Journal of Cardiology Cases 10 (2014) 226–230

Case Report

Prolonged hyponatremia due to hypopituitarism in a patient withnon-ST-elevation myocardial infarction

Kyohei Marume (MD)a,c, Yuichiro Arima (MD)a,c,*, Motoyuki Igata (MD)b,c,Takeshi Nishikawa (MD)b,c, Eiichiro Yamamoto (MD)a,c, Megumi Yamamuro (MD)a,c,Kenichi Tsujita (MD)a,c, Tomoko Tanaka (MD)a,c, Koichi Kaikita (MD, PhD)a,c,Seiji Hokimoto (MD, PhD)a,c, Hisao Ogawa (MD, PhD)a,c

a Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japanb Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japanc Department of Molecular Diabetology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

A R T I C L E I N F O

Article history:

Received 28 March 2014

Received in revised form 23 July 2014

Accepted 4 August 2014

Keywords:

Acute coronary syndrome

Hyponatremia

Hypopituitarism

Growth hormone deficiency

A B S T R A C T

A 58-year-old man was admitted for non-ST-elevation myocardial infarction. A medicated stent was

used for severe coronary artery stenosis. However, consciousness level progressively deteriorated after

angioplasty. Computed tomography showed no brain lesion but laboratory tests showed hyponatremia

(serum sodium: 113 meq./l) and urine analysis showed syndrome of inappropriate antidiuretic hormone

secretion (SIADH). SIADH was first suspected to be drug-induced by enalapril. However, hyponatremia

persisted even after withdrawal of enalapril and required oral sodium intake. Hormone assays indicated

secondary adrenal insufficiency, which was caused by adrenocorticotropic hormone (ACTH) deficiency.

Furthermore, in addition to ACTH deficiency, adult growth hormone deficiency was diagnosed following

tests. Treatment with hydrocortisone relieved hyponatremia and re-institution of enalapril did not

reduce serum sodium concentration. The final diagnosis was hyponatremia caused by hypopituitarism.

<Learning objective: Secondary adrenal insufficiency with subsequent hypopituitarism should be

suspected in cases with sudden-onset and prolonged hyponatremia in acute illness. Furthermore, the

management of hypopituitarism should include assessment of growth hormone release to exclude

growth hormone deficiency.>

� 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

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Journal of Cardiology Cases

jo u rn al ho m epag e: ww w.els evier . c om / lo cat e/ jcc as e

Introduction

Various disease states are associated with hyponatremia [1,2].In acute coronary syndrome (ACS), one study reported thepresence of hyponatremia on admission in 20 (10.5%) of 235patients with myocardial infarction, and demonstrated thathyponatremia in the early phase of ACS was a predictor ofnegative clinical outcome [3].

ACS results in marked activation of the renin–angiotensinsystem and increased catecholamine production. These factorspromote renal vasoconstriction leading to diminished glomerularfiltration rate and subsequent delivery of tubular fluid to thediluting segment of the nephron, further contributing to a

* Corresponding author at: Department of Cardiovascular Medicine, Graduate

School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku,

Kumamoto 860-8556, Japan. Tel.: +81 96 373 5175; fax: +81 96 362 3256.

E-mail address: arimay@kumamoto-u.ac.jp (Y. Arima).

http://dx.doi.org/10.1016/j.jccase.2014.08.002

1878-5409/� 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All right

reduction in renal water excretion. Consequently, patients withACS are predisposed to hyponatremia, especially in the presence ofmarked neurohormonal activation [4]. We describe a patient whopresented with non-ST-elevation myocardial infarction (NSTEMI),developed disturbances of consciousness following angioplasty,and was found to have hyponatremia associated with adrenalinsufficiency and hypopituitarism.

Case report

A 58-year-old Japanese man with no past medical historyvisited our hospital due to exacerbating chest pain, whichappeared 6 months earlier. He had visited a general practitioner1 week before, and the electrocardiogram (ECG) and chest X-raytaken at that visit showed no significant findings. The coronary riskfactors included dyslipidemia and smoking, but he was free ofother risk factors including hypertension, diabetes mellitus, andfamilial history. His height, weight, and body mass index were

s reserved.

K. Marume et al. / Journal of Cardiology Cases 10 (2014) 226–230 227

176 cm, 79.1 kg, and 25.54. He did not show any disturbance ofgrowth in childhood. He did not take any medications.

