Cushing ’s syndrome (1)

Cushing ’s syndrome
Anwar Ali Jammah
PGY4

Hypothalmus-Pituitary-Adrenal
Axis

ACTH (+) (-) Cortisol
CRH
(+)
(-)

Clinical findings I
• Central obesity with insulin resistance, & Weight gain.
• Diabetes mellitus or Impaired glucose tolerance and their
sequelae of atherosclerosis and cardiovascular disease.
• Dyslipidemia
• Osteoporosis
• Nephrolithiasis
• Neuropsychiatric problems
• Polycystic ovary syndrome is common in women with the
Cushing syndrome.
– Pt. with PCOD should be tested to exclude
endogenous hypercortisolism
Kaltsas Clin Endocrinol 2000

• Hypertension
• Coetaneous wasting
• Cervical (dorsal) fat pad fat pads.
• Facial rounding with plethora
• Supra-clavicular fullness
• Proximal myopathy
• Striae
• Thin skin
Clinical findings II

+ Likelihood ratio’s
– Ecchymoses 10 - 11.3
– Osteopenia or fracture 8 - 13.8
– Weakness, prox muscles 8 - 12.6
– Hypertension 4.35 – 5.29
– Edema 2.82 – 3.88
– Striae (purple; > 1 cm) 2.72 – 2.91
– Plethora 2.51 – 3.03
– Hirsutism 2.21 – 2.90
– Gen. Obesity/weight ↑ 1.75 - 3.10
– Headache 1.27 - 1.57
L. Nieman, Handbook of Diagnostic Endocrinol

Cushing’s Syndrome Causes
• ACTH-dependent (bilateral adrenal hyperplasia)
– Pituitary ACTH-dependent Cushing’s syndrome
(Cushing’s disease)
– Ectopic ACTH syndrome
– Ectopic CRH syndrome
• ACTH-independent
– Adrenal Adenoma or Carcinoma
– Adrenal hyperplasia (Micro- and macro-)
– Glucocorticoids administration

Causes of Cushing's syndrome
• The most common cause of hypercortisolism is
ingestion of prescribed medication, usually for
Non-Endocrine disease.
– Oral
– Injected
– Topical (intra-articular, epidural, nasal, & dermal)
– Inhaled glucocorticoids
Cizza J Clin Endocrinol Metab. 1996
Raff H. The Endocrinologist. 1998

Frequency of causes of Cushing's
syndrome
• Diagnosis Percent of patients
• ACTH-dependent Cushing's syndrome
– Cushing's disease 68%
– Ectopic ACTH syndrome 12%
– Ectopic CRH syndrome <<1%
• ACTH-independent Cushing's syndrome
– Adrenal adenoma 10%
– Adrenal carcinoma 8%
– Micronodular hyperplasia 1%
– Macronodular hyperplasia <<1%
• Pseudo-Cushing's syndrome
– Major depressive disorder 1%
– Alcoholism <<1%
630 patients Vanderbilt University Medical Center

200
400
600
800
1000
1200
1400
1600
1800
-15 0 15 30 45 60 90 120
CD
[n=101]
ECTOPIC
[n=14]
Serum
cortisol
(nmol/l)
Time (min)
(Newell-Price, Morris et al., 2002)

Sederberg-OlsenJ Clin Endocrinol Metab 1973.

ACTH (-)
CRH
(+)
Exogenous
Hydrocortisone
(-) Cortisol
Iatrogenic
Cushing’s Syndrome
(-)

ACTH (+) (-) Cortisol
CRH
(+)ACTH-dependent
Cushing’s disease
Autonomous ACTH secreting tumour

ACTH (-) (+) Cortisol
CRH
(+)Adrenocortical tumour
Autonomous cortisol secreting tumour

ACTH (+)
(+) Cortisol
CRH
(+)Ectopic ACTH
syndrome
Ectopic ACTH secreting tumour

ACTH (+) (+) Cortisol
CRH (+)
Ectopic CRH
producing tumour
Ectopic CRH secreting
tumour

Diagnosis of Cushing syndrome
• Does the patient have Cushing's
syndrome?
• Determining if the Cushing's syndrome is
corticotropin (ACTH)-dependent or
(ACTH)-independent.
• Determining the source of the ACTH in
ACTH-dependent Cushing's syndrome.

Dennis A. Ann Intern
Med. 2003

Urinary free cortisol (UFC)
• Free cortisol may be detected by
– Structurally-based techniques (eg, high
performance liquid chromatography).
– Antibody-based techniques (immunoassays):
less specific since antibodies may cross-react
with other steroids.

• When several UFC collections are normal,
CS is unlikely.
• May use early morning UFC/creatinine
(nmol/l:mmol/l) ratio of greater than 50 is
suggestive of CS.
• Four-fold greater than the upper limit of
normal, is considered diagnostic test.

