Hyponatremia and hyperkalemia in adrenal insufficiency

INTRODUCTION — The electrolyte disturbances in primary adrenal insufficiency are due to diminished secretion of cortisol and aldosterone (see "Causes of primary adrenal insufficiency (Addison disease)"). A major function of aldosterone is to increase urinary potassium secretion. As a result, hypoaldosteronism can be associated with hyperkalemia and mild metabolic acidosis [1,2]. Sodium wasting is a variable feature of this disorder. It is not prominent in adults with isolated hypoaldosteronism, probably because aldosterone secretion is only modestly reduced. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

Although aldosterone normally enhances sodium reabsorption, other sodium-retaining factors (such as angiotensin II and norepinephrine) are able to compensate for the decreased availability of aldosterone [1]. However, patients with primary adrenal insufficiency may have severe hypoaldosteronism, leading to salt wasting and possibly hypotension and adrenal crisis. (See "Clinical manifestations of adrenal insufficiency in adults".)

Other causes of hyponatremia and hyperkalemia, as well as the evaluation of patients with hyponatremia or hyperkalemia, are discussed elsewhere:

●(See "Causes of hypotonic hyponatremia in adults".)

●(See "Causes and evaluation of hyperkalemia in adults".)

●(See "Diagnostic evaluation of adults with hyponatremia".)

HYPONATREMIA AND HYPERKALEMIA — Hyponatremia and hyperkalemia are the two major electrolyte abnormalities of primary adrenal insufficiency. Hyponatremia is mediated by increased release of antidiuretic hormone (ADH), which results in water retention and a reduction in the plasma sodium concentration [3,4]. Both cortisol and aldosterone deficiency contribute to this problem:

●The hypersecretion of ADH seen in cortisol deficiency may be due in part to the reductions in systemic blood pressure and cardiac output induced (via an unknown mechanism) by the lack of cortisol. However, a more important mechanism may be that cortisol deficiency results in increased hypothalamic secretion of corticotropin-releasing hormone (CRH), an ADH secretagogue [5-8]. Cortisol feeds back negatively on CRH and corticotropin (ACTH), an inhibitory effect that is removed with adrenal insufficiency [5,9]. In addition, cortisol appears to directly suppress ADH secretion [10-12]. Thus, ADH levels increase when plasma cortisol levels are low.

●Glucocorticoid deficiency also reduces renal free water clearance [13,14]. Animal models suggest that glucocorticoid deficiency can result in impaired urinary diluting ability and increased distal tubular water permeability. At the molecular level, glucocorticoid deficiency results in increased expression and phosphorylation of the vasopressin-sensitive water channel aquaporin 2 (AQP2) in the collecting duct [15].

●The hypersecretion of ADH induced by aldosterone deficiency is caused by renal salt wasting with resultant volume depletion. Hypovolemia increases ADH levels by reducing the osmotic threshold for ADH release from the hypothalamus and increasing the magnitude of ADH release for a given change in plasma osmolality [16,17]. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Role of ADH in volume regulation'.)

Hyponatremia is most often seen with primary adrenal insufficiency; in a large series of patients with autoimmune primary adrenal insufficiency, for example, 84 percent had a serum sodium below 137 mEq/L [18]. Hyponatremia can also occur with ACTH deficiency (secondary or tertiary adrenal insufficiency) but is less common [3,19,20]. In the latter setting, both the general preservation of aldosterone release and the generally less prominent reduction in cortisol secretion account for the lower prevalence of hyponatremia.

Hyperkalemia in adrenal insufficiency is entirely due to hypoaldosteronism since one of the major functions of aldosterone is to promote the urinary excretion of dietary potassium [1,2]. However, not all patients develop hyperkalemia. As an example, in a multi-center study of 272 patients diagnosed with autoimmune primary adrenal insufficiency, serum potassium exceeded 5.0 mEq/L in only 34 percent [18]. The normokalemia found in many hypoadrenal patients is attributable to aldosterone-independent regulation of potassium secretion by the distal nephron. (See "Causes and evaluation of hyperkalemia in adults".)

