PRACTICE
com
RATIONAL TESTING
Investigating hyponatraemia
Ammar Wakil, Jen Min Ng, Stephen L Atkin
EDITORIAL by Amin and The commonest causes of hyponatraemia
Meeran
are syndrome of inappropriate antidiuretic
Hull Royal Infirmary, Hull HU3 2RW
Correspondence to: A Wakil hormone (SIADH) and drugs, usually
ammar.wakil@gmail.com thiazides
Cite this as: BMJ 2011;342:d1118
doi: 10.1136/bmj.d1118 The patient
A 70 year old woman with chronic obstructive pulmonary
disease who smoked 30 cigarettes daily was admitted to
the emergency department after a fall and a fracture of the
left neck of femur. Her daughter stated that her mother had
lately seemed confused and unsteady, and that she had
lost weight. She was using a β agonist inhaler and taking
no other drugs. On examination, she looked emaciated,
had nicotine stained fingers, and was disorientated in
time. Blood pressure was 140/85 mm Hg with no postural
drop. Chest examination found scattered wheeze; no car­
diac, abdominal, or other neurological abnormalities were
found. Results of biochemistry were sodium 122 mmol/L
(normal range 136-146 mmol/L), potassium 4.8 mmol/L
(3.5-5.3 mmol/L), urea 1.7 mmol/L (2.1-7.6 mmol/L),
and creatinine 55 mmol/L (51-107 mmol/L). Liver func­
tion tests, plasma glucose concentration, and lipids were
normal. Computed tomography of the brain was normal.
This series of occasional What is the next investigation?
articles provides an update on Hyponatraemia (a serum sodium concentration <136
the best use of key diagnostic
tests in the initial investigation mmol/L) is found in up to 42% of inpatients.1 Hyponatrae­
of common or important mia may be asymptomatic if it is mild to moderate (>125
clinical presentations. The mmol/L) and chronic (>48 hours). Symptoms and signs due
series advisers are Steve Atkin,
professor, head of department to brain oedema occur in severe (≤125 mmol/L) or acutely
of academic endocrinology, developing (<48 hours) hyponatraemia.2 As hyponatraemia
diabetes, and metabolism, Hull advances, clinical features are headache, malaise, nausea,
York Medical School; and Eric
Kilpatrick, honorary professor, vomiting, cramps, lethargy, disorientation, unsteadiness
department of clinical and seizure, respiratory arrest, and death.3 Additionally,
biochemistry, Hull Royal patients may present with the symptoms and signs of the
Infirmary, Hull York Medical
School. To suggest a topic for underlying cause. In a study on the aetiological factors of
this series, please email us at severe hyponatraemia (≤125 mmol/L), 79 out of 105 inpa­
practice@bmj.com. tients had multiple causes, including heart failure in 27,
LEARNING POINTS
History, especially drug history, and focused examination of heart rate, blood pressure,
venous filling, peripheral oedema, and cognitive function should identify possible causes,
severity, and the fluid status in patients with hyponatraemia
Hyponatraemia usually has multiple causes with SIADH and drugs (especially thiazides) the
commonest
The criteria to diagnose SIADH are hyponatraemia, urine osmolality >100 mOsm/kg and
urinary sodium ≥30 mmol/L in the absence of hypovolaemia and hypervolaemia
594 BMJ | 12 MARCH 2011 | VOLUME 342
For the full versions of these articles see bmj.
dehydration in 20, thiazide drugs in 29, liver disease in 21,
pneumonia in 15, central nervous system lesions in 13,
and other drugs in 46. Causes of syndrome of inappropriate
antidiuretic hormone (SIADH), also known as syndrome of
inappropriate antidiuresis (SIAD), were present in 65 of the
105 patients.2  4 The box shows possible underlying causes.
The first step in establishing the cause of hyponatraemia
is a careful history focusing on the predisposing causes
(see box), especially drug history and background history
of heart failure, renal failure, liver disease, respiratory
symptoms, and fluid loss.5 Clinical examination should be
focused on fluid status, including blood pressure, postural
deficit, heart rate, peripheral oedema, and central venous
filling, as well as chest and heart examination. This clinical
assessment should identify potential causes, establish the
severity of hyponatraemia, and determine if the patient is
hypovolaemic, euvolaemic, or hypervolaemic.
