Unexpected Cause of Hyponatremia in Chronic Obstructive Pulmonary Disease：Pituitary Adenoma

Correspondence and requests for reprints : Dr. Wen-Jen Tsai

Address : Division of Nephrology, Department of Medicine, Mackay Memorial Hospital, Taitung Branch. No.1, Lane 303, Changsha Street, Taitung 950, Taiwan

Unexpected Cause of Hyponatremia in Chronic Obstructive Pulmonary Disease

Pituitary Adenoma

Wen-Jen Tsai, Yi-Chou Chen

, Chien-Liang Wu

, Han-Hsiang Chen

, Jui-Chi Yeh

, and Chih-Jen Wu

Abstract

Hyponatremia in patients with chronic lung disease may be caused by a variety of disorders, but treatable, curable disorders may be overlooked. A 75-year-old man with chronic obstructive pulmonary disease (COPD) presented with an episode of syncope. He denied the use of diuretics or systemic steroids. He used oral bronchodilators for his lung disease. His blood pressure and volume status were normal. He had hyponatremia with a serum sodium level of 122 mmol/L. This was initially attributed to the very common syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The hypona- tremia persisted despite good control of the COPD. Measurement of hormones indicated hypopitu- itarism. Magnetic resonance imaging of the brain showed a pituitary macroadenoma in the sella. The tumor was removed by transsphenoidal surgery and the patient was treated with glucocorticoid and thyroid hormone replacement temporarily. His serum sodium normalized without further treatment. Non- functional pituitary adenoma with hypopituitarism should be kept in mind as a cause of hyponatremia in pulmonary diseases, especially in the elderly patients. ( J Intern Med Taiwan 2007; 18: 360- 364 )

Key Words Hyponatremia, Syndrome of inappropriate secretion of antidiuretic hormone, Chronic obstructive pulmonary disease, Pituitary adenoma

Division of Nephrology, Department of Medicine, Mackay Memorial Hospital, Taitung Branch;

1

Division of Nephrology,

Division of Chest, Department of Medicine, Mackay Memorial Hospital, Taipei

Introduction

Hyponatremia is the most common electrolyte

disorder seen in hospitalized patients and may con- tribute substantially to morbidity and mortality.

Patients with chronic obstructive pulmonary disease

(COPD) are susceptible to hyponatremia for a num- ber of reasons. Chronic hypoxia and hypercapnia sec- ondary to the underlying pulmonary illness, heart fail- ure or renal insufficiency, use of diuretics, SIADH, hypokalemia attributed to bronchodilators or steroids, malnutrition, and poor intake during acute exacerbations are common contributing factors for hyponatremia in such patients

. Activation of the renin-angiotensin-aldosterone system and inappro- priately elevated plasma arginine vasopressin (AVP) in COPD may cause hyponatremia mimicking SIADH

. SIADH is associated with a number of pul- monary disorders, including pneumonia, tuberculo- sis, asthma, pneumothorax, lung cancer, bronchial adenoma, and positive-pressure ventilation, in addi- tion to non-pulmonary causes such as diseases of the central nervous system, medications, severe stress condition, and ectopic AVP production

. The dan- ger in managing a patient with COPD is simply at- tributing hyponatremia to SIADH without consider- ing other causes. We report a case illustrating this point.

Case Report

A 75-year-old Chinese man had had mild COPD and hypertension for six years. He had a 30-to-40 pack-year smoking history. He reported dyspnea on exertion and a cough productive of yellow sputum for one month before admission. Medications within the previous six months included oral sustained release salbutamol 8mg/day and sustained release diltiazem 90 mg/day. He had not been treated with steroids, and he denied any recent weight gain or loss. He also drank 300 to 500 ml of water before sleep because of thirst, and his diet was generally bland. He was ad- mitted because of an episode of syncope when he went to the toilet in the morning. He regained conscious- ness about one hour later when his family found him lying on the floor. He denied having a severe bout of coughing prior to the event, nor was it directly asso- ciated with either micturation or defecation. The pa-

