Endocrine disorders: Causes of hyponatremia not to neglect

Abstract

Hyponatremia is a common electrolyte abnormality with the potential for significant morbidity and mortality. Endocrine disorders, including adrenal deficiency and hypothyroidism, are uncommon causes of hyponatremia. Primary adrenal insufficiency (i.e. Addison's disease) may well be recognized by clear hall-marks of the disease, such as pigmentation, salt craving, hypotension, and concomitant hyperkalemia. Addison's disease is an important diagnosis not to be missed since the consequences can be grave. On the other hand, hypothyroidism and secondary adrenocortical insufficiency originating from diseases of the hypothalamus and/or pituitary (hypopituitarism) require a high index of suspicion, because the clinical signs can be quite subtle. This review focuses on clinical and pathophysiological aspects of hyponatremia due to endocrine disorders.

Key words::

• Adrenal insufficiency
• hyponatremia
• hypopituitarism
• hypothyroidism
• syndrome of inappropriate antidiuresis

Key messages

• Hyponatremia is the most common electrolyte disturbance in hospitalized patients.

• Endocrine disorders are uncommon causes of hyponatremia.

• Testing for adrenal insufficiency should be part of the hyponatremic work-up, as this disorder responds promptly to hormone replacement, while the consequences can be grave when the diagnosis is missed.

Introduction

Hyponatremia is the most common electrolyte disturbance in hospitalized patients with an incidence varying considerably (up to 30%), depending on the definition, and a potential for significant morbidity and mortality (1,2). It can be seen either in isolation or, as most often is the case, as a complication of other medical illnesses. Endocrine disorders are uncommon causes of hyponatremia. Primary adrenal insufficiency (i.e. Addison's disease) may well be recognized by clear hall-marks of the disease, such as pigmentation, salt craving, hypotension, and concomitant hyperkalemia. Addison's disease is an important diagnosis not to be missed since the consequences can be grave. On the other hand, hypothyroidism and secondary adrenocortical insufficiency originating from diseases of the hypothalamus and/or pituitary (hypopituitarism) require a high index of suspicion, because the clinical signs can be quite subtle. Adrenal insufficiency is probably the most important disorder to exclude, since the consequences can be grave when adrenal insufficiency is missed (3).

This review focuses on clinical and pathophysiological aspects of hyponatremia due to endocrine disorders.

Pathogenesis of hyponatremia

Hyponatremia is generally attributed either to water retention or (less often) to loss of effective solutes (sodium plus potassium) in excess of water. Since the capacity for water excretion may be large even under normal conditions, retention of water leading to hyponatremia occurs only in the presence of conditions that impair renal excretion of water (4). An exception to this rule is acute primary polydipsia (‘acute water intoxication’) in which the excessive water intake can overwhelm even the normal excretory capacity (4).

Taking into account that the suppression of arginine vasopressin (antidiuretic hormone (ADH)) secretion is essential for the excretion of any water load, the presence of high serum concentrations of ADH is a condition sine qua non for the development and maintenance of hyponatremia. Virtually all the causes of hyponatremia (except for renal failure, primary polydipsia, beer potomania, and low dietary solute intake) are characterized by an excess of ADH (despite the presence of hypotonicity) most frequently due to the syndrome of inappropriate ADH secretion (SIADH) or to depletion of effective circulating volume, which is a normal stimulus to ADH secretion (5,6). Hypovolemia induces an activation of the carotid sinus baroreceptors, thus resulting in an appropriate increase in the secretion of ADH. Hyponatremia owing to increased ADH activity can take place in: 1) hypovolemic states due to extrarenal (e.g. diarrhea, vomiting) or renal salt loss (e.g. diuretics, cerebral sodium-wasting syndrome, mineralocorticoid deficiency); 2) euvolemic states (e.g. SIADH, hypothyroidism or adrenocorticotropin, adrenocorticotropic hormone (ACTH) deficiency); and 3) hypervolemic states (e.g. congestive heart failure, hepatic cirrhosis with ascites). The fact that the aforementioned completely different clinical entities present with hyponatremia emphasizes the importance of a careful diagnostic approach in order to select the appropriate treatment (7).