Temporary hyperkalemia may develop in patients with primary aldosteronism who undergo a unilateral adrenalectomy for an aldosterone-producing adenoma [21,22]. In such patients, suppression of aldosterone production by the normal adrenal gland may result in transient adrenal insufficiency after the abnormal gland is removed. A contralateral suppression index (aldosterone-to-cortisol ratio of the nondominant adrenal vein divided by the aldosterone-to-cortisol ratio of the inferior vena cava) of <0.47 at adrenal vein sampling has been shown to be the predictive cutoff for postoperative hyperkalemia after adrenalectomy for unilateral hyperaldosteronism [23].

Treatment — Hyponatremia in adrenal insufficiency is rapidly corrected by cortisol and volume repletion, which shut off ADH release and allow excess water to be excreted [3,24]. Rarely, the rate of rise in the plasma sodium concentration is so rapid that it leads to osmotic demyelination syndrome, a severe neurologic disease. By contrast, the administration of saline alone is relatively ineffective in the presence of isolated cortisol deficiency (ie, due to ACTH deficiency) since the elevated ADH levels and consequent impairment in water excretion will persist [3]. (See "Osmotic demyelination syndrome (ODS) and overly rapid correction of hyponatremia", section on 'Overly rapid rate of correction' and "Treatment of adrenal insufficiency in adults" and "Overview of the treatment of hyponatremia in adults".)

Physiologic cortisol replacement with hydrocortisone (or cortisone acetate, which is converted to hydrocortisone) also may increase potassium excretion, indicating that cortisol can act as a mineralocorticoid in the absence of aldosterone [25] (see "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)"). However, other forms of glucocorticoid replacement (eg, dexamethasone or prednisone) do not have significant mineralocorticoid activity.

Mineralocorticoid replacement is required in most patients with primary adrenal insufficiency. The standard treatment is fludrocortisone, taken once daily in the morning to mimic diurnal variation in endogenous aldosterone secretion. Inadequate mineralocorticoid replacement in such patients may lead to excessive use of glucocorticoids [26]. The adequacy of mineralocorticoid replacement can be monitored by asking about symptoms of postural hypotension and by measuring supine and upright blood pressure and pulse, serum potassium, and plasma renin activity [27].

We measure plasma renin activity when first initiating therapy and in patients who develop salt craving or nausea despite normal potassium and normal hemodynamics since these symptoms may suggest that mineralocorticoid levels are deficient. In addition, we routinely measure plasma renin activity on an annual basis, with a goal of keeping this in the high-normal range [28]. The dose of mineralocorticoid, but not glucocorticoid, should generally be increased in patients with elevated plasma renin activity. However, other factors (such as the patient's blood pressure, serum sodium, and serum potassium) should also be taken into account since plasma renin measurements are complex and vary according to posture and concomitant medications [29]. (See "Treatment of adrenal insufficiency in adults", section on 'Mineralocorticoid replacement for selected individuals'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyponatremia" and "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY

●Pathogenesis – The major electrolyte disturbances in primary adrenal insufficiency (hyponatremia and hyperkalemia) are due to diminished secretion of cortisol and aldosterone. (See 'Introduction' above.)

Hyponatremia is mediated by increased release of antidiuretic hormone (ADH), which results in water retention and a reduction in the plasma sodium concentration. Both cortisol and aldosterone deficiency contribute to this problem. Hyponatremia is most often seen with primary adrenal insufficiency; it can also occur with corticotropin (ACTH) deficiency (secondary or tertiary adrenal insufficiency). (See 'Hyponatremia and hyperkalemia' above.)

Hyperkalemia in adrenal insufficiency is entirely due to hypoaldosteronism since one of the major functions of aldosterone is to promote the urinary excretion of dietary potassium. However, only approximately one-third of patients with primary adrenal insufficiency develop hyperkalemia. (See 'Hyponatremia and hyperkalemia' above.)

●Management – Hyponatremia in adrenal insufficiency is rapidly corrected by cortisol and volume repletion. Although physiologic cortisol replacement with hydrocortisone (or cortisone acetate, which is converted to hydrocortisone) also may increase potassium excretion, mineralocorticoid replacement is required in most patients with primary adrenal insufficiency. (See 'Treatment' above.)

ACKNOWLEDGMENT — The author and editors thank Dr. Lynnette Nieman, who contributed to previous versions of this topic review.