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Clinical disorders

Excess
vasopressin/syndrome
of
inappropriate antidiuretic hormone
The syndrome of inappropriate ADH (SIADH)
refers to the release of vasopressin when
normal regulatory mechanisms should restrict
its secretion into the circulation (Case
history 5.5). This is a difficult and dangerous
clinical
situation
(Box
5.12)
where
hyponatraemia and low osmolality can cause
irreversible brain damage and death.
Symptoms and signs

Headache and apathy progress to nausea,


vomiting,
abnormal neurological signs and impaired
consciousness. In very severe cases, there may be
coma,
convulsions and death. Generalized oedema is
not

Box 5.12 Excess


vasopressin/SIADH
Definition
Hyponatraemia + low serum osmolality
(<270 mOsm/kg) + inappropriately high
urine osmolality
Causes
Tumours (e.g. small cell cancer of the
lung)
Any brain disorders (trauma, infection,
tumour)
Pneumonia
Cytotoxic therapy (chemotherapy or
radiotherapy)
Narcotics and analgesics
Hypothyroidism
Hypoadrenalism
Treatment
Identify and treat underlying cause where
possible
Restrict fluid intake (up to 1 L/day) and
replace sodium lost in the urine
Vaptans act as V2 receptor antagonists
Demeclocycline may induce partial
diabetes insipidus (see below) but it is less commonly
used now

a feature because free water is evenly


distributed across all body compartments.
Investigation, diagnosis and treatment

The cardinal features of SIADH are low serum


osmolality, hyponatraemia and inappropriately
high
urine osmolality. Other common causes of
hyponatraemia, especially in the elderly, are
congestive
cardiac failure and diuretic use. In SIADH,
identifying the underlying cause is important (Box
5.12).
Vaptans are new non-peptide drugs that can
be
given orally in chronic SIADH. They
antagonize
the V2 receptor lowering the number of
aquaporin
water channels in the renal collecting duct
thus
reducing water re-absorption from the urine.

Case history 5.5


A 74-year-old man presented to the
emergency medical service with a 2-week
history of a cough productive of bloody
green sputum, fever, shortness of breath
and pleuritic chest pain. He was a life-long
smoker. Serum sodium was 124 mmol/L
(124 mEq/L), potassium 3.6 mmol/L
(3.6 mEq/L), urea 2.7 mmol/L (7.6 mg/dL)
and creatinine 73 mol/L (0.8 mg/dL).
Serum osmolality was 258 mOsm/kg and
urine osmolality was 560 mOsm/kg.
What is the most likely endocrine cause
for the hyponatraemia and what acute
condition underlies it?
What measures might be taken to rectify
the situation?
What further investigations might be
considered?
Answers, see p. 97

Deficiency of vasopressin/diabetes insipidus

Even when damage to the posterior pituitary


occurs,

vasopressin or oxytocin deficiency commonly


does

94 / Chapter 5: The hypothalamus and pituitary gland

not arise so long as the hypothalamic


neurones
that
transport the hormones remain intact
(see
earlier
anatomy section). When deficiency of
vasopressin
or its action does occur, it results in
diabetes
insipidus (DI). Deficiency of vasopressin
production
by
the
hypothalamus
and
posterior
pituitary
is
termed
cranial DI, whereas deficient action
at
the
V2
receptor causes nephrogenic DI (Table
5.6).
In
the
former, the vast majority of vasopressin
production
needs to be lost (90%) before water
balance
is
necessarily affected. The term DI stems
from
when
physicians used to taste urine and
contrast
it
with
the sweet urine of diabetes mellitus.
Symptoms and signs

Patients with DI pass extremely large


and
frequent
volumes
of
low
osmolality
urine
(potentially 20 L in
24 h). This polyuria and passing urine at
night
(nocturia) demonstrate that in DI the patient
is
unable
to reduce urine flow. Clinically, problems
only
tend
to arise when the patient also lacks
sensation
of
thirst or is deprived of water, when
plasma
osmolality rises.
Investigation and diagnosis

Some centres have access to a


vasopressin
immunoassay, which allows the diagnosis to
be
made
by
monitoring
serum
vasopressin

concentration
after
an infusion of hypertonic saline. Most
endocrinologists still rely on the water deprivation
test
and
the
use of the vasopressin analogue,
desmopressin
(Table 5.6).
Treatment