The diagnostic approach of patients with hyponatremia (based on history, physical examination, and laboratory parameters) has been reported and effectively described in several algorithms (4,8,9). Testing for adrenal insufficiency and hypothyroidism should be part of the hyponatremic work-up, as the disorders respond promptly to hormone replacement. In either case, the serum levels of thyroid-stimulating hormone (TSH), T4 (to exclude pituitary hypothyroidism since TSH can be within normal range in this context), cortisol, and adrenocorticotropic hormone (ACTH) should be measured, because hypothyroidism and hypoadrenalism can coexist as a polyendocrine deficiency disorder (i.e. Schmidt's syndrome) (10). Not infrequently the definitive etiologic clinical diagnosis of hyponatremia is delayed or even missed, with adrenal insufficiency (primary or secondary) representing the most prominent example (11).

Pathogenesis of adrenal insufficiency

Primary adrenal insufficiency

Almost all causes of Addison's disease affect the adrenal cortex as a whole and lead to deficiencies of cortisol, aldosterone, and adrenal androgen of varying extent (12). Most cases (75%–80%) are attributed to autoimmune adrenalitis, which is often associated with autoimmune disorders (13,14). Less frequent causes of primary adrenal insufficiency include infections (tuberculosis and acquired immunodeficiency syndrome (AIDS)), metastatic carcinoma, and several medications (12,15).

Rare causes of primary adrenal insufficiency

Isolated glucocorticoid deficiency is an autosomal recessive disease that is associated with primary adrenocortical insufficiency, without mineralocorticoid deficiency (16).

Selective aldosterone deficiency can occur as primary isolated hypoaldosteronism or as a result of depressed renin secretion and angiotensin II formation (hyporeninemic hypoaldosteronism). Hyporeninemic hypoaldosteronism is most common in patients with mild to moderate renal insufficiency due to diabetic nephropathy or chronic interstitial nephritis, while medications such as renin inhibitors, beta-blockers, non-steroidal anti-inflammatory drugs, cyclosporine, and tacrolimus are less frequent causes (17,18).

Type 1 pseudo-hypoaldosteronism (PHA1) is a rare congenital disease limited to early infancy and is due to renal resistance to the action of aldosterone (19). A secondary form of PHA1 has been related to drugs, such as potassium-sparing diuretics, trimethoprim, pentamidine, and cyclosporine, or tubulointestinal diseases, including tubulointestinal nephritis, and sickle cell nephropathy (20).

Secondary adrenocortical insufficiency

Secondary adrenocortical insufficiency originates in diseases of the hypothalamus and/or pituitary (hypopituitarism). Corticotropin-releasing hormone (CRH) and/or ACTH release are impaired, causing dysfunction along the hypothalamus-pituitary-adrenal axis. In such cases, ACTH is low or absent, and cortisol secretion is markedly reduced, but aldosterone levels are sustained given that aldosterone secretion is more dependent on angiotensin II than on ACTH. Chronic steroid use resulting in adrenal suppression is the most common cause of secondary adrenocortical insufficiency (15). Pituitary or hypothalamic tumors (primary or metastatic mainly breast or lung cancers) and infections, such as tuberculosis and histoplasmosis, as well as craniopharyngioma, pituitary surgery or radiation, empty sella syndrome, lymphocytic hypophysitis should be considered (12,21). Of note, hypopituitarism (especially due to space-occupying lesions) is usually accompanied by more than one pituitary hormone deficiency (22). Nonetheless, isolated corticotrophin (ACTH) deficiency mainly due to either traumatic injury or lymphocytic hypophysitis has rarely been described (23–25).

Pathogenesis of hyponatremia due to hypothalamic-pituitary-adrenal axis disorders

Primary and secondary adrenal insufficiency (hypopituitarism) represent well established causes of hyponatremia (26). Taking into consideration that cortisol is a physiological tonic inhibitor of ADH secretion, hyponatremia in patients with hypopituitarism should be ascribed to inappropriate secretion of ADH because of hypocortisolism (27). The hypersecretion of ADH in cortisol deficiency may be in part due to the reductions of systemic blood pressure and cardiac output (28,29). Hypocortisolism-mediated altered renal sensitivity to ADH is also possible as suggested by aquaporin-2 water channel up-regulation in glucocorticoid-deficient rats (30). In addition, vasopressin-independent factors, such as impaired renal hemodynamics and decreased distal fluid delivery to the diluting segments of the nephron are also implicated in the defective water handling in glucocorticoid deficiency (29,31).