On admission, the ECG showed inverted T wave in V1–4 (Fig. 1),and blood tests showed leukocyte count of 7000 mm�3, serumsodium of 137 meq./l, potassium of 4.4 meq./l, creatine kinase(CK) of 223 U/l, CK-MB 16 U/l, and high-sensitive cardiac troponinT of 0.78 ng/mL. The clinical diagnosis was NSTEMI. He wastreated with infusion of isosorbide dinitrate, heparin, oral aspirin(100 mg/day), carvedilol (2.5 mg/day), rosuvastatin calcium(2.5 mg/day), and enalapril (2.5 mg/day).

On day 4, plasma sodium concentration decreased to 123 meq./lwith low plasma osmolality of 237 mOs/l, high urinary osmolalityof 673 mOs/l, and high urinary sodium concentration of 250 meq./l.At that point, we suspected drug-induced syndrome of inappropri-ate antidiuretic hormone secretion (SIADH) and started the infusionof normal saline for correction of hyponatremia. However, the chestsymptom exacerbated and ECG showed ST-segment elevation onday 5 despite adequate infusion therapy. Percutaneous coronaryintervention (PCI) was urgently performed; coronary angiography

Fig. 1. Electrocardiogram recorded on admission showed inverted T waves in V1–4.

showed 90% narrowing of the left anterior descending artery,segment 7 (Fig. 2). A drug-eluting stent was implanted successfullyduring the same PCI. Infusion of normal saline was continued duringthe PCI. However, marked disorientation and mental confusiondeveloped after the PCI. An urgent computed tomography showedno brain lesion. Based on a further decrease in serum sodiumconcentration to 113 meq./l, worsening hyponatremia wassuspected as the cause of the disorder of consciousness. Westarted the correction of sodium concentration using 3% sodiumchloride and stopped the prescription of enalapril, which wasthought to be the causative drug. Besides, he also showed lowconcentration of cortisol (6.1 mg/dL, at the day before PCI), weinfused 100 mg hydrocortisone for 3 days. Serum sodiumconcentration rose to 118 meq./l the following day, togetherwith recovery of mental status. Based on the improvement, theinfusion was replaced with normal saline. Although serumsodium concentration continued to rise to 132 meq./l, the patientwas placed on oral sodium chloride intake to maintain serumsodium concentration (Fig. 3).

Fig. 2.Coronary angiogram showed 90% stenosis of the left anterior descending artery, segment 7 (left). A drug-eluting stent was deployed in the culprit lesion with

excellent result (right).

0

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Hydrocortisone 5 mg (Oral)

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Fig. 3.

Clinical course showing changes in serum sodium concentrations and cortisol. Hyponatremia progressively worsened after admission to the hospital. The lowest

sodium concentration was recorded the day after percutaneous coronary intervention (PCI). Hyponatremia continued after cessation of enalapril. Oral sodium

chloride was prescribed to increase serum sodium concentration. Sodium chloride supplementation was not needed following the use of hydrocortisone, which

was prescribed following the diagnosis of hypopituitarism.

K. Marume et al. / Journal of Cardiology Cases 10 (2014) 226–230228

No chest pain occurred after the PCI and he could be dischargedwithout any complaint. However, low cortisol level persisted for along time after discharge. Based on this finding, the patientunderwent a battery of hormonal assays after suspicion of adrenaldysfunction.

The response of adrenocorticotropic hormone (ACTH) tocorticotropin releasing hormone (CRH) administration was almost

blunted. Rapid ACTH test first showed reduced increase of cortisolconcentration, but the continuous ACTH test showed normalcortisol response (Table 1). Based on these findings, the provisionaldiagnosis was secondary adrenocortical insufficiency due to ACTHdeficiency. Thyrotropin-releasing hormone (TRH) test and leute-nizing hormone releasing hormone (LH-RH) test showed normalresponse (Table 1). Next we performed the growth hormone

Table 1 Results of various hormonal tests.