Having diagnosed DI, it remains


important
to
consider and investigate the underlying
cause,
which
may be curable. Otherwise management
of
DI
relies
on intact thirst and access to
adequate
fluid.
For
cranial DI, replacement of vasopressin
is
all
that
is
required. Desmopressin, either by
intranasal
spray,
tablet or injection, is a synthetic
analogue
that
acts
predominantly on the V2 receptor and
therefore
has
minimal
hypertensive
side-effects.
Desmopressin
is
sometimes also used in normal children
who
suffer
from nocturnal enuresis (bed-wetting).
Nephrogenic
DI and psychogenic polydipsia can be
harder to

treat effectively. In the latter, the high


urine flow rate tends to dilute the
solutes that create the counter-current
exchange mechanism in the renal
parenchyma such that the kidney loses its
ability to concentrate urine.

Case history 5.6


A 58-year-old woman was referred by her
family doctor because of complaints of
passing urine every hour during both the day
and night. Nothing else was
volunteered in the history and the doctor had
excluded diabetes mellitus. The
patient had browsed the internet and felt
she had diabetes insipidus. Serum sodium
was 135 mmol/L (135 mEq/L), potassium
4.5 mmol/L (4.5 mEq/L), urea 4.3 mmol/L
(12.0 mg/dL) and creatinine 93 mol/L
(1.1 mg/dL).
What other aspects of the history need
direct questioning?

What test(s) is appropriate to confirm or


refute a diagnosis of diabetes
insipidus?
If diabetes insipidus is confirmed, in
which two sites might the pathology
lie?
Answers, see p. 97

Oxytocin
The major roles of oxytocin are during
birth and breast-feeding (see Chapter
7). It is also emerging as a brain
neurotransmitter with roles in modulating behaviour and overeating.
Effects and mechanism of action
Oxytocin has two main sites of action:
the
uterus
and the mammary gland. It is the
hormone
of
parturition, literally meaning quick birth.
It
increases
the contraction of the myometrium
during labour

Chapter 5: The hypothalamus and pituitary gland / 95

Table 5.6 Diabetes insipidus (DI).


In brief
Deficient vasopressin secretion or actionlarge volume of low osmolality urine problems from high serum
osmolality
Cranial DI

Nephrogenic DI

Causes

Causes

CNS tumours

Drugs (e.g. lithium, demeclocycline)

Head trauma

Familial X-linked recessive (i.e. males affected):

Infection (e.g. meningitis and encephalitis)


Familial autosomal dominant:

V2 receptor gene mutation*


Autosomal recessive:

Vasopressin gene mutation*


DIDMOAD syndrome (DI, diabetes mellitus, optic
atrophy and deafness)

Aquaporin 2 gene mutation*


Chronic renal disease

Idiopathic
Investigated by the water deprivation test
Conducted over 8 h during the day with repeated measurements of weight and serum (S OSM) and urine
(UOSM) osmolality
Terminate test if body weight falls 5% (dangerous) and allow the patient to drink DI
diagnosed if:
SOSM rises to 293 mOsm/kg (normal: 283-293 mOsm/kg); U OSM remains 300 mOsm/kg
Desmopressin (a synthetic vasopressin analogue) is given to distinguish between cranial and
nephrogenic DI**:
Cranial DI, urine now concentrates to 750 mOsm/kg
Nephrogenic DI, urine still fails to concentrate, U OSM remains 750 mOsm/kg
Hypokalaemia and hypercalcaemia can suggest nephrogenic DI
Psychogenic polydipsia (i.e. habitual excess water intake): S OSM should remain 293 mOsm/kg,
commonly with partial concentration of urine. If S OSM remains normal and UOSM fails to concentrate with
continued urine output, suspect covert drinking
Treatment
Ensure an intact sense of thirst and free access to fluid
Desmopressin provides hormone replacement for cranial DI
*Syndromes arising from gene mutations are due to loss of function.
**If desmopressin has been administered at the end of the water deprivation test, restrict fluid intake to <500 mL over the next
8h to avoid risk of profound hyponatraemia (e.g. in cranial DI or polydipsic patients).