adaptation to chronic water and sodium loss leads to overshooting of water and sodium retention with ensuing heart failure [ 2]. Development of heart failure with fludrocortisone therapy was reported for the first time in a series of adults with Addison’s disease [ 1]. Patients with heart failure from that series, however, had preexisting ischemic, valvular, or hypertensive heart disease and were older patients. In these patients, heart failure was managed with a dose reduction or cessation of fludrocortisone [ 1].
Also without preexisting cardiovascular disease, mineralocorticoid overdose has been implicated in ventricular dysfunction in Addison’s disease (Table  1) [ 2, 4, 7]. It remains unclear why our patient received an unusually high dose of fludrocortisone 300 μg/day, three times more than recommended [ 10]. She had gained 8 kg of weight after initiation of therapy, and heart failure regressed with reduction of fludrocortisone.
However, her clinical presentation was not compatible with pure volume overload. She showed ECG changes similar to those of myocardial ischemia, albeit the absence of cardiovascular risk factors, her clinical course, and her normal levels of creatine kinase with only slight elevations of troponin and no indications for myocardial ischemia on repeated cardiac MRIs virtually ruled out this possibility. The findings and her clinical course resemble apical TTC, characterized by symptoms and ECG signs of acute myocardial infarction, transient left ventricular dysfunction but without angiographic evidence of coronary stenosis [ 11]. Since coronary angiography was not carried out, we cannot establish definitively the diagnosis of TTC. Different acute psychic and physical triggers of TTC, including endocrine disorders like Addison’s disease, have been described [ 12]. Traumatic head injury with concussion and nasal bone fracture, which had occurred 9 days before admission, could have been a major stressor event, additionally triggering TTC.
Regarding the pathomechanism of TTC in Addison’s disease, there are only animal data available. Studies in adrenalectomized animals suggest that cardiac function may be markedly impaired when stress is superimposed, and increased catecholamine levels are toxic to a myocardium that is unprotected by glucocorticoids [ 13]. Glucocorticoids have been shown to be important for the maintenance of membrane calcium transport function in the cardiac sarcoplasmic reticulum from the rat, and may therefore affect myocardial contractility [ 14]. Microsomal phosphorylase activity in rat heart muscle is depleted by adrenalectomy. The decreased phosphorylase activity may impair glycogenolysis and thus induce derangement of excitation–contraction coupling of the heart [ 15]. It was speculated that cortisone deficiency might lead to myocardial injury and that probably hydrocortisone can exert a toxic effect on a previously cortisone-starved myocardium [ 8]. Furthermore, it can be assumed that rather than a direct toxic role of steroids, a greater sensitivity to the adrenergic system induced by the administration of steroids may play a role in the pathogenesis of reversible left ventricular dysfunction.
Myocarditis could be another explanation for the transient left ventricular dysfunction. However, neither history, nor blood tests, nor MRI were indicative of myocarditis [ 16]. A further pathomechanism might be a transient affection of the myocardium by an underlying autoimmune disorder. In our patient, her systolic function recovered, whereas in a previously described patient with PGA II, the autoimmune cardiomyopathy required heart transplantation [ 17].
The reason for her collapse that occurred 9 days before her actual admission remains unclear. Since her serum potassium level was low at the actual admission (Table  2), it can be assumed that hypokalemia due to fludrocortisone overdose might have played a role, either by generalized muscle weakness or by inducing arrhythmia [ 18]. A further cause for the collapse could be arrhythmia due to QT prolongation; however, no ECG had been recorded at the time of her collapse.
Limitations of the presented case are that no coronary angiography was carried out to establish the diagnosis of TTC and no myocardial biopsy was carried out to definitively exclude myocarditis, thus the case does not fulfill all the diagnostic requirements for TTC according to the Mayo Clinic diagnostic criteria [ 11]. Furthermore, the cause of our patient’s collapse which occurred 9 days before her actual admission remains unclear and no ECG recordings are available from the time when her symptoms started. Thus it cannot be assessed whether she also showed ST elevations which are reported to occur less frequently in patients with TTC than in acute coronary syndromes [ 19].

Conclusions

Patients with Addison’s disease should be monitored for cardiac abnormalities during therapy for acute adrenal insufficiency. If they develop symptoms suggestive for arrhythmia, their serum electrolytes should be measured and an ECG should be recorded. If they develop heart failure or left ventricular dysfunction, hormonal therapy should be considered to be a possible iatrogenic trigger.

Acknowledgements

No acknowledgements.

Funding

No funding.

Availability of data and materials

The data reported in the article are available at the Rudolfstiftung. Clinical, electrocardiographic, laboratory, echocardiographic, and magnetic resonance imaging data were obtained by commercially available instruments.

Authors’ contributions

RC collected clinical data and drafted the manuscript. MH performed and analyzed the cardiac magnetic resonance imaging studies and drafted the manuscript. CSt conceived the case report, drafted the manuscript, and is the corresponding author. JB collected clinical data and drafted the manuscript. JF collected clinical data and drafted the manuscript. CSc collected clinical data and drafted the manuscript. FW collected clinical data and drafted the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

Unsere Produktempfehlungen

e.Med Interdisziplinär

Kombi-Abonnement

Für Ihren Erfolg in Klinik und Praxis - Die beste Hilfe in Ihrem Arbeitsalltag als Mediziner

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de.

e.Med Allgemeinmedizin

Kombi-Abonnement

Mit e.Med Allgemeinmedizin erhalten Sie Zugang zu allen CME-Fortbildungen und Premium-Inhalten der allgemeinmedizinischen Zeitschriften, inklusive einer gedruckten Allgemeinmedizin-Zeitschrift Ihrer Wahl.

Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2016

Journal of Medical Case Reports 1/2016 Zur Ausgabe