Best Practice & Research Clinical Endocrinology & Metabolism 26 Suppl. 1 (2012) S7–S15

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Differential diagnosis of hyponatraemia Chris Thompson MD FRCPIa, *, Tomas Berl MDb,A , Alberto Tejedor MD PhDc,B , Gudmundur Johannsson MD PhDd,C a Academic

Department of Endocrinology, Beaumont Hospital and RCSI Medical School, Beaumont Road, Dublin 9, Ireland of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA c Department of Nephrology, Laboratory of Renal Physiopathology, Hospital General Universitario Gregorio Mara˜ no ´n, Doctor Esquerdo 46, 28007 Madrid, Spain d Department of Endocrinology, Institute of Medicine, Sahlgrenska Academy, University of G¨ oteborg, S-413 45 G¨ oteborg, Sweden b Division

Keywords: algorithm diagnosis hyponatraemia syndrome of inappropriate secretion of antidiuretic hormone (SIADH) sodium

The appropriate management of hyponatraemia is reliant on the accurate identification of the underlying cause of the hyponatraemia. In the light of evidence which has shown that the use of a clinical algorithm appears to improve accuracy in the differential diagnosis of hyponatraemia, the European Hyponatraemia Network considered the use of two algorithms. One was developed from a nephrologist’s view of hyponatraemia, while the other reflected the approach of an endocrinologist. Both of these algorithms concurred on the importance of assessing effective blood volume status and the measurement of urine sodium concentration in the diagnostic process. To demonstrate the importance of accurate diagnosis to the correct treatment of hyponatraemia, special consideration was given to hyponatraemia in neurosurgical patients. The differentiation between the syndrome of inappropriate antidiuretic hormone secretion (SIADH), acute adrenocorticotropic hormone (ACTH) deficiency, fluid overload and cerebral salt-wasting syndrome was discussed. In patients with SIADH, fluid restriction has been the mainstay of treatment despite the absence of an evidence base for its use. An approach to using fluid restriction to raise serum tonicity in patients with SIADH and to identify patients who are likely to be recalcitrant to fluid restriction was also suggested. © 2012 Elsevier Ltd. All rights reserved.

* Corresponding author. Chris Thompson. Tel.: +353 183 76532; Fax: +353 183 76501. E-mail address: [email protected]. A Tel: +1 303 7244803; Fax: +1 303 7244868. E-mail address: [email protected]. B Tel: +34 91 4265145; Fax: +34 91 5868214. E-mail address: [email protected]. C Tel: +46 31 3423101; Fax: +46 31 821524. E-mail address: [email protected]. This supplement was commissioned by Otsuka Pharmaceutical Europe Ltd. The European Hyponatraemia Network Academy meeting was organised and supported by Otsuka Pharmaceutical Europe Ltd. 1521-690X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.

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1. Introduction Hyponatraemia, defined as a serum sodium concentration ([Na+ ]) 20 mmol/L

> 20 mmol/L

Diuretic excess

Vomiting

Glucocorticoid deficiency

Mineralocorticoid deficiency

Diarrhoea

Hypothyroidism

Acute or chronic renal failure

Third spacing of fluids in burns, pancreatitis and trauma

Drugs

> 20 mmol/L Renal losses

Salt-losing nephropathy Bicarbonaturia with renal tubular acidosis and metabolic alkalosis

Pregnancy

< 20 mmol/L

Nephrotic syndrome Cirrhosis Heart failure

SIADH

Ketonuria Cerebral salt-wasting syndrome Fig. 1. Algorithm for the differential diagnosis in a patient with hypotonic hyponatraemia. Adapted from Chonchol M & Berl T. Hyponatraemia. In: DuBose T & Hamm L (eds). Acid-base and electrolyte disorders: a companion to Brenner and Rector’s The Kidney, pp 229–240. Saunders; 2002.4

Patients with hypervolaemic hyponatraemia (due to heart failure, cirrhosis and nephrotic syndrome) characteristically also have a sodium retaining disorder in addition to the water retention reflected in the decrement of sodium serum. Thus, their urinary sodium is 20 mmol/L.4 In euvolaemic hyponatraemia there is an excess of total body water relative to a normal amount of total body sodium. These patients characteristically have a urinary sodium >20 mmol/L, as this reflects their sodium intake. 3. Algorithms for the diagnosis of hyponatraemia: an endocrinologist’s view The key to the differential diagnosis of hyponatraemia is: 1. The estimation of the blood volume of the patient. 2. The measurement of urine sodium concentration. The algorithm used in practice is shown in Table 1. 3.1. Classification of volume status The classification of the patient’s volume status (as euvolaemic, hypervolaemic or hypovolaemic) is a critical first step in the diagnosis of the underlying aetiology of hyponatraemia. Bedside evaluation of the patient relies on a thorough physical examination;6 the key clinical parameters to aid the judgement of the clinician are shown in Table 1. The most useful is the measurement of central venous pressure, but this is invasive and not always available. In addition to clinical evaluation, biochemical

