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Three screening tests are commonly used:

Assessment of diurnal variation of cortisol


24-h urinary free cortisol measurement
Low-dose dexamethasone suppression test.
For blood-based screening tests, ensure no
confounding issues with CBG. For instance, in
severely

Box 6.10 Symptoms


Cushing syndrome

and

signs

of

Muscle wasting, relatively thin limbs


Easily bruised, thin skin; poor wound
healing
Striae (purple or violaceous rather than
white)
Thin (osteoporotic) bones that easily fracture
Diabetes mellitus
Central obesity, rounded (moon) face,
buffalo hump
Susceptibility to infection
Predisposition to gastric ulcer
Hypertension
Disturbance of menstrual cycle; symptoms
overlapping with polycystic ovarian
syndrome (see Chapter 7)
Mood disturbance (depression, psychosis)

ill patients (e.g. those on intensive care),


serum CBG may be decreased, and in female
patients, testing must be conducted off the
combined oral contraceptive pill, which
increases CBG and thus total serum cortisol
levels.
Autonomous production results in loss of
diurnal variation
cortisol at

(a)

with

serum

or

salivary

(b)

Figure 6.9 Cushing syndrome due to an


adrenocortical adenoma secreting cortisol and sex steroisd
precursors. The patients face is shown
prior to operation and 6 months after right
adrenalectomy (the CT scan for the same patient is shown in
Figure 4.7). The striking difference required the patient to renew
her passport.

(a)
(b)

Figure 6.8 The effects of glucocorticoid excess in Cushing disease and the benefits of treatment. (a) Florid
signs of excess cortisol in a 15-year-old boy: round face, greasy skin, severe acne, truncal obesity with stretch marks (striae) and
bruising from a venepuncture site on the right arm. (b) Aged 16, 1 year after curative transsphenoidal surgery and an operation to
remove excess abdominal skin.

Chapter 6: The adrenal gland / 113


Table 6.2 Dexamethasone suppression tests

midnight or bedtime failing to drop from


daytime
values (see Figure 6.5). Bedtime
salivary
collection
avoids problems with CBG and can be
done
at
home, avoiding the cortisol-raising
stress
and
expense of hospitals (in-patient testing
should
be
preceded by an acclimatization period
of
1
or
2
days). In moderate-to-severe Cushing
syndrome,
cortisol is also raised several-fold in
the
urine.
Patients are advised to collect all urine
following
the
first micturition of the day and include
the
first
sample from the following morning (i.e.
capturing
an entire 24-h period). Collection is
relatively
inconvenient
to
perform
and
is
frequently
incomplete. Subtle increases in cortisol
excretion
are
seen in obesity and polycystic ovarian
syndrome
(PCOS). The third test is the low-dose
dexamethasone suppression test (Table 6.2); a
dynamic
test
based on the endocrine principle if
overactivity
is
suspected, try to suppress it.
Dexamethasone
is
a
potent
synthetic
glucocorticoid,
available
orally,
that
inhibits
physiological
ACTH
production
from the anterior pituitary by negative
feedback,
decreasing cortisol production by the
adrenal.
There
are two forms of the low-dose
dexamethasone

Low-dose dexamethasone suppression test


Diagnoses glucocorticoid excess
0.5 mg8 doses 6-hourly ending at 3
single 1 mg dose at midnight

am

or

Positive diagnosis of Cushing syndrome: failure


to suppress 9 am serum cortisol the following
morning to below 50 nmol/L (1.8 g/dL)
High-dose dexamethasone suppression test
Localizes glucocorticoid excess
2 mg8 doses 6-hourly ending at 3 am
Anterior pituitary source: >50% suppression of
9 am serum cortisol from pre- to post-test
Extra-pituitary ectopic source of ACTH (or
adrenal tumour):<50% suppression of 9 am
serum cortisol from pre- to post-test

test (Table 6.2). Occasionally, patients fail


the
1-mg
overnight test because they rapidly
metabolize
the dexamethasone; this should not
occur
using
the formal 48-h test, which is otherwise
more
intrusive. Using either approach, Cushing
syndrome
is excluded if cortisol is less than 50
nmol/L
(1.8 g/dL) the morning following the
tablet(s).
Additional factors can increase serum
cortisol
and
complicate the differential diagnosis of
Cushing
syndrome. This is called pseudo-Cushing
syndrome
(Box 6.11).
Alongside
cortisol,
DHEA
and
androstenedione, which can be converted into potent
androgens
causing
hirsuitism
and
menstrual irregularities in women, may
be elevated.
If cortisol remains high after low-dose
dexamethasone testing, is raised in the urine
and
shows
loss
of
diurnal
variation
(clinical
endocrinologists
commonly
use
a
combination
of
screening
tests),

Cushing syndrome has been diagnosed.


