Case history 6.

2
A 44-year-old woman had suffered
symptoms that she attributed to PCOS by
virtue of reading articles on the internet.
She went to see the doctor because of
feeling generally unwell, having put on
10 kg in weight and developing nocturia. She took
no medication. The doctor
suspected diabetes and, indeed, the
patients fasting blood glucose was
8.5 mmol/L (153 mg/dL). However, the doctor was
more struck by the patients appearance of a flushed
round face, poor facial skin quality and purple
stretch
marks on the abdomen. Blood pressure
was 160/95 mmHg. The doctor arranged
several tests that confirmed the diagnosis.
Serum ACTH was then measured and was
undetectable.
What is the initial diagnosis and what
tests were used to make it?
Where is the causative lesion and what
imaging investigations might be
considered?
Answers, see p. 124

Primary mineralocorticoid excess - Conn

syndrome
Tumours or bilateral idiopathic hyperplasia of
the zona glomerulosa result in excess
aldosterone with normal cortisol levels.
Symptoms and signs

Hyperaldosteronism
most
characteristically
presents
with
hypokalaemic
hypertension.
In
common
with diagnosing any of the more unusual
causes
of hypertension, a high index of suspicion
is
required
(Box
6.13).
The
electrolyte
disturbance
may be unmasked or exacerbated by
concomitant
potassium-losing diuretic therapy prescribed for
the

Box 6.13 Think of unusual causes of

hypertension, especially in
younger patients
Conn syndrome
Phaeochromocytoma
Renal artery stenosis
Coarctation of the aorta

hypertension
(e.g.
thiazides).
However,
aldosterone
excess
also
underlies
a
subset
of
normokalaemic
hypertension. The symptoms tend to be vague.
Hypertension may present with headaches
and
visual disturbances; hypokalaemia may cause
muscle
fatigue or tiredness (Case history 6.3). Initial
biochemical screening becomes increasingly
relevant
in
younger patients with marked hypertension,
especially
if
it
is
resistant
to
multiple
antihypertensive
drugs and accompanied by hypokalaemia
(either
spontaneous or induced by diuretics). The
incidence of Conn syndrome is seemingly higher
in
women in their third decade. If blood pressure
is
normal for age, other causes of hypokalaemia
merit
consideration (Box 6.14).
Diagnosis

The diagnosis of primary aldosterone excess

requires
assessment
of
the
renin-angiotensinaldosterone
axis by screening and then diagnostic
tests.
Concomitant
use
of
antihypertensive
medications
that affect the hormone axis is potentially confounding. MR antagonists need to be
withdrawn
for 4 weeks. It is debatable whether other

agents,
such as diuretics, -blockers and ACE
inhibitors,
need to be stopped for initial screening because
the
hypertension can be dangerous and difficult to
control without treatment. If initial testing is
equivocal, medications may need to be withdrawn or
substituted with drugs such as doxazasin, an -

adrenergic blocker. Serum potassium should

be
restored to the normal range with oral
supplementation in the days prior to testing. Salt intake
should
be unrestricted to ensure the patient is
sodium
replete. For screening, plasma aldosterone and
renin

116 / Chapter 6: The adrenal gland

Box 6.14 Causes of hypokalaemia

Primary hyperaldosteronism
Vomiting with metabolic alkalosis
Diarrhoea or other fluid loss from the lower
bowel:
leostomy

I
illous adenoma of the rectum
V
Diuretic use
Hypomagnesaemia
Insulin infusion

Rare

causes

include

renal

tubular

acidosis

and various monogenic defects of renal

tubule function:
itelman

syndrome

normotensive)
G

(usually

iddle syndrome (hypertensive)

L
artter syndrome (usually hypo- or
Bnormo-tensive)
ypokalaemic periodic paralysis

(either plasma activity or serum

concentration)
are
measured mid-morning (aldosterone
levels
fall
during the day) with the patient having
been
seated
for 15 min, but having been out of
bed
for
a
couple of hours. Positive screening
detects
a
high
ratio
of
aldosterone
to
renin
concentration
or
activity in the serum. Applied cut-offs vary
and
depend
on assay units. For instance, measuring
aldosterone
in pmol/L and renin activity in nmol/L/h,
a
ratio
of more than 2000 gives a very high
likelihood
of
primary
hyperaldosteronism.
Some
endocrinologists argue that the ratio is best
interpreted
only
when serum aldosterone is above a
certain
threshold

[e.g. 200 pmol/L (7 ng/dL)]. This

avoids
misleading high ratios simply due to a very
low
renin
concentration. A normal or low ratio
excludes
primary aldosterone excess (see Box
6.13
for
potential causes other than essential
hypertension).
If the aldosterone:renin ratio is
raised,
a
variety
of tests in the specialist setting confirm
the
diagnosis by observing a failure of aldosterone
suppression
in response to intravenous saline or
fludrocortisone.
Once a biochemical diagnosis has
been
made,
the
cause of excess aldosterone needs to be
determined.

