Severe hyponatraemia due to hypothalamic–pituitary adrenal insufficiency

Johannes Jacobi, Jens Titze, Patricia Niewerth, Rainer Lang, Bernd Schulze and Harald D. Rupprecht

Medizinische Klinik IV, Department of Medicine, Nephrology, University of Erlangen-Nürnberg, Germany

Keywords: hyponatraemia; hypothalamic–pituitary adrenal insufficiency

Introduction

Hyponatraemia results from water retention due to an inability to excrete ingested water or an excessive loss of sodium in relation to water. Rarely, hyponatraemia can be the consequence of acute or chronic adrenal insufficiency [1,2]. Adrenal insufficiency may result from dysfunction of the adrenal glands, or from disorders of the pituitary gland or the hypothalamus.

Case

A 61-year-old woman was admitted to our hospital complaining of general fatigue, dizziness, and loss of appetite. Past medical history was remarkable for hepatitis B infection in 1963 following a blood transfusion after a car accident which resulted in neck trauma. Her other medical history was unremarkable and she was on no current medication. The patient had no children and had never been pregnant; menstruation was reported as having been regular; menopause occurred at the age of 48.

On admission blood pressure was 120/75 mmHg, heart rate 92/min, respiratory rate 12 per min, and body temperature 36.8°C. The patient was euvolaemic, body mass index was 21.3 kg/m2. Striking findings on inspection were pale skin, loss of axillar hair and scarce pubic hair. Physical examination was only significant for cerebellar ataxia noted in the balancing task test (Romberg). Chest X-ray and ECG were normal.

Initial laboratory studies showed the following abnormal results: serum sodium was 111 mmol/l, potassium 3.2 mmol/l, chloride 89 mmol/l, and cholesterol 221 mg/dl. The haemogram, liver function tests, parameters of renal function (urea nitrogen 20 mg/dl, serum creatinine 0.8 mg/dl), glucose level (89 mg/dl), acid–base status (pH 7.35; bicarbonate 24.5 mmol/l) and clotting test were within the normal ranges. Urinalysis showed no abnormalities, specific gravity was 1.010.

Due to the low serum sodium concentration, further laboratory tests were performed. Initial serum osmolality was 254 mOsmol/kgH2O, urine osmolality 235 mOsmol/kgH2O, urinary sodium excretion 10 mmol/day, and free water clearance 0.042 ml/min. Plasma antidiuretic hormone (ADH) concentration was 1.2 pg/ml and thus inadequately high compared to the low plasma osmolality.

On admission the patient was treated with physiological saline solution until serum sodium concentration was within a safe range (Figure 1Go). Cessation of infusion initially resulted in a further increase of serum sodium concentration that was followed by a slow yet progressive decrease (Figure 1Go). On day 8 the patient was put on a salt-rich diet with additional salt supplement (3 g/day) and water restriction (1 l/day). Normal saline solution was added again from day 9 on (1 l/day). With this treatment sodium concentration could be kept around 125 mmol/l.



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Fig. 1. Impact of therapy on sodium concentration and serum and urine osmolality. NS, normal saline solution.

 
On day 8 a 24-h cortisol and ACTH (adrenocorticotrophic hormone) profile showed values that were all below the normal range of 5–25 µg/dl and 15–60 pg/ml respectively. In addition, urinary excretion of 17-hydroxycorticosteroids (17-OHCS) was low at 2.50 mg/day (normal range 3–15 mg/day). Thus, further hypothalamic–pituitary–adrenal function tests were performed. Cortisol showed a moderate yet significant increase in response to rapid administration of 250 µg ACTH (ACTH test), suggesting a diagnosis of secondary or tertiary adrenal insufficiency. The CRH test (corticotropin releasing hormone) induced an increase of both ACTH and cortisol, suggesting hypothalamic or partial pituitary insufficiency. Because of these findings additional laboratory tests were performed to study the concentration of other hormones released by the pituitary gland such as luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), prolactin and thyroid stimulating hormone (TSH) (Table 1Go). Interestingly, levels of FSH, LH, and GH were also reduced. Pituitary anterior lobe stimulation test with growth-hormone releasing hormone (GHRH) was positive in that an increase of GH was observed, whereas LH and FSH did not significantly rise in response to luteinizing-hormone releasing hormone (LHRH). Prolactin and TSH were both elevated. Increased TSH levels together with reduced peripheral thyroid hormones (fT3, fT4) indicated manifest primary hypothyroidism. This diagnosis was strengthened by an exaggerated increase of TSH in the provocation test with thyrotrophin-releasing hormone (TRH). Slightly elevated thyroid peroxidase antibodies (TPO) pointed to a diagnosis of Hashimoto thyroiditis.