In Addison's disease, not only cortisol deficiency but aldosterone deficiency also contributes to hyponatremia by causing sodium wasting and hypovolemia. Aldosterone deficiency explains why hyperkalemia may also be present (12). It is worth mentioning that primary (due to Hashimoto's thyroiditis) or secondary hypothyroidism may coexist with Addison's disease and hypopituitarism, respectively contributing to hyponatremia (32).

Pathogenesis of hyponatremia due to hypothyroidism

Hypothyroidism can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. In the vast majority of cases, it is caused by thyroid disease (primary hypothyroidism) (33). Much less often, it is caused by decreased secretion of thyrotropin (TSH) from the anterior pituitary gland or by decreased secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus (secondary or tertiary hypothyroidism). Worldwide, iodine deficiency remains the foremost cause of hypothyroidism. In areas of adequate iodine intake, autoimmune thyroid disease (Hashimoto's thyroiditis) is most common. The patient's presentation may vary from asymptomatic to, rarely, coma with multisystem organ failure (myxedema coma) (33).

Hyponatremia has been reported in patients with moderate to severe hypothyroidism (28,34). Warner et al. showed a statistical association between hyponatremia and hypothyroidism: for every 10 mU/L rise in thyroid-stimulating hormone, serum sodium decreased 0.14 mmol/L (35). The proposed mechanism by which hypothyroidism induces hyponatremia in patients with normal fluid intake involves the inability to maximally suppress ADH (28,36). This is due in part to a reduced cardiac output, which can lead to the release of ADH via the carotid sinus baroreceptors (36). Some patients have been described to fulfill criteria for SIADH since the urine sodium is not low as would be expected if a reduced cardiac output were responsible (37). On the other hand, the glomerular filtration rate has been reported to be decreased in hypothyroidism, which leads to diminished water delivery to the diluting segments and subsequently diminished free water excretion (38). The net effect of the impaired water excretion is retention of ingested water and dilutional hyponatremia.

Diagnostic clues of hyponatremia due to impaired hypothalamic-pituitary-adrenal axis function

Clinical and laboratory characteristics of patients with hyponatremia due to primary adrenal insufficiency

The diagnosis of acute adrenocortical insufficiency (adrenal crisis) is relatively straightforward in a patient presenting with weakness, abdominal pain, confusion, nausea, vomiting, diarrhea, fever, and hypotension combined with compatible laboratory findings, including hyponatremia, hyperkalemia, and raised blood urea (12). The coexistence of hypoglycemia, hypercalcemia, eosinophilia, and hypotension is also helpful, if present. However, the diagnosis of chronic adrenocortical insufficiency (Addison's disease) and hypopituitarism is often overlooked in patients with hyponatremia possibly due both to lack of specific symptoms and misinterpretation of serum cortisol levels (11,39).

Addison's disease should be included among the greatest imitators in medicine because it may exhibit non-specific clinical and biochemical features complicating the diagnostic approach of hyponatremic patients (40). Common symptoms of Addison's disease such as fatigability, weakness, anorexia, nausea, and vomiting may be attributed to hyponatremia per se (Table I). On the other hand, hypovolemia (due to mineralocorticoid deficiency in patients with primary adrenal insufficiency) as assessed on clinical grounds may be absent (41). It has been reported that a large sodium deficit does not always lead to hemodynamic instability because of three possible protective mechanisms: 1) A decrease in serum sodium concentration creates an osmotic gradient between extracellular and intracellular fluid in cells causing movement of water into cells and consequently cellular edema. Red blood cell swelling increases plasma volume and therefore the effective circulating volume (42). 2) Cellular edema raises the interstitial pressure thus favoring the movement of fluid from the interstitium to the vascular space. 3) Hypovolemic states are associated with activation of sympathetic function which in turn causes venous constriction and subsequent increased blood delivery to the heart (43).

Table I. Differences between primary and secondary adrenal insufficiency regarding pathogenesis, clinical picture, laboratory tests, and management of hyponatremia related to these disorders.