• Sensitivity of 94.4%, false negative 5.6%
and a false positive 3.3%
– 315 patients with Cushing's syndrome and 479 lean, obese, or
chronically ill patients who did not have Cushing's syndrome
Crapo L, Metabolism 1979
• Diagnostic sensitivity 100% and specificity
98%
– 48 patients with Cushing's syndrome, 95 obese, and 94 normal
subjects
Mengden Clin Invest 1992

• Sensitivity problem
• In patients with mild CS, UFC levels may be consistently normal, .
Trainer Lancet 2000
• 10% to 15% of patients with the Cushing syndrome, at least one of
four 24-hour determinations of urine free cortisol level are within the
normal range
Nieman Endocrine Soc; 1990
• Specificity problem
• Elevated UFC levels may also be found in:
– ETOH, Phenytoin, Phenobarbital, primidon
– Pregnant women
– 40-60% of depressed inpatients
– Patients with Polycystic Ovarian Syndrome (PCOS)
Carroll 1976, Cizza 1996, and Yanovski 1993

Salivary cortisol levels
• Many studies have demonstrated great
promise In the use of this test as a
screening test for CS
– More than 140 patients found an Increased
bedtime salivary cortisol levels yield both a
• Sensitivity of 93%
• Specificity of 100%
Papanicolaou J Clin Endocrinol Metab. 2002

Low-Dose Dexamethasone Suppression Test
• 1mg of dexamethasone at 2300 hours and
measurement of plasma cortisol at 0800 or 0900
hours the next morning.
– High diagnostic accuracy with a sensitivity of
98% using a post-dexamethasone serum
cortisol value of less than 50nmol/l (1.8µg/l)
• Consensus opinion in the United Kingdom: value
of less than 50nmol/l (1.8µg/l) effectively
Excludes the Cushing syndrome
Wood Ann Clin Biochem1997

• False positive results can occur because:
– Failure to take dexamethasone as prescribed.
– Accelerated hepatic metabolism
• Phenytoin, Carbamazepine, Barbiturates,
Aminoglutethimide or Rifampicin), and ETOH.
– Increased concentration of cortisol binding
globulin (CBG)
• Pregnancy or Estrogen treatment.

Dexamethasone-CRH Test
• Dexamethasone (0.5 mg Q 6 hours) is given X8, the first dose at
noon and the last dose at 6:00 a.m.
• Corticotropin-releasing hormone CRH (1µg/kg) is then administered
IV at 8:00 a.m., and plasma cortisol and ACTH levels are obtained
at 15-minute intervals for 1 hour.
• Cortisol level greater than 39 nmol/L (1.4 g/dL) measured 15
minutes after the administration of CRH correctly identifies patients
with the Cushing syndrome, and levels of 39 nmol/L or less (1.4
g/dL) are considered normal.
• ??Normal ACTH response.
– Patients with the Cushing syndrome usually have a peak ACTH
response exceeding 3.3 pmol/L (15 pg/mL) during the test.

• The dexamethasone-CRH test is usually
reserved for patients with equivocal results
on other diagnostic tests and a high index
of suspicion for the Cushing syndrome.

Measurement of ACTH
• IRMA (Immunoradiometric assay) is more
sensitive and specific assay than RIA
(radioimmunoassay) for ACTH.
• Some tumors secrete active Large ACTH
fragments not detected by IRMA; therefore RIA
is preferred for initial evaluation.
Wallach, 7th
edi, 2000

Measurement of ACTH
• A suppressed ACTH concentration <10pg/ml at
0900 hours, with concomitant increased cortisol
production indicates adrenal-dependent Cushing
syndrome (ACTH-Independent) caused by
classic negative feedback both at the
hypothalamus (to decrease CRH release) and at
the pituitary (to decrease ACTH release).
• Plasma ACTH levels greater than 4.4 pmol/L (20
pg/mL) imply an ACTH-dependent cause

• Values between 1.1 and 4.4 pmol/L (5 to
20 pg/mL) usually require a CRH
stimulation test.
– Patients with ACTH independent Cushing
syndrome usually have a subnormal peak
ACTH response to CRH stimulation (usually <
6.6 pmol/L [30 pg/mL]).

DIFFERENTIATION OF PITUITARY AND
ECTOPIC ACTH-DEPENDENT CUSHING
SYNDROME

1-Serum potassium
• Serum potassium is usually low in the ectopic ACTH
syndrome; therefore, this may be a discriminator.
– Hypokalemia has high sensitivity for the ectopic ACTH syndrome
(almost all), but up to 10% of patients with Cushing’s disease
exhibit hypokalemia
???
• Saturation of 11ß-hydroxysteroid dehydrogenase by
excessive cortisol, which under normal physiological
circumstances protects the mineralocorticoid receptor
from the effects of cortisol.
Endocrine Reviews 19 (5): 647-672 1998