Aside
from
rare
genetic
causes,
hyperaldosteronism
usually arises from two pathologies: a
discrete
adenoma (Conn tumour) or bilateral
hyperplasia
that can often be discriminated by MRI
or
CT.
If the patient is over 40 years old, when
there
is
increased risk of an incidental nonfunctional
adenoma, or if imaging is equivocal,
adrenal
vein
sampling helps to localize the source of
mineralocorticoid excess (but this is challenging;
see
earlier
details on adrenal anatomy).
Treatment

A Conn tumour is ideally treated by

unilateral
adrenalectomy when hypertension can be
cured
or
improved such that the number and dose
of
antihypertensives can be markedly reduced.
Bilateral
hyperplasia or adenomas in patients
unfit
for
surgery
are
managed
by
drugs.
Spironolactone
has
been used for many years as an MR
antagonist.
Indeed, a clue to diagnosis can come
from
its
use
followed by a rapid fall in previously
refractory
high
blood pressure. Unfortunately, the drug
also
antagonizes the androgen receptor (AR),
causing
breast

development (gynaecomastia) in men

and
necessitating contraceptive advice in fertile
women
to
guard against feminizing a male fetus.
The
more
specific but less potent antagonist,
eplerenone,
is
available
as
an oral
twice-daily
preparation.
Tumours involving the zona reticularis
In addition to cortisol, tumours from the
fasciculata
and reticularis zones can secrete sex
steroid
precursors. These steroids are converted in the
periphery
to
androgens
and,
potentially,
oestrogens,
causing
virilization in women (deepened voice
and
clitoromegaly) or feminization in men (e.g.
gynaecomastia). The tumours may be diagnosed by
increased
serum DHEA (some laboratories only
measure
DHEAS), androstenedione, testosterone
and
oestradiol according to sex, and assessment of
glucocorticoid status. Where cortisol is normal,
and
only
sex
steroids and their precursors are raised,
discrimination between an adrenal or gonadal
source
requires
imaging by CT or MRI and potential
catheterization and sampling of the adrenal and
ovarian
veins.
The tumours are treated surgically with
removal
of
the offending adrenal gland.

Chapter 6: The adrenal gland / 117

Case history 6.3

A physically active 23-year-old student is
referred with a blood pressure of
158/94 mmHg. On examination, body
mass index (BMI) is 20.5 kg/m 2. Serum
sodium was 144 mmol/L (144 mEq/L) and
serum potassium was 2.8 mmol/L
(2.8 mEq/L).
What endocrine diagnosis should be
suspected?
What biochemical screening test is
required with what electrolyte
preparation?
Outline the subsequent investigation
plans if the screening test is positive.
Answers, see p. 125

Other tumours of the adrenal cortex

Adrenocortical carcinoma

The commonest malignant tumour of

the
adrenal
cortex is metastatic. Primary adrenal
carcinoma
is
rare. The vast majority is functional
(80%),
and
most secrete a mixture of steroids
characteristic
of
different zones and best detected by mass
spectrometry. The clinical picture tends to be one
of
rapidly
progressive Cushing syndrome and
virilization
accompanied by the more general
effects
of
an
aggressive tumour (e.g. weight loss,
abdominal
pain,
anorexia and fever). Most tumours have
metastasized by presentation so adrenalectomy
is
no
longer
curative. Mitotane, an adrenolytic
drug,
palliates
symptoms and can reduce tumour
growth,
but
sur-

vival is poor; historically, 20% or less

of
patients
have survived 5 years. Newer trials
with
additional
agents are underway.
Incidentalomas

An
increasing
problem
is
the
management
of
tumours identified on CT or MRI
performed
for
other reasons (Box 6.15). These
incidentalomas
are
common in individuals over 40 years,
potentially
affecting 5% of individuals (Case
history 6.4).

Box 6.15 A pragmatic approach to

adrenal incidentalomas?
Exclude over-secretion of aldosterone,
glucocorticoid, sex steroid precursors and
catecholamines (see other sections)
Assess likelihood that it is a metastasis:
ull history and examination

F
s it poorly demarcated on CT or MRI?
onsider
I
C
chest X-ray in smokers
If

>4 cm, risk of malignancy is increased,

unilateral adrenalectomy advised
If<4 cm, hormone-negative and not
suspicious on imaging: follow-up with
repeat investigation at 6 months and
potentially annually thereafter if no change or
discharge

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is
an
autosomal recessive disorder (i.e. inactivating
mutations
in both copies of the gene are required for
the
phenotype). The causative genes encode
enzymes
in
the
pathway to cortisol (see Figure 6.3, plus
others
not
shown for simplicity, such as cytochrome
P450
oxidoreductase). This leads to cortisol

deficiency,
diminished negative feedback at the
anterior
pituitary and raised ACTH (see Figure
6.4).
High
ACTH
and
raised
intermediaries
upstream
of
the
inactive enzyme increase flux through
the
remaining intact steroidogenic pathways. For
instance,
inactivating mutations in CYP21A2
account
for
90% of CAH and cause decreased
cortisol
and
raised 17-hydroxyprogesterone; in the
presence
of
high ACTH, pathways are stimulated to
convert
this build-up of CYP21A2 substrate to
sex
steroid
precursors and potent androgens. In
addition
to
the
cortisol deficiency, this causes:
Ambiguous genitalia in females at
birth (Figure
6.10)
Precocious puberty in males; and
Hirsuitism, menstrual irregularities
and
subfertility in women.
Many patients also have inadequate
aldosterone production (salt wasting
CAH); some do not