tient was 170 centimeters tall and weighed 68 kilo- grams. His temperature was 36.7 , pulse rate 90 per minute with a regular rhythm, respiratory rate 20 per minute, and blood pressure 130/80 mmHg without postural hypotension. His extracellular fluid volume appeared to be normal. There was paucity of axillary and pubic hair. On chest auscultation, left basal crack- les were heard. The rest of the examination was un- remarkable. In particular, there was no evidence of skull trauma, symptoms or signs of increases in- tracranial pressure, visual disturbance, neck rigidity, focal neurological deficits, Cushingoid changes, or abnormal skin pigmentation.

He had leukocytosis with a mild left shift (15900/ l with 86% neutrophils). The only abnor- malities on initial biochemical tests were a sodium of 122 mmol/L and a serum osmolarity of 260 mosm/kg (Table.1). Urine testing revealed a relatively high sodium excretion (55 mmol/L) and an inappropriate- ly concentrated urine (337 mosm/kg). The electro- cardiogram was normal. A chest x-ray film displayed increased bronchovascular markings in both lower lung fields. High resolution computed tomography of the lung demonstrated slight bronchial dilatation in the posterior basal segments of both lower lobes con- sistent with traction bronchiectasis as well as diffuse interlobular septal thickening and panlobular and centrilobar emphysema. He was thought to have an exacerbation of his COPD associated with a lung in- fection. Based on the serum and urine electrolyte da- ta and the patient's euvolemic state, the hyponatrem- Table 1.Biochemical studies on admission

Plasma Range Urine

Na

(mmol/L) 122 135-147 Na

(mmol/L) 55 K

(mmol/L) 4.6 3.5-5.3 K

(mmol/L) 30.9 Cl

(mmol/L) 95 95-108 Cl

(mmol/L) 75 Creatinine(mg/dl) 1.0 0.5-1.3 Creatinine(mg/dl) 68.9 Osmolality 260 285-295 Osmolality 337

(mosm/kg) (mosm/kg)

Urea(mg/dl) 16 5-22 Volume(ml/day) 1,430

Uric acid(mg/dl) 3.6 2.5-7.5

ia was attributed to SIADH secondary to his pul- monary disease. He was treated with broad-spectrum antibiotics which brought his pulmonary infection under control. However, after intravenous fluid ad- ministration of potassium chloride 20 meq added in normal saline 1,000 ml daily for two weeks, he re- mained hyponatremic with a serum sodium of 129 mmol/L. No explanation for his initial syncopal episode had been found, as there was no evidence of cardiovascular disease, a cerebral vascular accident, medication side effects, or orthostatic hypotension.

Further testing was undertaken and the patient was unexpectedly found to have partial anterior hy- popituitarism, with an elevated prolactin level and low levels of human growth hormone, luteinizing hormone, and testosterone (Table.2). An MRI study of the brain with and without contrast enhancement revealed a pituitary tumor extending into the suprasel- lar area up to the inferior border of the optic chiasm (Fig.1). Bitemporal hemianopia developed three weeks later. The patient then underwent transsphe- noidal resection of the pituitary tumor. We had start- ed glucocorticoids and thyroid hormone replacement two days prior to surgery until one week after opera-

tion to cover the stress during and after tumor resec- tion. Normal diet was initiated after surgery. The fol- low-up serum sodium levels on the first day and in the third week after operation had normalized to 139 mmol/L and 139 mmol/L respectively. The serum sodium level remained normal over the next three months of follow-up.

Discussion

The initial findings in our patient of COPD with secondary infection and impaired water excretion re- sulting in hypo-osmotic hyponatremia all seemed consistent with SIADH, a relatively common finding.

SIADH is defined as excess secretion or action of AVP in a euvolemic patient without a commensurate reduction in fluid intake resulting in water retention and decreased plasma osmolarity and sodium

. Our patient met these criteria, with his history of nightly fluid intake and a bland diet further supporting the diagnosis. Free water administration combined with a low salt and solute intake further worsen hypona- tremia when water excretion is impaired.