2-Ectopic co-secretion
• In up to 70% of cases, occult ectopic tumors
may express and co-secrete one or more
additional peptides ie. calcitonin, somatostatin,
gastrin, pancreatic polypeptide, vasoactive
intestinal peptide, glucagon, hCG-ß, GHRH,
CRH, and carcinoembryonic antigen.
measurement of these specific peptides may
sometimes be useful
Endocrine Reviews 19 (5): 647-672 1998

3-High-Dose Dexamethasone Suppression Testing
• HDDST has a sensitivity of 81% and a specificity of 67%
– (112 patients & BIPSS as gold standard)
?? less accurate than the pretest likelihood of Cushing’s
disease (70%).
Findling et al, Endocrinol Metab Clin North Am. 1999 & 2001 , and Aron
DC, J Clin Endocrinol Metab. 1997.
• Some authors have suggested: the HDDST provides
little diagnostic advantage in the differential diagnosis of
ACTH-dependent CS in relation to other tests both in
adult and paediatric patients.
Dias Horm Res
2006

4-Other tests
CRH or Desmopressin Stimulation Test
• Pituitary adenomas, express the CRH receptor, ectopic
tumors are not pituitary cells and would not be expected
to respond to CRH.
– Some occult ectopic tumors express the CRH receptor and
do respond to CRH
Becker M Endocrinol Metab Clin North Am. 1994
– Desmopressin, the vasopressin V2 agonist has the same
effect.
• Neither (CRH & Desmopressin) test provides adequate
information to justify its use in the differential diagnosis
of ACTH-dependent Cushing syndrome.
Dennis A. Ann Intern Med. 2003

Bilateral simultaneous inferior petrosal sinus
sampling
Blood samples are
obtained from each
inferior petrosal sinus
and a peripheral vein in
the basal state and at 2
or 3, 5, and 10 minutes
after CRH (1 g/kg) is
administered
intravenously. Ratios of
right and left inferior
petrosal sinus to
peripheral ACTH are
then calculated at each
time point

Pituitary (Central) and Peripheral values C/P ACTH
ratio
• Cushing disease: ratio greater than 3.0 after the
administration of CRH with about 100% sensitivity and
specificity
• Ectopic ACTH: will have a ratio less than 2 before and
after CRH.
Polyzois, HORMONES 2006
• The rate of Localization has been reported to range
from 70% to 90%.
– Tumor localization by IPSS, in experienced hands, shown to
be ?more reliable than pituitary MRI.

• IPSS has been associated with co-morbid and
fatal complications, including:
– Deep venous thrombosis.
– Pulmonary emboli.
– Brain Stem vascular damage.
• In a series of more than 300 patients, IPSS was
associated with one episode of DVT
– The use of intravenous heparin during the procedure
to help prevent thrombosis is recommended.

RADIOLOGICAL DIAGNOSIS OF
CUSHING'S SYNDROME
• Imaging of the pituitary is essential.
• MRI of the pituitary with gadolinium exhibits a
sensitivity of 60-70% in identifying a
microadenoma and should be the imaging
modality of choice.
• 10% of the population may have co-incidental
tumors of the pituitary shown on MRI (Not
always indicative of significant pathology).

• A correlation between biochemical DX of CD
and a tumour on MRI, is about 75-98% Others
reports have demonstrated a correlation of only
of 52%.
– Therefore If pituitary microadenomas are not
visualized on MRI further studies, i.e. IPSS,
are necessary.
Polyzois, HORMONES
2006

• CT scan of the chest and mediastinum.
– When the investigations are indicative of Ectopic CS.
• CT of the abdomen.
– In order to exclude more rare causes of CS (e.g.pancreatic
islet cell tumours, intestinal carcinoids tumours, and
pheochromocytomas).
• imaging with 111In-DTPA-octreotide
– High suspicion for Ectopic CS and the conventional imaging
has failed to localize an ACTH secreting tumor.
– Can identify bronchial carcinoids of a size greater than 5mm
with a sensitivity of approximately 70%

• Adrenal CT
– If CS is due to an autonomously functioning adrenal
tumor, a unilateral mass, 2cm or larger in diameter, is
usually seen on adrenal and the remaining ipsilateral and
contra-lateral adrenal gland should be atrophic or of
normal size.
– CT scan of the adrenal glands in patients with ACTH-
dependent hypercortisolism reveals bilaterally
hyperplastic adrenal glands, with and without nodules.

SUMMARY I
• Repeated measurements of cortisol secretion
(urine free cortisol or late-night salivary cortisol
levels) over an extended period may be needed
to establish a diagnosis.
• The low-dose dexamethasone suppression test
(overnight 1-mg test) may be useful in some
patients.
• Finally, the dexamethasone-CRH test is a
reasonable approach in patients with equivocal
data.

SUMMARY II
• If CS diagnosed the next step is a plasma
ACTH measurements.
• Inferior petrosal sinus ACTH sampling with
CRH stimulation have provided the
diagnostic tools to establish the cause of
the Cushing syndrome.
• Radiological modality then chosen
according to clinical and biochemical
diagnosis

Cushing ’s syndrome (1)

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