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Table 1. Endocrinological data

 
Gadolinium-enhanced MRI scan showed hypothalamic atrophy and tiny ischaemic lesions within this region and the thalamus. Furthermore, MRI images showed herniation of the diaphragma sellae with extension of the suprasellar subarachnoid space into the sella turcica and consecutive compression of the pituitary gland and the hypophyseal stalk against the posterior rim of the pituitary fossa (Figure 2Go).



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Fig. 2. T1 weighted sagittal MRI scan of the brain. SS, sphenoid sinus; P, pons; C, cerebellum. Arrow indicates herniation of the third ventricle into the pituitary fossa.

 
Interestingly, apart from neck trauma past medical history was unremarkable for cerebral stroke, cranial surgery, or irradiation.

After having completed endocrinological tests the patient was treated with hydrocortisone (20 mg in the morning and 5 mg in the evening) starting at day 16. Steroid therapy rapidly corrected hyponatraemia and all previous efforts to control sodium concentration were discontinued on the following day (Figure 1Go). Treatment was also associated with noticeable improvement in well-being of the patient and full recovery of neurological functions.

Discussion

In euvolaemic subjects with hypo-osmolal hyponatraemia, the differential diagnoses that have to be taken into consideration are glucocorticoid deficiency, hypothyroidism, psychogenic polydipsia, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Our case illustrates a rare presentation of hypo-osmolal hyponatraemia caused mainly by adrenal insufficiency. Based on stimulation tests, adrenal insufficiency with consecutive hyponatraemia was the consequence of hypothalamic–pituitary dysfunction. MRI images showed hypothalamic atrophy with ischaemic lesions and herniation of the diaphragma sellae, the so called empty sella syndrome. The radiological features of this syndrome are frequently seen in asymptomatic patients with an age-related incidence of 10–35% [3]. Due to the functional reserve of the pituitary gland patients with an empty sella syndrome very rarely present with endocrinological disorders.

Clinical symptoms resulting from hypothalamic or pituitary anterior lobe insufficiency include lack of axillary or pubic hair (FSH+LH{Downarrow}), apathy (TSH{Downarrow}), adynamia (ACTH{Downarrow}) and alabaster skin (MSH{Downarrow}) [4], which were in part observed in our patient, who had a complex endocrinological status suggesting combined hypothalamic–pituitary insufficiency.

Interestingly, single treatment with hydrocortisone immediately corrected serum sodium concentrations and led to full recovery from neurological symptoms such as the ataxia often found in these patients as a consequence of cerebral oedema [5].

The exact mechanisms by which adrenal insufficiency causes hyponatraemia are unclear. Glucocorticoid deficiency seems to be an important non-osmotic stimulus of vasopressin secretion, since hypersecretion of ADH relative to plasma osmolality can be corrected by steroid treatment [2,68]. In addition, hypocortisolism has been shown to exert direct, vasopressin-independent renal tubular effects by decreasing free water clearance [7,9]. Interestingly, in our patient ADH levels were below the normal range of healthy individuals, but inappropriately high in face of the severe serum hypo-osmolarity.

In agreement with previous reports the renin–angiotensin–aldosterone system did not substantially contribute to the pathophysiology of hyponatraemia in this case, since both renin and aldosterone concentrations were within the normal ranges suggesting an intact zona glomerulosa of the adrenal glands [4]. Normally, hyponatraemia is associated with development of hyperaldosteronism due to a direct stimulation of the zona glomerulosa. However, in an animal model of panhypopituitaric rats, Decaux et al. reported rather low aldosterone levels compared to normal rats, in which hyponatraemia induced a threefold increase of aldosterone concentration [10]. Interestingly, corticosteroids restored aldosterone levels in rats with panhypopituitarism, pointing to the crucial role of corticosteroids in the development of hyponatraemia-related hyperaldosteronism.

Conclusions

In patients with hypo-osmolal hyponatraemia in the absence of cardiac, hepatic, or renal disease and with normal volume status, glucocorticoid deficiency due to adrenal insufficiency is a rare differential diagnosis. Hypothalamic–pituitary–adrenal provocation tests help to define whether adrenal insufficiency is primary, secondary, or tertiary in these cases. Correction of hyponatraemia due to adrenal insufficiency is readily achieved by substitution of hydrocortisone, and results in prompt recovery from hyponatraemia, and adrenal insufficiency-induced neurological symptoms.

Notes

Correspondence and offprint requests to: Dr Johannes Jacobi, Medizinische Klinik IV/4, University of Erlangen-Nürnberg, Breslauer Str. 201, D-90471 Nürnberg, Germany. Back

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Received for publication: 14.10.00
Revision received 3. 3.01.



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