The degree of hyponatremia in patients with COPD generally correlates with the severity of the lung disease. It is particularly common in patients who are relatively hypercapnic and hypoxic and un- Table 2.Results of hormonal tests

Test Result Range

Prolactin(ng/ml) 29.6 1-18

Human growth hormone 0.39 <5 (HGH)(ng/ml)

Luteinizing hormone <3 <25 (LH)(mIU/ml)

Testosterone(ng/ml) <0.2 1.81-7.72 Thyroid stimulating hormone 1.36 0.50-5.15 (TSH)( IU/ml)

Thyroxine,free 1.14 0.8-2.0

(FT4)(ng/dl)

Adrenocorticotropic hormone 41.2 9-52 (ACTH)(pg/ml)

Cortisol(8AM)( g/dl) 8.4 5-20

Cortisol(5PM)( g/dl) 4.59 2.5-10

Renin(supine)(pg/ml) 7.86 2.4-22

Aldosterone(supine)(pg/ml) 76.9 29.9-158.8

Fig.1.MRI of the sella with contrast enhancement on

sagittal and coronal sections. The pituitary gland

is enlarged, measuring from 14 to 16 mm and ex-

tends to the suprasellar area, contacting the infe-

rior border of the optic chiasm. There was en-

hancement of the pituitary stalk enhances and is

slightly displaced to the left. No involvement of the

cavernous sinuses or abnormal enhancement in

the hypothalamus is seen.

der substantial physiologic stress, as may occur in se- vere COPD, serious secondary infection, or acute res- piratory failure

. The hyponatremia should not be ignored, as it is a risk factor for a poor outcome of pneumonia in elderly patients

. But our patient's lung disease was not that severe, and his infection seemed to respond adequately to antibiotics. It was the persistence of the hyponatremia despite his improved pulmonary condition that prompted us to look for another cause of SIADH and led to the finding of partial anterior hypopituitarism secondary to a pituitary macroadenoma.

Hyponatremia alone is not uncommon in a pa- tient with untreated hypopituitarism, where it is usu- ally attributed to secondary hypothyroidism and/or hypocortisolism

, but there are not many reports in the literature of SIADH directly caused by a pituitary tumor

. Proposed explanations of the SIADH as- sociated with pituitary tumors include (a) chemical stimuli of the hypothalamus-neurohypophyseal- adrenal system

or (b) the tumor exerting local me- chanical stress

. SIADH may develop in patients with pituitary tumors who have no evidence of pitu- itary dysfunction; in such cases removal of the tumor may resolve the SIADH

.

Our patient's tumor was non-functioning, and he had only partial hypopituitarism. His serum sodium level remained normal after discontinuance of hor- monal replacement over the next three months post- surgically. The thyroid and adrenal function had not yet been compromised. That makes it reasonable to hypothesize that his non-functioning pituitary macroadenoma exerted pressure on the stalk, induc- ing over-secretion of AVP, which resulted in SIADH.

The MRI study showed evidence that the macroade- noma displaced the pituitary stalk slightly to the left (Fig.1). The postoperative return of his sodium to nor- mal levels supports this hypothesis.

In summary, hyponatremia due to SIADH is not uncommon in patients with lung disease, but it should not be casually dismissed as a transient phenomenon

secondary to the underlying disease. This is particu- larly important in elderly patients who may have a number of comorbidities and multiple medications that confuse the picture. At the very least, the histo- ry and physical examination should be carefully re- viewed for any signs or symptoms of intracranial le- sions. If the hyponatremia fails to resolve as the un- derlying lung disease improves, a search for other causes of SIADH should be undertaken to avoid miss- ing potentially curable disorders.

Acknowledgment

We are grateful to Dr. Shih-Hua Lin and Dr.

Mary Jeanne Buttrey for critical review and revision of the manuscript.

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1 2 1 1 1

1 2

122 mmol/L

( SIADH )