The
next
phase of investigation seeks to locate the
causative
site of the disease.
Diagnosing the cause and site of
glucocorticoid excess

Primary adrenal Cushing syndrome is


most
commonly due to a benign adenoma of the
zona
fasciculata. The excess cortisol suppresses
pituitary
ACTH
by
negative
feedback
usually
to
undetectable
levels
(Box 6.12). In contrast, ACTH-secreting
tumours
may not increase serum ACTH above
the normal

Box 6.11 Pseudo-Cushing


syndrome
Causes
Obesity
Alcoholism
Depression
Distinction from Cushing syndrome
Diurnal variation is usually retained
Cortisol falls on removal of alcohol abuse
Cortisol tends to rise with insulin-induced
hypoglycaemia

114 / Chapter 6: The adrenal gland

Box 6.12 Causes of Cushing


syndrome
Anterior pituitary tumour (Cushing
disease): ACTH inappropriately normal or
raised but can be suppressed by high
dose dexamethasone
Ectopic ACTH: extra-pituitary ACTHsecreting tumour: ACTH inappropriately
normal or raised, less easily suppressed
by high dose dexamethasone
Adrenocortical tumour: baseline ACTH
suppressed
Exogenous glucocorticoids: baseline
ACTH suppressed

reference range, but the hormone is


inappropriately
present for the level of circulating
cortisol.
The
ACTH comes either from a corticotroph
tumour
of
the anterior pituitary or from an ectopic
source,
e.g.
small cell carcinoma of the lung (see
Table
10.6).
The
high-dose
dexamethasone
suppression
test
has
been used to distinguish between
these
options
(Table 6.2). Baseline serum cortisol is
assessed,
followed by a total of 16 mg of
dexamethasone over
48 h (2 mg 6 hourly). ACTH-secreting
pituitary
adenomas usually retain negative
feedback
in
response
to
this
high-dose
dexamethasone
sufficient
to suppress serum cortisol by more than
50%
from
the baseline value. Cushing syndrome
due
to
a
corticotroph adenoma is referred to as
Cushing
disease.
Less effective suppression of serum
cortisol
(by
less
than 50%) suggests an ectopic source

of
ACTH.
Although unreliable, serum ACTH levels
tend
to
be
higher from ectopic tumours than
pituitary
tumours.
The
high-dose
dexamethasone
suppression test lacks complete sensitivity and
specificity;
in
experienced
centres,
venous
sampling
from
the
inferior petrosal sinus can be more
effective
for
determining the origin of ACTH
secretion,
albeit
with greater discomfort and risk from
an
invasive
procedure,
e.g.
a
very
small
percentage
risk
of
stroke.
Inferior
petrosal
sinus
sampling
(IPSS)
is
undertaken
by
interventional
radiologists.
The
hormone is measured in left and right
inferior
petrosal sinus following CRH stimulation.
A clear gra-

dient (3:1 or more) of ACTH from


petrosal
sinus
to peripheral blood points to the anterior
pituitary
rather than an ectopic source and can
also
help
to
lateralize the tumour within the pituitary
fossa.
Because the normal pituitary gland would
also
show
such a central:peripheral gradient, it is
imperative
that glucocorticoid excess is still present
when
IPSS
is undertaken.
Having defined the excess and gained
clues
to
location, it is now appropriate to image
the
anterior
pituitary by MRI; the adrenal glands by
MRI
or
CT; or continue the search for the ectopic
source
of
ACTH (potentially by fine-cut CT of the
chest,
PET scans where available or uptake
scans
that
might identify a carcinoid tumour; review
imaging
in Chapter 4).

Treatment

Cushing syndrome causes premature


mortality,
predominantly
from
cardiovascular
disease.
The
goal of treatment is to normalize
glucocorticoid
production
and
restore
diurnal
rhythm.
For
adrenal
adenomas,
unilateral
adrenalectomy
is

undertaken. For pituitary adenomas,


transsphenoidal surgery is commonplace in
major
centres
but should be restricted to nominated
surgeons
(either ENT or neurosurgeons). The
results
of
treating Cushing syndrome can be striking
(see Figures
6.8 and 6.9).
In the immediate postoperative
period,
if
the
cause of excess glucocorticoid has been
removed,
the hypothalamic-anterior pituitaryadrenal
axis
should
be
so
suppressed
that
endogenous
cortisol
cannot be detected. The body is so
accustomed
to high cortisol levels that the patient is
commonly
symptomatic
of
relative
adrenal
insufficiency
on
normal
hydrocortisone
replacement
doses.
Hydrocortisone therapy is needed for a
sufficient
period until the hypothalamic-anterior
pituitaryadrenal axis returns to normal function.
In
those
not fit for surgery, medical therapy,
e.g.
with
metyrapone,
can
directly
inhibit
glucocorticoid
secretion.
For
inoperable
pituitary
adenomas
or
following failed surgery, either because of
location
or size, pituitary radiotherapy remains a
valuable
option (review Chapter 5).