[Case Study] A Case of Hyponatremia Caused by Central Hypocortisolism - Page 2 (2025)

Discussion of Diagnosis

Hyponatremia, defined as a decrease in serum sodium concentration to below 135 mmol/l, is one of the most common electrolyte disorders, and affects up to 15% of all hospitalized patients in Western countries.^[1] Hyponatremia can be divided into three forms on the basis of plasma osmolality: hypotonic, nonhypotonic (essentially represented by pseudohyponatremia, i.e. hyponatremia in the presence of severe hyperlipidemia or paraproteinemia) and hypertonic (i.e. caused by hyperglycemia).

Hypotonic hyponatremia is the consequence of an excess of water in relation to total body sodium stores. Hypotonic hyponatremia results from depletion of total body sodium in excess of concurrent body water losses, or from dilution of total body sodium by increases in total body water.^[2] Depending on the patient's EVS, hypotonic hyponatremia can be classified as one of three types: hypovolemic, hypervolemic and normovolemic ( Table 2 ).^[1]

Normovolemic hyponatremia, essentially represented by the syndrome of 'inappropriate' secretion of antidiuretic hormone (SIADH), accounts for about 60% of all cases of chronic hyponatremia (inappropriate because secretion occurs other than in response to plasma hyperosmolarity, arterial hypotension or hypovolemia). The diagnostic criteria for SIADH include urine osmolality higher than 100 mOsm/kgH₂0, initial renal sodium excretion higher than 30 mmol/l, absence of edema or volume depletion, and normal renal, adrenal and thyroid function.^[3]

Normovolemic hyponatremia is also present in patients with secondary hypocortisolism, the clinical and biochemical features of which are hard to distinguish from those of SIADH.^[4] In secondary hypocortisolism the main cause of hyponatremia seems to be an increase in arginine vasopressin (AVP) production, which is mainly caused by loss of the tonic inhibitory effect of endogenous cortisol on AVP secretion;^[5] other factors—such as nausea and hypoglycemia—can also exert a similar effect.^[4] It has been demonstrated that hypocortisolism results in overexpression of aquaporin-2 water channels, which results in decreased water excretion by the kidney.^[6]

Hypothyroidism is another possible cause of normovolemic hyponatremia. The decreased cardiac output and effective arterial blood volume (EABV) that occur in patients with hypothyroidism reduce the glomerular filtration rate and, therefore, cause an increase in proximal tubular water reabsorption; moreover, decreased EABV stimulates AVP secretion, which further promotes water reabsorption.^[7]

This patient's biochemical features (normal serum levels of creatinine and urea, low serum levels of uric acid and low hematocrit) and clinical features (absence of edema or signs of volume depletion) were in agreement with a diagnosis of normovolemic hyponatremia; her plasma and urine osmolality values and sodium urinary excretion levels were consistent with a diagnosis of SIADH. This syndrome is often caused by tumors, drugs ( Table 3 ), central nervous system and pulmonary disorders;^[8] nevertheless, in this patient the association of gastrointestinal symptoms, amenorrhea, weight loss, and in particular hypoglycemia, were suggestive of hypocortisolism; her psychiatric symptoms could also be in agreement with this diagnostic hypothesis. In fact, hypocortisolism caused by reduced bioavailability of cortisol or impaired glucocorticoid responsiveness has been found to be associated with depression in a number of instances.^[9]

This patient's clinical features (presence of normovolemia and lack of skin pigmentation) and biochemical features (normal serum levels of potassium and urea and low levels of plasma renin activity) indicated that a diagnosis of primary adrenal failure was unlikely, whereas secondary hypocortisolism was considered a likely diagnosis. An extensive baseline and dynamic evaluation of her pituitary function revealed the presence of an isolated ACTH deficit. This rare condition is often associated with lymphocytic hypophysitis, a suggested autoimmune disorder,^[10] which has particularly been reported in women.

A diagnosis of lymphocytic hypophysitis can only be established by histologic examination, but several features of the patient supported this hypothesis—a close temporal relationship between clinical manifestation and pregnancy, the radiologic finding of pituitary stalk enlargement,^[11] the presence of hormonal pituitary abnormalities (such as hyperprolactinemia, but in particular an isolated ACTH deficiency) and the association with autoimmune thyroiditis ( Table 1 ). The natural history of lymphocytic hypophysitis might be variable, and spontaneous remission might be observed, but a careful follow-up is required in order to identify any abnormalities in other pituitary hormones.^[10]

A further aspect that should be considered in this patient is the presence of hypergonadotropic amenorrhea. In most cases, amenorrhea that occurs during chronic disease is characterized by low levels of gonadotropins. Hypocortisolism itself, however, might negatively affect ovarian function.^[12] Cortisol has also been demonstrated to stimulate the secretion of estrogen and progesterone by granulosa cells.^[13]