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Best Practice & Research Clinical Endocrinology & Metabolism 26 Suppl. 1 (2012) S7S15

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Best Practice & Research Clinical

Endocrinology & Metabolismj o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b e e m

2

Differential diagnosis of hyponatraemia

Chris Thompson MD FRCPIa, *, Tomas Berl MDb,A , Alberto Tejedor MD PhDc,B ,Gudmundur Johannsson MD PhDd,C

aAcademic Department of Endocrinology, Beaumont Hospital and RCSI Medical School, Beaumont Road, Dublin 9, Irelandb Division of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USAcDepartment of Nephrology, Laboratory of Renal Physiopathology, Hospital General Universitario Gregorio Maranon, Doctor

Esquerdo 46, 28007 Madrid, Spaind Department of Endocrinology, Institute of Medicine, Sahlgrenska Academy, University of Goteborg, S-413 45 Goteborg, Sweden

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 thehyponatraemia. 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 EuropeanHyponatraemia Network considered the use of two algorithms.

One was developed from a nephrologists view of hyponatraemia,

while the other reflected the approach of an endocrinologist. Bothof 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 theimportance of accurate diagnosis to the correct treatment of hy-

ponatraemia, special consideration was given to hyponatraemia in

neurosurgical patients. The differentiation between the syndromeof 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 mainstayof 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 berecalcitrant to fluid restriction was also suggested.

2012 Elsevier Ltd. All rights reserved.

* Corresponding author. Chris Thompson. Tel.: +353 18376532; Fax: +353 18376501.

E-mail address: [email protected] Tel: +1 303 7244803; Fax: +1 303 7244868.E-mail address:[email protected] Tel: +34 914265145; Fax: +34 915868214.E-mail address: [email protected] Tel: +46 313423101; Fax: +46 31821524.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 PharmaceuticalEurope Ltd.

1521-690X/$ see front matter 2012 Elsevier Ltd. All rights reserved.


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S8 C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15

1. Introduction

Hyponatraemia, defined as a serum sodium concentration ([Na+])


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C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15 S9

urinary [Na+] below 20 mmol/L reflects extra renal sodium losses. The potential underlying causes of

hyponatraemia in both these circumstances are outlined in Fig. 1.4

Hypotonic hyponatraemia

Assess volume status

Euvolaemia HypervolaemiaHypovolaemia

Urinary [Na ] > 20 mmol/L+

Measure urinary [Na ]+ Measure urinary [Na ]+

Glucocorticoid deficiency

Hypothyroidism

Drugs

SIADH

Acute or chronicrenal failure

Pregnancy

Nephrotic syndrome

Cirrhosis

Heart failure

< 20 mmol/L> 20 mmol/L< 20 mmol/LExtrarenal losses

> 20 mmol/LRenal losses

Vomiting

Diarrhoea

Third spacing offluids in burns,pancreatitis andtrauma

Diuretic excess

Mineralocorticoiddeficiency

Salt-losing nephropathy

Bicarbonaturia withrenal tubular acidosisand metabolic alkalosis

Ketonuria

Cerebral salt-wastingsyndrome

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 Rectors The Kidney,

pp 229240. 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 endocrinologists 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 patients 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 endocrinologists view would be that an algorithm is a usefulguideline, 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 patients volume status and

measurement of urinary [Na+].

Urine [Na+] 40mmol/L

Hypovolaemia

(dry tongue, decreased CVP, increased urea,

increased pulse, decreased BP)

Vomiting, diarrhoea,

skin losses, burns

Diuretics, Addisons,

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, cirrhosisNephrotic 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 theurine 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 intothis category, as do cerebral salt-wasting syndrome and salt-losing nephropathy. Urine [Na +] between

2040 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; diureticsdecrease 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


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Table 2

Essential and supporting criteria for the diagnosis of hyponatraemia secondary to SIADH. These diagnostic criteria should be

used to confirm a diagnosis of hyponatraemia secondary to SIADH. 10,11

Essential diagnostic criteria for SIADH

Decreased measured serum osmolality ( 100mOsm/kg H2O during hypo-osmolality

Clinical euvolaemia

No clinical signs of contraction of extracellular fluid (e.g., no orthostasis a, tachycardia, decreased skin turgor or dry

mucous membranes)

No clinical signs of expansion of extracellular fluid (e.g., no oedema or ascites)

Urinary [Na+] > 40mmol/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


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Although cerebral salt wasting is rare, the authors do believe it exists as an entity separate from

SIADH. There are several shared characteristics of SIADH and cerebral salt-wasting syndrome (outlined

in Table 4); both conditions are associated with a low serum [Na+] and an elevated urinary [Na+].14 The

main feature unique to cerebral salt-wasting syndrome is the presence of clinical hypovolaemia asa result of this volume depletion, patients may exhibit signs such as hypotension or reduced skin

turgor.13,23 The mechanism of cerebral salt-wasting syndrome is yet to be well defined, although

evidence from patients who experienced subarachnoid haemorrhage suggests that the inappropriately

elevated secretion of atrial and brain natriuretic peptides contribute to hyponatraemia following

neurosurgery.24,25

Table 4

Characteristics of SIADH and cerebral salt-wasting syndrome. For a diagnosis of SIADH, the criteria outlined in Table 2

should be used to confirm diagnosis.

