Aoife Garrahy

The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study

The syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia. Data on SIAD are mainly derived from retrospective studies, often with poor ascertainment of the minimum criteria for the correct diagnosis. Reliable data on the incidence of adrenal failure in SIAD are therefore unavailable. The aim of the study was to describe the aetiology of SIAD and in particular to define the prevalence of undiagnosed adrenal insufficiency.

How should we interrogate the hypothalamic-pituitary-adrenal axis in patients with suspected hypopituitarism?

Hypopituitarism is deficiency of one or more pituitary hormones, of which adrenocorticotrophic hormone (ACTH) deficiency is the most serious and potentially life-threatening. It may occur in isolation or, more commonly as part of more widespread pituitary failure. Diagnosis requires demonstration of subnormal cortisol rise in response to stimulation with hypoglycemia, glucagon, ACTH(1-24) or in the setting of acute illness. The choice of diagnostic test should be individualised for the patient and clinical scenario. A random cortisol and ACTH level may be adequate in making a diagnosis in an acutely ill patient with a suspected adrenal crisis e.g. pituitary apoplexy. Often however, dynamic assessment of cortisol reserve is needed. The cortisol response is both stimulus and assay- dependent and normative values should be derived locally. Results must be interpreted within clinical context and with understanding of potential pitfalls of the test used.

Mortality rates are lower in SIAD, than in hypervolaemic or hypovolaemic hyponatraemia: Results of a prospective observational study

Hyponatraemia is associated with increased mortality, but the mortality associated specifically with SIAD is not known. We hypothesized that mortality in SIAD was elevated, but that it was less than in hypervolaemic (HEN) or hypovolaemic (HON) hyponatraemia.

Secondary resistance to tolvaptan in two patients with SIAD due to small cell lung cancer

Sir, Syndrome of inappropriate antidiuresis (SIAD) is characterized by euvolaemic hyponatraemia due to the antidiuretic effects of inappropriate elevation of plasma vasopressin (pAVP, also referred to as antidiuretic hormone (ADH)). Randomized controlled trials report a good response to tolvaptan-induced vasopressin receptor blockade, with reversal of hyponatremia in SIAD [1], including those with lung cancer [2]. Prolonged treatment is effective for up to four years [3]. We report two patients with small cell lung cancer (SCLC) who showed an initial good response to tolvaptan, but who subsequently displayed resistance to the aquaretic effects of the drug.

Diagnosis and management of central diabetes insipidus in adults.

Central diabetes insipidus (CDI) is characterized by hypotonic polyuria due to impairment of AVP secretion from the posterior pituitary. In clinical practice, it needs to be distinguished from renal resistance to the antidiuretic effects of AVP (nephrogenic DI), and abnormalities of thirst appreciation (primary polydipsia). As nephrogenic diabetes insipidus is rare in adults, unless they are treated with lithium salts, the practical challenge is how to differentiate between CDI and clinical disorders of excess thirst. The differential diagnosis is usually straight forward, but the recommended gold standard test, the water deprivation test, is not without interpretative pitfalls. The addition of the measurement of plasma AVP concentrations improves diagnostic accuracy, but the radioimmunoassay for AVP is technically difficult, and is only available in a few specialized centres. More recently, the measurement of plasma copeptin concentrations has been claimed to provide a reliable alternative to measurement of plasma AVP, without the sampling handling challenges. In addition, the measurement of thirst ratings can help the differentiation between CDI and primary polydipsia. Once the diagnosis of CDI is biochemically certain, investigations to determine the cause of AVP deficiency are needed. In this review, we will outline the diagnostic approach to polyuria, revisit the caveats of the water deprivation test and review recent data on value of adding AVP/copeptin measurement. We will also discuss treatment strategies for CDI, with analysis of potential complications of treatment.

Syndrome of inappropriate antidiuresis should it be managed by specialised endocrinologists

The syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia in hospitalised patients, accounting for 43% of patients with a plasma sodium concentration of <130 mmol/l [1]. Although there are virtually no data on mortality in SIAD, mortality in all-cause hyponatraemia has been reported to be elevated in almost every paper on the subject [2–4]. Hyponatraemic patients are also vulnerable to morbidity related to falls [5], fractures [6] and osteoporosis [7]. In the absence of separate studies in SIAD, it is widely accepted that patients who have hyponatraemia due to SIAD are vulnerable to the same risk of the morbidities and mortality associated with all-cause hyponatraemia. This has prompted considerable interest in whether treatment of hyponatreamia can improve outcomes in SIAD. Unfortunately, there is little data in the literature upon which to construct evidence based guidelines for the management of hyponatraemia due to SIAD. In the absence of a solid evidence base, there are controversial differences between the US recommendations [8] and the European guidelines [9] on treatment of SIAD. The US recommendations acknowledge that second-line treatment of SIAD, after failure of water restriction can be vaptans, urea or frusemide with sodium chloride supplementation, whereas the European Guidelines specifically advise against vaptans. So where are the gaps in our knowledge in the literature? The mortality in SIAD separately from that due to all-cause hyponatraemia is not known. Mortality studies have assessed the effects of hyponatraemia on death rate, without separating out the relative mortality of SIAD from other causes of hyponatraemia. In addition, as very few studies have firmly ascertained the full diagnostic criteria for SIAD in their study cohorts [10], the accuracy of data from many SIAD studies is questionable. The situation is complicated by the lack of studies on the response of plasma sodium to established treatments for SIAD. There are no prospective randomised-controlled trials which have reported the effects of water restriction, and many second-line treatments, in SIAD. There is however firm data on the response of SIAD-related hyponatraemia to treatment with vaptans; the randomised, placebocontrolled SALT studies showed that a mixed population of patients with SIAD and hypervolaemic hyponatraemia demonstrated a larger rise in plasma sodium concentration in response to tolvaptan than to placebo [11], and a later subgroup analysis confirmed that similar biochemical responses were consistent in the SIAD subgroup [12]. However, we still await the results of trials which compare the proven benefits of vaptans with first-line treatment with water restriction. It is therefore timely to see the results of an intervention study in SIAD patients in this journal [13]; the paper reported the effects of specialised endocrine care on outcomes in SIAD. The authors have a proven track record in the field, and as a group who have highlighted the poor ascertainment of basic diagnostic criteria for SIAD in clinical practice [10], they have unsurprisingly defined their SIAD cohort rigorously, and we are comfortable that they have excluded adrenal insufficiency. They have compared the effect of general care of SIAD—which included some patients who had the benefit of endocrine consultation— with those managed entirely by endocrine input. The two * Chris J. Thompson christhompson@beaumont.ie

Glucocorticoid deficiency and syndrome of inappropriate antidiuresis: an underdiagnosed association?

Hyponatraemia is the commonest electrolyte disorder, which manifests in up to 20% of hospital inpatients. Approximately 40% of patients with hyponatraemia have the syndrome of inappropriate antidiuresis (SIAD), and there are a number of carefully considered guidelines for the assessment and management of patients with SIAD. The original definition of SIAD contains the criterion that glucocorticoid deficiency should be excluded before the diagnosis is made, and this criterion is reiterated in all of the recently published clinical guidelines. Pure glucocorticoid deficiency leads to failure to effect renal free water clearance, with the development of water retention and dilutional hyponatraemia. Although plasma volume is expanded slightly, the patients present as euvolaemic to clinical examination; the biochemical picture is identical to that of SIAD, with hyponatraemia, normokalaemia and elevated urine osmolality and urine sodium concentration. This is in contrast to the clinical and biochemical characteristics of primary adrenal failure, where the combination of glucocorticoid and mineralocorticoid deficiency typically causes hypovolaemic hyponatraemia, which is accompanied by hyperkalemia. Although cortisol is necessary to facilitate water excretion from the kidney, the permissive effect on water excretion is only part of the pathogenesis of glucocorticoid deficiency. Patients who are glucocorticoid deficient also have elevated plasma concentrations of the antidiuretic hormone, vasopressin (AVP). It is likely that the elevated plasma AVP concentrations are more important to the development of hyponatraemia in glucocorticoid deficiency; in adrenalectomized, but mineralocorticoid-replete rats, urinary dilution is almost completely restored by the administration of vasopressin receptor antagonists, arguing strongly for a causal role for AVP. However, published data strongly suggest that testing for glucocorticoid deficiency is not performed as frequently as recommended, and that this leads to the failure to identify steroid deficiency as a treatable cause of euvolaemic hyponatraemia. A retrospective review of routine clinical practice in 139 patients with allcause hyponatraemia, who were admitted to a London teaching hospital, showed that only 33% of patients had assessment of cortisol secretion, with similar low levels of measurement of urine osmolality or sodium concentration. In addition, the report of the Hyponatraemia Registry, an international observational study conducted in over 200 centres in the US and Europe, revealed that in 1524 patients specifically entered to the registry with a diagnosis of SIAD, only 33% had measurement of plasma cortisol concentrations. Even within the context of a prospective single-site observational study of almost 500 patients with carefully defined SIAD, only 88% had appropriate tests to exclude glucocorticoid deficiency. Given that these studies were all designed and run in centres with a specific interest in hyponatraemia, it would not be unreasonable to assume that the rates of cortisol measurement are likely to be even lower in centres without a specific interest in hyponatraemia. Although there are numerous case reports of hyponatraemia associated with hypocortisolaemia, the low rate of testing for plasma cortisol in published studies has dictated that the incidence of glucocorticoid deficiency in SIAD has until recently, remained undefined.