Our patient’s history provides clues to the extent of
hyponatraemia. Disorientation and unsteadiness are fea­
tures of severe hyponatraemia; in a smoker, emaciation and
weight could be caused by hyponatraemia. The absence
of signs of hypovolaemia (normal blood pressure with no
postural deficit) and hypervolaemia (lack of peripheral
oedema and normal venous pressure) indicates that she
has euvolaemic hyponatraemia.
Further biochemistry
Normal results of liver function tests, lipids, and glucose
concentration exclude rare causes of artifactual pseudo­
hyponatraemia (hyperproteinaemia and hyperlipidae­
mia) or hyperosmolar hyponatraemia, where water moves
from the intracellular to the extracellular compartment
(in severe hyperglycaemia).3 Therefore our patient has
true hyponatraemia, which can be classified as euvolae­
mic hyponatraemia (figure ). The differential diagnosis of
euvolaemic hyponatraemia includes SIADH, adrenocorti­
cal insufficiency, and debatably severe hypothyroidism,
but by far the most common cause is SIADH.4 Since there
are no clinical features of glucocorticoid deficiency (for
example, history of vomiting and low blood pressure on
examination) and hypothyroidism (for example, features of
myxoedema such as weight gain and nonpitting oedema),
a short tetracosactide (Synacthen) test and thyroid tests are
not needed and our patient is likely to have SIADH.
Serum osmolality
A diagnosis by exclusion, SIADH needs to be con­
firmed by results of paired serum and urine samples:

True hyponatraemia: serum sodium <136 mmol/L
History: drugs, congestive cardiac failure, liver failure, pneumonia
Examination: jugular venous pressure, heart rate, blood pressure, postural deficit and peripheral oedema
Peripheral oedema, ascites in
congestive cardiac failure, liver
disease, or nephrotic syndrome
Hypervolaemic hyponatraemia
Urine osmolality
>100 mOsm/kg and
urine sodium <30 mmol/L
Look for causes of SIADH:
Drugs (eg selective serotonin reuptake inhibitors)
Pulmonary (infections, tumours)
SIADH= Syndrome of inappropriate antidiuretic hormone
Clinical approach to diagnosing true hyponatraemia (SIADH=syndrome of inappropriate
antidiuretic hormone)
bmj.com Previous articles
in this series
ЖЖTesting for secondary
causes of osteoporosis
(BMJ 2010;341:c6959)
ЖЖInvestigation of
peripheral neuropathy
(BMJ 2010;341:c6100)
ЖЖInvestigating easy
bruising in a child
(BMJ 2010;341:c4565)
ЖЖInvestigating secondary
hyperhidrosis
(BMJ 2010;341:c4475)
ЖЖInvestigating fatigue in
primary care
(BMJ 2010;341:c4259)
ЖЖInvestigating mildly
abnormal serum
aminotransferase values
(BMJ 2010;341:c4039)
BMJ | 12 MARCH 2011 | VOLUME 342 595
PRACTICE
Causes of hyponatraemia
Hypovolaemia
Renal loss:
Thiazide diuretic
Adrenocortical insufficiency
Salt wasting nephropathy
Absence of features History of fluid
of hypovolaemia loss, hypotension,
Extrarenal loss:
or hypervolaemia tachycardia, postural deficit Diarrhoea
Vomiting
Excessive sweating
Euvolaemic hyponatraemia Hypovolaemic hyponatraemia
Third space loss:
Small bowel obstruction
Diagnose SIADH if urine Urine osmolality
osmolality >100 mOsm/kg, >100 mOsm/kg and
Pancreatitis
urine sodium 30 mmol/L in the urine sodium <30 mmol/L Burns
absence of history of exogenous Euvolaemia
desmopressin or diuretics,
and clinical features of Syndrome of inappropriate antidiuretic hormone (SIADH)
hypothyroidism or Drugs:
corticoid deficiency Selective serotonin reuptake inhibitors
Carbamazepine
Desmopressin
Central nervous system (strokes, infections) Phenothiazines
Stress (eg surgery)
Tricyclic antidepressants
Cyclophosphamide
Opiates
Vincristine
Non-steroidal anti-inflammatory drugs
Clofibrate
Chest:
serum hyposmolality must be <275 mOsm/kg (­normal Pneumonia
range: 275-295 mOsm/kg), and urine ­osmolality >100 Tuberculosis
mOsm/kg and sodium ≥30 mmol/L, in the absence Pulmonary abscess
of ­hypovolaemia, hypervolaemia, adrenal or thyroid Neoplastic:
­dysfunction and use of diuretics.2  6 Paired serum and Small cell lung cancer
Lymphoma
spot urine samples need to be sent for ­osmolality and
Central nervous system:
sodium to confirm both hyponatraemia and SIADH.
