Download Investigation of Cushings Syndrome

Case Hx
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25 years old female
Weight gain – 6 months
DM – 1 month
BP 130/90 mm Hg
Round plethoric face
Central obesity
Pinkish striae on abdominal wall
Proximal myopathy
Case Hx
• 24 hour urine cortisol – more than 3 fold rise
• LDDST
683 nmol/l
526 nmol/l
• ACTH – 81.2 pg/ml
• MRI Pituitary
Two microadenomas, one on left and one
on right side
Case Hx
• TSS performed
• Not fully cured
• 9 am Cortisol was 340 nmol/l (3 days after
surgery)
• Marked improvement in glycemic control
• Plan - Assessment after two months with 24
hour urinary cortisol and LDDST (if needed)
Cushing’s=hypercortisolism
• Cushing's Syndrome- Clinical effects of
increased glucocorticoid hormone - all causes
of excess cortisol
• Cushing's Disease- ACTH producing pituitary
adenoma
Clinical Features of Excess Cortisol
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Truncal obesity
Moon face
Fat deposits supraclavicular fossa
and posterior neck- buffalo hump
HTN
Hirsutism
Amenorrhea
Depression
Thin skin
Easy bruising
Purplish abdominal striae
Proximal muscle weakness
Osteoporosis
Diabetes Mellitus
Avascular necrosis
Wound healing impaired
Pysch symptoms
Hyperpigmentation
Hypokalemic alkalosis
Ectopic ACTH
All the previous clinical features but…..
• Ectopic dominated by :
– Hypokalemic alkalosis (dominant feature)
– Fluid retention
– HTN
– Glucose intolerance
– Steroid psychosis
• Absence of other features may be explained by more
sudden onset by acquired ACTH from tumor.
Causes of Cushing Syndrome
• Iatrogenic
• ACTH secreting pituitary
microadenoma (Cushing’s disease)
– 48% cases of Cushing’s syndrome
– 3 x more women than men
– 15% of pituitary tumors (usu 3rd or 4th
decade of life)
Causes of Cushing Syndrome
• Adrenal tumors- 32%, usually unilateral
- Small tumour – benign - mostly cortisol
- large- carcinoma - cortisol and androgens
• Ectopic ACTH secretion- 10%
- most common small cell lung CA
• 15%- cause not identified
Ectopic ACTH
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SCLC
Thymic carcinoid
Islet cell tumors
Bronchial carcinoid
Other carcinoids
Pheochromocytomas
>50%
15%
10%
10%
5%
2%
Investigation of
Cushing’s Syndrome
SCREENING TESTS
24 hour Urine Free Cortisol
• Useful for outpatient screening
• 3 times normal
• false –ve rate of 5–10% means that it should not
be used alone.
• Fenofibrate, carbamazepine, and digoxin may
lead to false +ves
• Reduced GFR <30mL/min may lead to false –ves.
• Mild elevation occurs in pseudo-Cushing’s and
normal pregnancy.
Overnight DST
• Administration of 1mg dexamethasone at 11 pm is
followed by a serum cortisol measurement at 9 a.m.
• Cortisol < 50nmol/L makes Cushing’s unlikely.
• False +ves (poor dexamethasone absorption or
hepatic enzyme induction).
• The false –ve value is 2% of normal individuals but
rises to upto 20% in obese or hospitalized patients.
Midnight Cortisol
• Loss of circadian rhythm of cortisol secretion is seen
in Cushing’s syndrome
• Demonstrated by measuring a serum cortisol at
midnight (patient must be asleep for this test to be
valid and ideally after 48h as an inpatient).
• In normal subjects, the cortisol at this time is at a
nadir (<50nmol/L), but in patients with Cushing’s
syndrome, it is elevated.
Salivary Cortisol
• A late evening salivary cortisol concentration can be
used to establish the diagnosis of Cushing's
syndrome.
• Saliva is easily collected and cortisol is stable in saliva
even at room temperature for several days.
• It is especially useful for patients suspected of having
cyclical or intermittent Cushing's syndrome, who can
collect many samples over an extended period of
time and return the accumulated samples to the lab
at one time.
False Positives
• Severe depression
• Severe stress
• Phenytoin/phenobarbital/rifampin
(accelerated metabolism of dexamethasone)
• Estrogen (pregnancy or OCP)
• Morbid obesity
CONFIRMATORY TESTS
LDDST
• Administration of 0.5mg dexamethasone 6-hourly (30
micrograms/kg/day) for 48h at 9 a.m., 3 p.m., 9 p.m.,
and 3 a.m. should lead to complete suppression of
cortisol to <50nmol/L in normal subjects (30
micrograms/kg/day).
• Serum cortisol is measured at time 0 and 48h (day 2).
LDDST
• Interfering conditions should be considered
with all dexamethasone testing
• ↓ dexamethasone absorption
• hepatic enzyme inducers (e.g. phenytoin,
carbamazepine, and rifampicin)
• ↑ CBG.
Pseudo-Cushings
• Patients with pseudo-Cushing’s syndrome will also
show loss of diurnal rhythm and lack of low-dose
suppressibility.
• However, alcoholics return to normal cortisol
secretory dynamics after a few days’ abstinence in
hospital.
• Severe depression can be more difficult to
differentiate, particularly since this may be a feature
of Cushing’s syndrome itself.
