Professional Documents
Culture Documents
1 (2012) S7–S15
* Corresponding author. Chris Thompson. Tel.: +353 183 76532; Fax: +353 183 76501.
E-mail address: christhompson@beaumont.ie.
A
Tel: +1 303 7244803; Fax: +1 303 7244868. E-mail address: tomas.berl@ucdenver.edu.
B
Tel: +34 91 4265145; Fax: +34 91 5868214. E-mail address: atejedor@nefro.hggm.es.
C
Tel: +46 31 3423101; Fax: +46 31 821524. E-mail address: gudmundur.johannsson@medic.gu.se.
1521-690X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
S8 C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7–S15
1. Introduction
Hyponatraemia, defined as a serum sodium concentration ([Na+ ]) <136 mmol/L, is the most commonly
encountered electrolyte disorder in clinical practice.1 However, evidence from the literature indicates
that the condition is often overlooked with patients remaining untreated.2,3 Successful treatment of
hyponatraemia depends upon accurate diagnosis of the underlying aetiology of hyponatraemia; again,
published data show that in many cases, clinicians do not order the appropriate tests to enable them to
arrive at the correct diagnosis.3 Unfortunately, there is no consensus on the best diagnostic approach to
uncover the primary cause of hyponatraemia. Experts from different specialties often propose different
diagnostic algorithms to facilitate the management of hyponatraemic patients in the hospital setting.
Traditionally, diagnosis and treatment of hyponatraemia has fallen within the remit of practitioners of
nephrology and endocrinology. Therefore, endocrinologists and nephrologists were brought together at
the European Hyponatraemia Network Academy Meeting to discuss two approaches to the differential
diagnosis of hyponatraemia using different diagnostic algorithms. The intention of this article is to
highlight the importance of clinical and biochemical evaluations of patients with hyponatraemia and
to utilise the approach to the differential diagnosis of neurosurgical hyponatraemia as an example of
a complex differential diagnostic entity.
Sodium is the predominant solute in the extracellular fluid compartment and, as such, the primary
determinant of serum tonicity. A decrease in serum [Na+ ] (i.e. hyponatraemia) generally, but not always,
reflects a state of hypotonicity. The presence of an increased concentration of solutes that do not cross
the cell membrane (such as glucose, mannitol or glycine) can lead to the development of translocational
hyponatraemia as a result of the movement of water from the cells to the extracellular space. Such
patients can have normal, or even high, serum osmolality. Another setting in which hyponatraemia is
associated with a normal serum tonicity occurs in the presence of high levels of lipids or proteins.4
This is designated as pseudohyponatraemia and is the result of the increased proportion of serum
volume taken up by these substances. The serum osmolality remains normal in pseudohyponatraemia
and can be used to eliminate this diagnosis.5
Once the presence of hypotonicity has been established, the urinary osmolality may be used to
differentiate between patients who do and do not have a disorder in the renal diluting mechanism.4
A urine osmolality below 100 mOsm/kg reflects a normal diluting mechanism, the hyponatraemia
resulting from a level of water intake that exceeds normal urinary diluting capacity (psychogenic
polydipsia). This can also be observed in infants fed dilute formula and patients with a low solute
intake. In contrast, a urine osmolality exceeding 100 mOsm/kg reflects impairment to the renal diluting
mechanism at a time when the urine should be maximally dilute in the setting of serum hypotonicity,
this most commonly is a consequence of persistent vasopressin in the circulation.4
In patients whose urine osmolality is greater than 100 mOsm/kg, assessment of volume status is
necessary to identify the underlying aetiology of the hyponatraemia. In hypovolaemic patients with
hyponatraemia, urinary [Na+ ] greater than 20 mmol/L is indicative of renal sodium losses, whereas a
C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7–S15 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
> 20 mmol/L < 20 mmol/L Urinary [Na+] > 20 mmol/L > 20 mmol/L < 20 mmol/L
Renal losses Extrarenal losses
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. Less commonly,
hypervolaemic hyponatraemia is seen in patients with advanced renal failure who cannot conserve
sodium, and therefore may have a urinary [Na+ ] >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.
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+ ].
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.
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
nor does its absence rule out the diagnosis; urine [Na+ ] can also be high in patients with Addison’s disease. Conversely,
some patients with SIADH can have low urinary [Na+ ] if they become hypovolaemic or solute depleted, which are conditions
sometimes produced by imposed sodium and water restriction.
c Fractional sodium excretion = (urinary sodium excretion/serum sodium)/(urinary creatinine/serum creatinine) × 100;
Table 3
The causes of neurosurgical hyponatraemia and their treatment.
ACTH = adrenocorticotropic hormone; IV, intravenous; SIADH = syndrome of inappropriate secretion of antidiuretic hormone.
wasting.12 Although the same authors estimated that cerebral salt wasting may have been responsible
for 6.5% of cases of hyponatraemia following subarachnoid haemorrhage, the data were derived from a
case note review and were incomplete in some cases.14 A subsequent prospective study of 100 patients
with subarachnoid haemorrhage showed that of 49 patients with hyponatraemia, none had cerebral
salt wasting; SIADH was responsible for 71% of cases and ACTH deficiency for 10%.22
C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7–S15 S13
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 – as
a 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.
BP = blood pressure; CVP = central venous pressure; SIADH = syndrome of inappropriate secretion of antidiuretic hormone.
Reproduced from Sherlock M et al. Postgrad Med J 2009; 85: 171–175.14 With permission.
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.
S14 C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7–S15
Practice points
Research agenda
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 Pharmaceutical
for 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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