Control 30 min 60 min 90 min 120 min Result

CRH test

ACTH (pg/mL) 32.3 38.6 39.9 32.5 33.9 Reduced

Cortisol (mg/dL) 5.4 5.9 6.7 6 5.4 Reduced

TRH test

TSH (mIU/mL) 2.54 13.73 10.95 8.11 6.33 Normal

PRL (ng/mL) 7.5 12.5 9.5 8 7.6 Normal

LH-RH test

LH (mIU/mL) 3.4 17.8 17.4 14.8 13 Normal

FSH (mIU/mL) 3.7 6.6 7.1 7.2 7 Normal

Rapid ACTH test

Cortisol (mg/dL) 2.2 7.7 9.2 9.9 9.2 Reduced

Control Day 1 Day 2 Day 3 Result

Continuous ACTH test

Urinary free-cortisol (mg/day) 12.4 43.4 318 735 Normal

Control 15 min 30 min 60 min Result

GHRP2 test

HGH (ng/mL) <0.1 0.2 0.4 0.3 Reduced

ACTH, adrenocorticotropic hormone; CRH, corticotropin releasing hormone; FSH, follicular-stimulating hormone; GHRP2, growth hormone releasing peptide 2; HGH, human

growth hormone; PRL, prolactin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; LH-RH, leutenizing hormone releasing hormone.

K. Marume et al. / Journal of Cardiology Cases 10 (2014) 226–230 229

releasing peptide 2 (GHRP2) test. Normally, the peak growthhormone concentration raises more than 16 ng/mL; however, hispeak concentration was only 0.4 ng/mL (Table 1). The level ofinsulin-like growth factor (IGF-1) showed low concentrationcompared with age-adjusted standard (IGF-1: 41 ng/mL). Basedon the results of the hormonal assays, the patient was diagnosedwith severe adult growth hormone deficiency (AGHD).

The assessment by brain magnetic resonance imaging (MRI)was difficult because of his severe claustrophobia at first, but wecould undertake this using the open MRI scanner. There were nodefinite findings of macroadenoma, hypophysitis, pituitary apo-plexy, or infiltration disorder.

Hydrocortisone was introduced for ACTH deficiency and theamount of oral sodium chloride was gradually decreased. Oralsodium chloride was finally withdrawn without subsequenthyponatremia. Furthermore, resumption of enalapril was notassociated with changes in serum sodium concentrations, whichinvalidated our previous diagnosis of drug-induced SIADH.

Discussion

We describe a patient with NSTEMI and prolonged hypona-tremia caused by adrenal insufficiency with subsequent hypopi-tuitarism. Hyponatremia sometimes accompanies ACS andcorrelates with poor clinical outcome. Previous reports warnedthat certain drugs used for the treatment of ACS, such asangiotensin-converting enzyme inhibitors, can cause SIADH. Inour patient, we first suspected the involvement of enalapril indrug-induced SIADH; however, cessation of enalapril did not resultin improvement of hyponatremia.

Adrenal insufficiency is another cause of hyponatremia, andlong-term hypocortisolemia is one of its important symptoms. Inour patient, the ability to release ACTH in response to CRH wasimpaired. In addition, treatment of the patient with cortisolrelieved continuous oral sodium chloride supplement. Thesefindings indicate that secondary adrenal insufficiency was thecause of hyponatremia.

In addition to adrenal insufficiency, our hormonal assaysshowed severely impaired growth hormone release in response toGHRP2. Thus, the AGHD was considered a comorbid diseaseinvolving adrenal insufficiency and hypopituitarism. In hypopitu-itarism, hormone deficiency often shows this order: growthhormone, FSH/LH, TSH, and ACTH. However, in our patient, no

abnormalities were evident in FSH/LH and TSH functions. The mostcommon cause of hypopituitarism in adults is hypothalamic-pituitary tumors or treatment of them with pituitary surgeryand/or radiotherapy [5]. Our patient had not undergone any brainsurgery, and no adenoma was visible on the MRI. While MRI cannotrule out only a small pituitary adenoma, a close long-term follow-up of the patient, including hormonal assays, is necessary to ruleout pituitary adenoma.

Growth hormone deficiency (GHD) is a known risk factor foratherosclerosis. The severity of GHD correlates with high levels ofserum total cholesterol, low-density lipoprotein-C (LDL), truncalfat, and risk of hypertension [6–8]. Furthermore, two previousstudies demonstrated that premature mortality in hypopituitarismis due to increased cardiovascular mortality, which correlates withGHD [9,10]. In our patient, hyponatremia had not been noted inannual health examinations before his admission. NSTEMI seemsto have triggered hypocortisolemia and adrenal insufficiency,because ACS raises the amount of ACTH and cortisol demand [11].It is also possible that GHD promoted the progression ofatherosclerosis and development of ACS.

Conflict of interest

The authors did not receive any fees, honoraria, grants orconsultancies that would constitute a conflict of interest with thisstudy.

Acknowledgment

This work was supported in part by a grant-in-aid for scientificresearch from the Japanese Ministry of Education, Culture, Sports,Science and Technology.

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