	Primary adrenal insufficiency (Addison's disease)	Secondary adrenal insufficiency
Pathogenesis	Primary disease of the adrenal (autoimmune adrenalitis, infections, including tuberculosis and fungal infections, hemorrhage, metastatic disease)	Diseases of the hypothalamus and pituitary (tumors, trauma, infection, infarction, radiation, surgery) or suppression of the hypothalamic-pituitary axis by exogenous steroids or endogenous steroids
Signs and symptoms	Weakness, pigmentation of skin, weight loss, abdominal pain, salt craving, diarrhea, constipation, syncope, vitiligo	Similar to those of Addison's disease; absence of hyperpigmentation
Laboratory findings	Aldosterone ↓; cortisol ↓; adrenal androgen ↓; ACTH ↑; renin activity ↑; potassium N or ↑	Cortisol ↓; ACTH ↓; renin N; aldosterone N or ↓; potassium N; other pituitary hormone deficiency possible
Treatment of hyponatremia	Normal saline plus hydrocortisone plus fludrocortisone (when saline infusion is stopped)	Hydrocortisone replacement therapy

↑ = elevated; ↓ = low; N = within normal range.

The diagnosis of primary adrenal insufficiency may be difficult to establish since hyperkalemia may be absent in approximately 30%–50% of patients with Addison's disease (40,44). This could, partly at least, be ascribed to low dietary potassium intake, increased entry of potassium into cells and increased gastrointestinal losses of potassium due to anorexia, pain, and vomiting that are common symptoms in Addison's disease. Gagnon et al. postulated the presence of circulating cationic substances in the context of autoimmunity or cancer (44). These substances by activating the calcium-sensing receptor in the thick ascending limb of the loop of Henle can induce a furosemide-like effect with natriuresis and also kaliuresis (44).

Adrenal insufficiency and tuberculosis

Hyponatremia is commonly observed in patients with active tuberculosis. It has been reported that approximately 11% of patients with active tuberculosis are affected of hyponatremia attributed to the syndrome of inappropriate antidiuretic hormone (SIADH) (45–47). However, tuberculosis-induced Addison's disease should be considered as a cause of hyponatremia (48). When treating tuberculosis it is important to keep in mind that rifampicin administration has the potential to sometimes induce adrenal crisis (48,49).

Adrenal insufficiency and hypothyroidism

Hyponatremia due to adrenal insufficiency can mistakenly be attributed to hypothyroidism. These diseases may coexist, but hypothyroidism is by far more frequent, and thyroid function tests are more often requested making the diagnosis easier (32). In such cases, it is of vital importance to replace hydrocortisone before thyroxin to avoid worsening of hypocortisolism or even precipitating an adrenal crisis.

Clinical and laboratory characteristics of patients with hyponatremia due to secondary adrenal insufficiency

Hypopituitarism with secondary adrenal insufficiency is another overlooked cause of hyponatremia often presenting with a ‘SIADH-like picture’ (euvolemic hyponatremia, low serum uric acid and urea levels, high urine sodium, and osmolality). It should be emphasized that hypopituitarism is frequently characterized by non-specific symptoms, such as fatigue and loss of energy. Of note, hypopituitarism is not a rare cause of hyponatremia in patients aged 65 years or older (50,51). Indeed, Ishikawa et al. have reported that 40% of patients aged 65 years or older presenting with hyponatremia have pituitary-adrenal dysfunction (50). The diagnosis of hypopituitarism is more complicated in the elderly patients in whom symptoms such as weakness or easy fatigability may be attributed either to aging per se or to associated co-morbidities. Thus, hypopituitarism often goes undiagnosed (11). Diederich et al. evaluated 28 patients (mean age 68 years, 75% women) with normovolemic hyponatremia (mean serum sodium 116 mmol/L) due to hypopituitarism and secondary adrenal insufficiency (11). Gonadotropins were below normal, and testosterone was low in six out of seven men. All women exhibited either below normal levels of gonadotropins or too low levels for the postmenopausal state. Thyrotropin (TSH) and thyroid hormones were low in 15 and normal in 8 patients. Prolactin was low basally and/or following stimulation by hypoglycemia in the majority of patients. Three patients had slightly increased basal prolactin due to a functional disruption of the pituitary stalk. Correct diagnosis was considerably delayed, and up to five admissions to several hospitals were required (11). It is suggested that hypopituitarism should be thought of in all patients with an SIADH-like clinical picture without an obvious cause and even in patients who appear to be mildly dehydrated (52).