SIADH Cerebral salt-wasting syndrome

Serum [Na+] Low Low

Blood urea Normal/low Raised

BP Normal Normal/postural fall

Urine volume Low High

Urinary [Na+] Raised Raised

CVP Normal Low

BP = blood pressure; CVP = central venous pressure; SIADH = syndrome of inappropriate secretion of antidiuretic hormone.

Reproduced from Sherlock M et al. Postgrad Med J2009; 85: 171175.14 With permission.

Regardless of the mechanism of cerebral salt-wasting syndrome, its treatment is dependent on

restoring the patients volume status through the administration of isotonic saline;13 therefore, fluid

restriction is not appropriate and, as mentioned previously, may worsen the condition. In contrast,

patients with SIADH may be treated with fluid restriction or a vasopressin receptor antagonist (vaptan).

Neurosurgeons are reluctant to contemplate fluid restriction because of their perception that volume

expansion is integral to the management of subarachnoid haemorrhage. It has been noted that there

is a paucity of data regarding the use of vaptans in the neurosurgical patient. It is crucial to confirm

that SIADH is the true cause of the hyponatraemia prior to administration13

as a misdiagnosis maylead to incorrect treatment that may worsen the hyponatraemia. Consequently, the initial monitoring

of therapy should always be rigorous regardless of the choice of therapy.

4. Summary

Accurate diagnosis of hyponatraemia is necessary to determine appropriate treatment and algorithms

can be developed and used to aid this process. However, clinical acumen is still important as algorithms

should act only as guidance, and are of most use when applied by physicians who understand them.

While diagnostic approaches for hyponatraemia can vary, the careful assessment of volume status

and urinary [Na+] is critical, as outlined in both of the approaches in this article. In neurosurgical

hyponatraemia, differentiation between euvolaemia and hypovolaemia is essential for the diagnosis

of SIADH and cerebral salt-wasting syndrome, respectively.

5. Acknowledgements

This supplement was commissioned by Otsuka Pharmaceutical Europe Ltd. and summarises the

proceedings of a meeting organised and supported by Otsuka Pharmaceutical Europe Ltd. The authors

have not received any honorarium in relation to this supplement. Otsuka Pharmaceutical Europe Ltd.

has had the opportunity to comment on the medical content and accuracy of the article and editorial

support has been provided by Otsuka Pharmaceutical Europe Ltd.; however, final editorial content

resides with the authors and Best Practice & Research: Clinical Endocrinology & Metabolism.


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Practice points

In patients with serum hypotonicity, translocational hyponatraemia and pseudohypona-

traemia must be ruled out before a diagnosis of hyponatraemia can be made.

Differential diagnosis of the aetiology of the hyponatraemia requires assessment of volume

status and urine sodium concentration.

In neurosurgical patients, hyponatraemia is caused most frequently by SIADH or acute ACTH

deficiency; cerebral salt-wasting syndrome is rare. It is important to differentiate between

these conditions (and to rule out any alternative causes of hyponatraemia) before initiating

treatment.

SIADH may be treated with fluid restriction, though neurosurgeons are reluctant to

contemplate this in subarachnoid haemorrhage patients. Vasopressin receptor antagonists

offer an alternative treatment but have not been studied in the neurosurgical context. Acute

ACTH deficiency requires glucocorticoid therapy and the rare cerebral salt-wasting syndrome

may be treated by administration of 0.9% isotonic saline.

Research agenda

There is a need to further elucidate the mechanisms underlying hyponatraemia in patients

with cerebral salt-wasting syndrome.

The usefulness of proposed algorithms in the differential diagnosis of the underlying aetiology

of hyponatraemia needs to be assessed in a clinical setting.

6. Conflict of interest

Prof. Thompson is on the Otsuka Pharmaceutical advisory board for tolvaptan and has received

honoraria from Otsuka Pharmaceutical for speaking at symposia. Prof. Berl is on the Otsuka

Pharmaceutical advisory board for tolvaptan and has received honoraria from Otsuka Pharmaceuticalfor speaking at symposia. Dr. Tejedor acts as an expert in nephrology for the European Medicines

Agency and belongs to the Steering Committee of the European Hyponatraemia Network. He has

been scientific advisor for drugs related to the kidney: torasemide (Boehringer Ingelheim) and

tolvaptan (Otsuka Pharmaceutical Europe Ltd.). Dr. Tejedor also owns a patent on cilastatin as a broad

nephroprotector. Prof. Johannsson has received honoraria from Otsuka Pharmaceutical for speaking at

symposia.

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