Serum osmolality is not necessary when there is
Meningitis
Stroke
an obvious ­contributory cause. It can confirm true Brain tumour
hyponatraemia (<275 ­m Osmol/kg) and rules out Postoperative pain
the rarer ­hyperosmolar hyponatraemia and pseudo­ Nausea
hyponatraemia (serum osmolality ≥275 mmol/L).3 Adrenocortical insufficiency
Urine osmolality (normal range 300-900 mOsm/kg) is Hypothyroidism
needed to confirm SIADH but it also helps in differentiat­ Hypervolaemia
ing it from two other conditions. By definition SIADH is
Congestive cardiac failure
an incomplete suppression of antidiuretic hormone (urine
Liver cirrhosis with ascites and peripheral oedema
osmolality >100 mOsm/kg); a spot urinary osmolality <100 Nephrotic syndrome
mOsm/kg indicates appropriate complete suppression.
Renal failure
Complete suppression of antidiuretic hormone is seen in
psychogenic polydipsia (history of mental illness) and mal­
nutrition (history of heavy alcohol consumption).7 content is sequestered in a body space (as in burns). The
urinary sodium concentration in all hypovolaemic hyponat­
Urinary sodium raemia is <30 mmol/L except when the kidney is the site of
Urinary sodium concentration is helpful when the cause the loss, for example with diuretic use, salt losing neph­
of hyponatraemia is not apparent from the history and ropathy, or mineralocorticoid deficiency.9
examination or when SIADH is suspected. In euvolaemic
hyponatraemia (including SIADH), the urinary sodium is Other investigations
≥30 mmol/L (normal values varies with diet8).6 Hypervolae­ When the fluid status is difficult to determine clinically,
mic hyponatraemia should be apparent clinically; because low serum concentrations of urea and uric acid indicates
of the reduced effective circulating volume, the kidney con­ SIADH, and a raised concentration of urea is more likely to
centrates the urine (>100 mOsm/kg) and conserves sodium reflect hypovolaemia.7
(<30 mmol/L; but it can be higher when the patient is taking
diuretics).6 The clues to hypovolaemia in the history (see Outcome
box) include obvious fluid loss (through diuretics, for exam­ That this patient had SIADH is evidenced by her serum
ple) or third space fluid loss, when fluid with high sodium osmolality of 235 mOsm/kg, urinary osmolality of
 PRACTICE
1
Nuffield Department of Surgical
Sciences (University of Oxford),
John Radcliffe Hospital, Oxford
OX3 9DU, UK
2
MRC Harwell, Harwell Science and
Innovation Campus, UK
3
School of Medicine, University of
Southampton, Southampton, UK
4
Bielefeld Academic Teaching
Hospital, Münster University,
D-33604 Bielefeld, Germany
Correspondence to: M F Bhutta
m.bhutta@doctors.org.uk
Cite this as: BMJ 2011;342:d1088
doi: 10.1136/bmj.d1088
This is one of a series
of occasional articles
highlighting conditions that
may be more common than
many doctors realise or may be
missed at first presentation.
The series advisers are
Anthony Harnden, university
lecturer in general practice,
Department of Primary
Health Care, University of
Oxford, and Richard Lehman,
general practitioner, Banbury.
To suggest a topic for this
series, please email us at
easilymissed@bmj.com.
596 BMJ | 12 MARCH 2011 | VOLUME 342
350 mOsm/kg, and urinary sodium concentration of
95 mmol/L. Her intake of fluids was restricted and she was
given tolvaptan 15 mg once daily, which gradually raised
the serum sodium concentration. Chest imaging showed
a lesion in the left lung, and a biopsy confirmed small cell
carcinoma of the lung.
Contributors: SLA had the idea for the article; AW performed the literature
search and wrote the article. JMN and SLA edited and contributed to the
writing. SLA is guarantor.
Competing interests: All authors have completed the Unified Competing
Interest form at www.icmje.org/coi_disclosure.pdf (available on request
from the corresponding author) and all authors declare: no support from
any organisation for the submitted work; no financial relationships with
any organisations that might have an interest in the submitted work in the
previous three years; no other relationships or activities that could appear to
have influenced the submitted work.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent not required (patient is hypothetical).
EASILY MISSED?