Biochemistry tests differentiating hyponatremia in patients with adrenal insufficiency and SIADH (Table II).

The syndrome of inappropriate antidiuretic hormone (SIADH) is the most common cause of hyponatremia (53). The diagnosis of SIADH is made in patients who fulfill the following criteria: 1) hyponatremia and hypo-osmolality; 2) increased urine osmolality (Uosm > 100 mOsm/kg); 3) inappropriate natriuresis (> 40 mmol/L); 4) normovolemia; 5) normal renal, pituitary, adrenal, and thyroid function; and 6) normal acid-base and potassium balance (53–55). The diagnosis of SIADH is also supported by the presence of hypouricemia, as well as by low serum urea and phosphate levels, if present (56). SIADH is mainly caused by neuropsychiatric disorders, pulmonary diseases, malignancies, and drugs. Not infrequently the cause of SIADH cannot be identified especially in the elderly (57). Although some of these cases may be diagnosed as idiopathic, a careful, repeated, and costly monitoring for the presence of an occult tumor is usually warranted. Surprisingly, many physicians tend to diagnose SIADH before excluding other causes despite the fact that SIADH, by definition, is a diagnosis of exclusion (8).

Table II. Clues to differential diagnosis of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) and primary and secondary adrenal insufficiency.

	SIADH	Primary adrenal insufficiency	Secondary adrenal insufficiency
Volume status	Euvolemia	Hypovolemia	Euvolemia
Serum potassium	N	N or ↑	N
Serum uric acid	N or ↓ (< 4 mg/dL; 237.9 μmol/L)	N or ↑	N or ↓
FE uric acid	> 12% (> 16% in the elderly)	N or ↓ (< 12%)	> 12% (> 16% in the elderly)
Serum urea	N or ↓	N or ↑	N or ↓
FE urea	N (50%–55%) or ↑	N or ↓	N (50%–55%) or ↑
Arterial blood gases	Metabolic alkalosis	Metabolic acidosis	HCO3 – ↓, PCO2 ↓

FE = fractional excretion; ↑ = elevated; ↓ = low; N = within normal range.

The differential diagnosis of hyponatremia with a high urine sodium osmolality includes diuretic use, primary and secondary adrenal insufficiency, cerebral salt wasting, salt-wasting nephropathy, and SIADH (8,42). Some diagnostic tests are better than others to assist in the differential diagnosis. Uric acid appears to be a valuable index to assess the extracellular fluid volume during hyponatremia. During extracellular fluid volume expansion (SIADH, hypocortisolism), uric acid reabsorption in the renal proximal tubule is inhibited, producing a low serum concentration and a high fractional excretion. The opposite is usually true for a contracted extracellular fluid volume (such as occurs with diuretics, primary adrenal insufficiency, and salt-wasting nephropathy), although a caveat is that cerebral and some forms of renal salt wasting can also cause renal uric acid loss (56). In these instances, it may be useful to also analyze urea (serum concentration close to the upper limit of the reference interval, low fractional excretion) as a measure of extracellular fluid volume contraction. A tendency toward metabolic alkalosis suggests SIADH or diuretic use, whereas metabolic acidosis suggests primary adrenal insufficiency (58). It has been proposed that secondary adrenal insufficiency might be differentiated from SIADH by the presence of a low plasma bicarbonate level (probably because of aldosterone deficiency) and low carbon dioxide levels (59). Hypokalemia may accompany hyponatremia in diuretic use, whereas hyperkalemia is more typical for primary adrenal insufficiency (12).

Diagnostic approach of patients with a suspicion of primary or secondary adrenal failure

Patients with adrenal insufficiency are not easily identified by routine laboratory studies, and the determination of endocrine parameters is required for the diagnosis of hypothalamic-pituitary-adrenal axis disorders (Figure 1). Specifically, a morning (at 8 to 9 a.m.) serum cortisol concentration equal to or greater than 19 μg/dL (525 nmol/L) virtually rules out adrenal insufficiency, whereas concentrations equal to or less than 3 μg/dL (83 nmol/L) are highly suggestive of the diagnosis (60). Dynamic testing is necessary in all other cases.