Pseudo-Cushings
• Typically, patients with pseudo-Cushing’s show a
normal cortisol rise with hypoglycaemia (tested using
ITT) whereas patients with true Cushing’s syndrome
show a blunted rise.
• However, this is not 100% reliable, as up to 20% of
patients with Cushing’s syndrome (especially those
with cyclical disease) show a normal cortisol rise with
hypoglycaemia.
Pseudo-Cushings
• The combined DST–CRH test
• 0.5mg dexamethasone 6-hourly for 48h followed by
ovine CRH 1 microgram/kg IV 2h after last dose of
dexamethasone, may be helpful, as patients with
pseudo-Cushing’s are thought to be under chronic
CRH stimulation, thus showing a blunted response to
CRH after dexamethasone suppression
• IV desmopressin 10 micrograms increases ACTH in
80–90% with Cushing’s but rarely in patients with
pseudo-Cushing’s.
Underlying Cause
Serum ACTH
• Once the presence of Cushing’s syndrome has
been confirmed, a serum basal ACTH should
be measured to differentiate between ACTHdependent and ACTH-independent aetiologies
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• ACTH may not be fully suppressed in some
adrenal causes of Cushing’s; however, ACTH
>4pmol/L is suggestive of an ACTH-dependent
aetiology.
Serum ACTH
• The basal ACTH is, however, of very little value
in differentiating between pituitarydependent Cushing’s syndrome and ectopic
Cushing’s syndrome, as there is considerable
overlap between the two groups, although
patients with ectopic disease tend to have
higher ACTH levels
Serum Potassium
A rapidly spun potassium is a useful
discriminatory test, as hypokalaemia
<3.2mmol/L is found in almost 100% of
patients with ectopic secretion of ACTH
but in <10% of patients with pituitarydependent disease.
HDDST
• The high-dose dexamethasone suppression test is
performed in an identical way to the low-dose test
but with 2mg doses of dexamethasone
• In Cushing’s disease, the cortisol falls by >50% of the
basal value.
• In ectopic disease, there is no suppression.
• However, approximately 10% of cases of ectopic
disease, particularly those due to carcinoid tumours,
show >50% suppression, and 10% of patients with
Cushing’s disease do not suppress.
CRH Test
• The administration of 100 micrograms of CRH IV
leads to an exaggerated rise in cortisol (14–20%) and
ACTH (35–50%) in 95% of patients with pituitarydependent Cushing’s syndrome.
• No response in ectopic ACTH disease
• There are occasional reports of patients with ectopic
disease who show a similar response.
IPSS
• Bilateral simultaneous inferior petrosal sinus
sampling with measurement of ACTH centrally and in
the periphery in the basal state and following
stimulation with IV CRH allows differentiation
between pituitary-dependent and ectopic disease.
• A central to peripheral ratio of >2 prior to CRH is very
suggestive of pituitary-dependent disease, and >3
following CRH gives a diagnostic accuracy
approaching 90–95% for pituitary-dependent
disease.
Pituitary Imaging
• MRI (gadolinium enhanced) localizes
corticotroph adenomas in up to 80% of cases.
• 10% of the normal population harbour
microadenomas and, therefore, the
biochemical investigation of these patients is
essential, as a patient with an ectopic source
to Cushing’s syndrome may have a pituitary
‘incidentaloma’.
Treatment
• Cushing’s Disease: Transphenoidal resection of
pituitary adenoma
• Adrenal neoplasms: resection
• Ectopic ACTH: resection if possible
• Bilateral adrenal hyperplasia: may need
adrenalectomies (lifelong glucocorticoid and
mineralcorticoid replacement)
‘Medical’ Adrenalectomy
Medications that inhibit steroidogenesis
• Ketoconazole (600 to 1200 mg/day)
• Metyrapone (exacerbates female virilization, 23 g/day)
• Mitotane(2-3 G/day)- slow onset
• Aminoglutethimide (1g/day)
• Ocreotide can work in 1/3 of patients.
Major side affect is adrenal insufficiency,
therefore start at lowest dose and titrate
Follow up and Monitoring
• Successful treatment for Cushing’s disease
leads to a cortisol that is undetectable
(<50nmol/L) following surgery.
• An undetectable post-operative cortisol leads
to a significantly higher chance of long-term
cure compared to the patients who have postoperative cortisol between 50–300nmol/L.
• The aim of follow-up is to detect recurrent
Cushing’s.
Follow up and Monitoring
• After successful surgery, the adrenals are suppressed.
• Patients need to have regular assessment of cortisol
production off glucocorticoid replacement.
• When cortisol is detectable following surgery,
recurrent disease must be excluded (low-dose
dexamethasone suppression).
• If recurrence is excluded, adequacy of ACTH reserve
should be assessed with ITT after patient is weaned off
glucocorticoids.
Follow up and Monitoring
• Adequacy of glucorticoid replacement is
assessed by
- Clinical examination and lying/standing
BP monitoring
- Hydrocortisone day curve
- 24 hour urine cortisol
Prognosis
• Benign adrenal adenoma- 95% 5 year survival,
90% 10 year
• Cushing’s disease (pituitary adenoma) same
survival, but 10-20% transphenoidal resection
failure rate over 10 years.
• Ectopic ACTH survival depends on malignancy
• Unknown cause of elevated ACTH- 65% 5 year
survival, 55% 10 year survival
• Adrenal carcinoma- median survival 7 months