Cholesteatoma
Mahmood F Bhutta,1 2 Ian G Williamson,3 Holger H Sudhoff4
A cholesteatoma is a lesion of the ear, formed of a mass
of stratified keratinising squamous epithelium (fig 1).1
Aetiology is debated,2 but cholesteatoma probably arises
from the lateral epithelium of the tympanic membrane,
and then grows as a self perpetuating mass into the mid­
dle ear. This may activate local osteoclasts,3 possibly as a
result of infection of dead epithelium at the centre of the
lesion, with potentially serious consequences from local
tissue destruction.
Why is cholesteatoma missed?
The onset of disease may be insidious with intermittent
or mild symptoms. Typically cholesteatoma presents
with intermittent unilateral otorrhoea (ear discharge)
and a progressive hearing loss,6 which may mimic and
be misdiagnosed as recurrent or chronic otitis externa
or otitis media. Successful negligence claims have been
filed in the United Kingdom (http://boyesturnerclaims.
com/case-study.html?id=85) and the United States (www.
upton-hatfield.com/news/verdicts.html) for complica­
tions resulting from a missed diagnosis in primary care,
although no published data are available on frequency
of misdiagnosis.
CASE SCENARIO
A 24 year old man presented to his general practitioner
several times over a year with an intermittently discharging
left ear and associated hearing loss. Visualisation of
the tympanic membrane was not possible owing to
otorrhoea and oedema in the external auditory canal. He
was treated for presumed otitis externa with repeated
courses of topical antibiotic drops, but as improvement
was only temporary he was referred to a specialist. An
otolaryngologist cleared the external auditory canal of
debris (“aural toilet”) and discovered a cholesteatoma
arising from the left tympanic membrane; this was
successfully treated by surgical excision.
1 Hawkins RC. Age and gender as risk factors for hyponatremia and
hypernatremia. Clin Chim Acta 2003;337:169-72.
2 Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med
2007;356:2064-72.
3 Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;342:
1493-9.
4 Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical
in-patients: aetiology, assessment and outcome. QJM 2006;99:
505-11.
5 Yeates KE, Singer M, Morton AR. Salt and water: a simple approach to
hyponatremia. CMAJ 2004;170:365-9.
6 Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH.
Hyponatremia treatment guidelines 2007: expert panel recommendations.
Am J Med 2007;120:S1-21.
7 Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: a systematic
approach to laboratory diagnosis. CMAJ 2002;166:
1056-62.
8 Zenenberg RD, Carluccio AL, Merlin MA. Hyponatremia: evaluation and
management. Hosp Pract (Minneap) 2010;38:89-96.
9 Schrier RW. Body water homeostasis: clinical disorders of urinary dilution
and concentration. J Am Soc Nephrol 2006;17:1820-32.
Accepted: 15 November 2010
Why does it matter?
A cholesteatoma is a self perpetuating mass, which if
untreated, can cause extensive local tissue destruction. At
presentation the ossicles are often eroded, contributing to
conductive hearing loss.7 Rarely cholesteatoma may erode
into the inner ear causing sensorineural hearing loss or ver­
tigo, or lead to facial palsy from damage to the facial nerve as
it traverses the middle ear.8 Cholesteatoma can also lead to
spread of infection through the tegmen (roof) of the middle
ear causing meningitis or intracranial abscess (fig 2), a risk
estimated to be 1 in 10 000 a year of untreated disease.9
How is cholesteatoma diagnosed?
Clinical features
Symptoms of cholesteatoma—such as persistent hearing
loss (present in 83% of 23 ears in a case series), otor­
rhoea (56%), otalgia (39%), vertigo, or tinnitus—are non-
specific,6 and so the diagnosis rests on the appearance
on otoscopic examination. Cholesteatoma is classically
described as “wax in the attic”: a yellow or white crust
visible in the upper part (pars flaccida or “attic”) of the
tympanic membrane, often surrounded by pus, and with
a perforation of the adjacent tympanic membrane and ero­
HOW COMMON IS CHOLESTEATOMA?
The estimated incidence of cholesteatoma in northern
Europe is 9.2 per 100 000 population a year4
Therefore a general practitioner with a practice size of 2500
patients would be expected to see on average one new
case every four to five years
The peak incidence is in the age range 5-15 years,5 but
cholesteatoma can arise in any age group
Seven per cent of people diagnosed will subsequently
develop cholesteatoma in the contralateral ear5
The incidence is reportedly higher in white than non-white
populations.
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