Figure 1. Diagnostic approach to suspected adrenal insufficiency. (Blood samples should be drawn at 8 a.m.).

Short ACTH stimulation test represents the first step in the diagnostic work-up. A rise in serum cortisol concentration to a peak of 18–20 μg/dL (497–552 nmol/L) or more, 30–60 minutes after the intravenous administration of 250 μg of corticotrophin, indicates a normal response to the high-dose ACTH stimulation test and excludes primary adrenal insufficiency and most patients with secondary adrenal insufficiency (60–65). In cases of severe secondary adrenal insufficiency, due to adrenocortical atrophy, the administration of corticotropin is accompanied by a slight or no increase of serum cortisol levels. In patients with secondary adrenal insufficiency that is mild or of recent onset, however, the test may be normal since the large dose of ACTH that is given (250 μg) possibly represents a supraphysiologic stimulus leading to stimulation of a partially diseased adrenal. In such cases the insulin-induced hypoglycemia or metyrapone tests are reliable (66–68).

It must be noted that the insulin-induced hypoglycemia test is contraindicated in patients with coronary artery disease, epilepsy, and those aged more than 60 years (12,25). Special attention should also be paid since both tests may precipitate an acute adrenal crisis. In this regard, the low-dose (1 μg) ACTH stimulation test in patients with suspected secondary adrenal insufficiency should be performed. Indeed, serum cortisol concentration equal to or lower than 18–20 μg/dL (497–552 nmol/L) 30 minutes after the intravenous administration of 1 μg of corticotrophin is possibly the most accurate test to establish the diagnosis of secondary adrenal insufficiency in non-stressed patients (69). This test has also been validated in Addison's disease wherein an increase of serum cortisol concentrations greater than 18 μg/dL (497 nmol/L) is compatible with normally functioning adrenal glands (70).

Finally, a careful interpretation of the laboratory results in critically ill patients (e.g. severe sepsis, major trauma) is of paramount importance. In such patients, a serum cortisol value in the normal range does not rule out adrenal insufficiency. Despite the fact that a safe cut-off is unknown, adrenal insufficiency is possibly excluded if the random serum cortisol concentration is higher than 25 μg/dL (700 nmol/L) (71). The low-dose ACTH stimulation test, again, is the best test in establishing the diagnosis, in which a cortisol level lower than 25 μg/dL (700 nmol/L) or a rise over base-line lower than 9 μg/dL (250 nmol/L) represents an inadequate adrenal response (69).

Serum ACTH concentration is considered the best parameter in distinguishing between primary and secondary adrenal insufficiency. The former is characterized by increased serum ACTH concentration, i.e. higher than 100 pg/mL (22 pmol/L), even if the serum cortisol levels are within normal range (72). The latter is associated with low-normal serum ACTH concentration. In fact, a serum ACTH value within the normal range is inappropriately low and confirms the diagnosis of secondary adrenal insufficiency. Measurement of serum renin activity and aldosterone concentrations is also helpful: in Addison's disease serum renin activity or concentration is increased (because of the sodium wasting), whereas serum aldosterone concentration is low or at the lower range of normal values (because of inability of the adrenal cortex to produce it) (72). On the contrary, serum levels of renin and aldosterone are usually unaffected in secondary adrenal insufficiency, though mineralocorticoid deficiency may occur after very prolonged deficiency of ACTH. Finally, serum concentrations of renin and aldosterone are also useful in distinguishing rare disorders of adrenal glands (Table I).

Conclusion

Endocrine disorders, including thyroid and adrenal dysfunction, should be considered in the differential diagnosis of hyponatremia. Adrenal insufficiency not infrequently causes diagnostic confusion, because the classic clinical and biochemical features may not be present. Testing for adrenal insufficiency should be part of the hyponatremic work-up, as this disorder responds promptly to hormone replacement, while the consequences can be grave when the diagnosis is missed.

Declaration of interest: The authors state no conflict of interest and have received no payment in preparation of this manuscript.