Hyponatraemia for the Clinical Endocrinologist

Euvolaemic Hyponatraemia

Euvolaemic hyponatraemia is the most heterogeneous and common cause of hyponatraemia in hospitalized patients. It can occur in any of the above settings and additionally is seen in the following contexts.

Hypothyroidism

Hyponatraemia is reported in up to 10% of hypothyroid patients, although it is usually mild and rarely causes symptoms.^[24] In water-loading studies, patients with hypothyroidism have a diminished ability to excrete free water and fail to achieve maximum urine dilution. Although some studies have reported elevated AVP levels in patients with hypothyroidism the literature is inconsistent. In hypothyroid rats there is no up-regulation of hypothalamic AVP gene expression. The reduction in cardiac output and GFR observed in severe hypothyroidism may be nonosmotic stimuli to AVP release.

Hypopituitarism and Secondary Adrenal (Glucocorticoid) Insufficiency

Hypopituitarism is often overlooked as a cause of hyponatraemia. In a recent study, hypopituitary patients presenting with hyponatraemia had been admitted to other hospitals between one and four times before the underlying hypopituitarism was finally diagnosed.^[18] Previous hyponatraemic episodes were documented in 43% of these patients. Elderly patients with secondary adrenal failure are particularly prone to develop hyponatraemia. Glucocorticoid deficiency is probably the most important factor causing the hyponatraemia in hypopituitarism as the hypo-osmolality recovers as soon as cortisol deficiency is corrected and long before thyroid deficiency is biologically substituted.^[18] Since SIADH is a prime component of the hyponatraemia of glucocorticoid deficiency, it is usually indistinguishable from SIADH as a result of other causes (see below).

SIADH

SIADH is a diagnosis of exclusion and is a common complication of a wide range of clinical disorders and drugs ( Table 2 ). The diagnostic criteria include hyponatraemia, plasma hypo-osmolality, hypertonic urine with no dehydration or oedema, and normal renal and adrenal function.^[25] Additional tests to confirm the diagnosis, but which are rarely used in clinical practice, include an abnormal water load test (i.e. inability to excrete at least 90% of a 20 ml/kg water load in 4 h and/or failure to dilute urine osmolality <100 mosm/kg), and the finding of plasma AVP levels inappropriately elevated relative to plasma osmolality. In practice, the time required to obtain AVP assays mean that such data are available long after the clinical episode has ended. SIADH is characterized by hyponatraemia secondary to increased total body water resulting from impaired renal free water excretion. Patients with SIADH fail to suppress AVP secretion even when plasma osmolality falls below the normal osmotic threshold triggering AVP release (previously reviewed by Smith et al.^[10]). Hyponatraemia in SIADH is limited by the 'escape phenomenon' in which urine flow rises and urine osmolality falls after a few days of free water retention to re-establish fluid balance. This effect tends to protect against water retention and severe hyponatraemia, and may be caused by reduced expression of aquaporin-2 in the collecting ducts.

As many as 1020% of patients with hyponatraemia, who have a clinical and laboratory picture consistent with SIADH, have AVP levels at or below the limits of detection by radioimmunoassay. A recent study of two unrelated infants with hyponatraemia whose clinical presentation was consistent with SIADH but who had undetectable AVP levels, identified a novel mutation in the V₂ receptor leading to constitutive activation of the receptor and consequent nephrogenic syndrome of inappropriate antidiuresis'.^[26] Future research may identify further mutations in the V₂ receptor gene and/or signalling cascade in such patients with 'apparent' SIADH.

Drug-induced Hyponatraemia

While thiazides and other diuretics often cause hyponatraemia, a long list of other agents cause SIADH as an uncommon effect. A comprehensive list is not within the intended scope of this article, but important examples are psychoactive drugs, which may stimulate AVP release (phenothiazines and some newer antipsychotics, tricyclics, SSRIs), renal AVP receptor agonists (dDAVP, oxytocin) and others such as chlorpromazine, carbamazepine and omeprazole. The common drug of abuse ecstasy (E, MDMA) can cause hyponatraemia.

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