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parameters such as blood urea and creatinine are valuable. Plasma renin activity is potentially a very sensitive marker of blood volume status but the results rarely come back in time to make a meaningful contribution to what remains a predominantly clinical judgement. In many cases it can be difficult to determine volume status, and the endocrinologist’s view would be that an algorithm is a useful guideline, which still requires experienced clinical acumen for optimum use. Table 1 Proposed matrix for the differential diagnosis of the underlying aetiology of hyponatraemia. Diagnosis of the underlying aetiology of the hyponatraemia using this system relies on an accurate assessment of the patient’s volume status and measurement of urinary [Na+ ]. Urine [Na+ ] 40 mmol/L

Hypovolaemia (dry tongue, decreased CVP, increased urea, increased pulse, decreased BP)

Vomiting, diarrhoea, skin losses, burns

Diuretics, Addison’s, cerebral salt-wasting syndrome, salt-losing nephropathy

Euvolaemia

Hypothyroidism Any cause + hypotonic fluids

SIADH Glucocorticoid deficiency Drugs

Hypervolaemia (oedema, ascites, LVF, increased JVP, increased CVP)

CCF, cirrhosis Nephrotic syndrome

Renal failure, any cause + diuretics

BP = blood pressure; CCF = congestive cardiac failure; CVP = central venous pressure; LVF = left ventricular failure; JVP = jugular venous pressure; SIADH = syndrome of inappropriate secretion of antidiuretic hormone. Presented by Prof. Thompson at the European Hyponatraemia Network Academy meeting in February 2011.

Distinguishing hypovolaemic hyponatraemia from euvolaemic hyponatraemia can be particularly problematic. Hypovolaemic hyponatraemia is typically recognised by clinical signs such as a dry tongue, decreased central venous pressure, increased urea, increased pulse and decreased blood pressure. However, evidence suggests that the detection of mild-to-moderate volume contraction may be difficult in clinical practice.7 Many clinicians find that the differentiation between mild volume depletion and euvolaemia is difficult and that recommended clinical and biochemical parameters are insufficiently reliable to accurately make the distinction. In practice, a common approach is to treat ‘grey cases’ as if they had volume depletion, and administer intravenous saline when in diagnostic doubt; however, in any case, the osmolality of the infusate must be higher than the osmolality of the urine in order to prevent worsening of the hyponatraemia. Typically, hypervolaemic hyponatraemia is more easily recognised, by the presence of peripheral or sacral oedema, signs of pulmonary oedema, ascites, increased jugular venous pressure and increased central venous pressure. Euvolaemia may be diagnosed in the absence of any clinical signs of volume depletion or volume expansion, as outlined above.8 Following determination of the volume status, the next step in the differential diagnosis of hyponatraemia is the assessment of urinary [Na+ ]. In patients with hypovolaemic hyponatraemia, a urinary [Na+ ] 40 mmol/L indicates that the mineralocorticoid effects of secondary hyperaldosteronism are not conserving renal sodium. This is indicative of renal solute loss and demonstrates that the kidney is the site of the problem. Thiazide diuretic use is the commonest cause of hypovolaemic hyponatraemia with high urine [Na+ ]. Primary adrenal insufficiency, with loss of aldosterone and cortisol secretion also falls into this category, as do cerebral salt-wasting syndrome and salt-losing nephropathy. Urine [Na+ ] between 20–40 mmol/L may occur in patients with renal or extra-renal sodium loss and is a diagnostic grey area which still requires individual clinical judgement. In patients with hypervolaemia, a urinary [Na+ ] 40 mmol/L suggest the hyponatraemia results from renal failure.

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It is important to recognise a number of caveats to the use of algorithms: 1. They are only guidelines, and it is important to exercise clinical acumen in the application of all algorithms. 2. Differential diagnosis of hyponatraemia can be complicated in patients receiving diuretics; diuretics decrease the reabsorption of sodium within the nephron and increase urinary sodium excretion. They can affect the clinical presentation and laboratory results for hyponatraemia, and may lead to misdiagnosis. Diseases classified as typically associated with low urine [Na+ ] may present with high urine [Na+ ].7 Consequently, urinary sodium excretion should be used cautiously as a diagnostic marker in patients treated with diuretics.9 In these patients, fractional uric acid excretion (FE-UA) can instead be used to aid the differential diagnosis of hyponatraemia, particularly in differentiating between SIADH and hypovolaemic hyponatraemia (an FE-UA cut-off value of 12% appears to be optimal to confirm the diagnosis of SIADH [positive predictive value of 100%], whereas an FE-UA 40 mmol/L with normal dietary sodium intake b • Normal thyroid and adrenal function determined by both clinical and laboratory assessment • No use of diuretic agents within the week prior to evaluation Supporting diagnostic criteria for SIADH • Serum uric acid