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Investigation of Cushing's Syndrome: Diagnosis and Testing, Study notes of Biochemistry

An in-depth investigation into cushing's syndrome, a condition characterized by the overproduction of cortisol by the adrenal gland. Indications for testing, first and second line screening tests, and the principles behind various diagnostic tests such as the overnight dexamethasone suppression test, low dose dexamethasone suppression test, and yanovski test. It also discusses the role of acth levels in diagnosis and references several studies for further reading.

Typology: Study notes

2021/2022

Uploaded on 09/27/2022

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BLOOD SCIENCES
DEPARTMENT OF CLINICAL BIOCHEMISTRY
Title of Document: Investigation of Cushing’s Syndrome
Q Pulse Reference No: BS/CB/DCB/EN/11 Version NO6
Authoriser: Paul Thomas
Page 1 of 3
INVESTIGATION OF CUSHING'S SYNDROME
Introduction
Cushing’s syndrome is a collective name for a number of endocrine conditions associated
with the overproduction of cortisol by the adrenal gland. Cortisol production is controlled by
the secretion of adrenocorticotrophic hormone (ACTH) from the pituitary and is under
negative feedback control from cortisol. Excess cortisol production can be secondary to an
ACTH secreting pituitary tumour (Cushing’s disease, 70% of cases), ectopic secretion of
ACTH (12% of cases) or an adrenal adenoma/carcinoma (18% of cases).
Indications
Testing for Cushing’s syndrome in adults, after excluding exogenous glucocorticoid use, is
recommended with:
Multiple and progressive features compatible with the syndrome, particularly those with a
high discriminatory value (e.g. facial plethora, easy bruising, striae, and proximal myopathy)
Unusual features for age (e.g. osteoporosis, hypertension, and type 2 diabetes);
Adrenal incidentaloma;
First line screening tests
Random cortisol is not an effective screening tool
Those that may be used are:
1. Overnight dexamethasone suppression test (see BS/CB/DCB/EN/10)
2. At least two 24 hour urinary free cortisol
3. At paired midnight and waking salivary cortisol
In general, these tests have equal accuracy in detecting Cushing’s syndrome but 24 hour urine
free cortisol can be increased by high fluid intake, stress and medications, whilst midnight
salivary cortisol may be affected in shift workers, depression and the critically unwell. There
are also difficulties with collecting saliva and 24 hour urine so the local policy is to
recommend an overnight dexamethasone suppression test which is more appropriate in
morbid obesity, depression, alcohol excess and diabetes.
There are some special circumstances that apply;
Pregnancy Advise 24 hour urinary cortisol
• Women on the combined contraceptive should ideally stop 6 weeks prior to dexamethasone
suppression test or use 24 hour urinary free cortisol.
Enzyme inducing medication, e.g. anticonvulsants, can increase dexamethasone clearance
therefore 24 hour urinary cortisol advised.
Chronic kidney disease- dexamethasone suppression test should be used rather than 24h
hour urinary cortisol.
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DEPARTMENT OF CLINICAL BIOCHEMISTRY

Title of Document: Investigation of Cushing’s Syndrome Q Pulse Reference No: BS/CB/DCB/EN/11 Version NO 6 Authoriser: Paul Thomas Page 1 of 3

INVESTIGATION OF CUSHING'S SYNDROME

Introduction

Cushing’s syndrome is a collective name for a number of endocrine conditions associated with the overproduction of cortisol by the adrenal gland. Cortisol production is controlled by the secretion of adrenocorticotrophic hormone (ACTH) from the pituitary and is under negative feedback control from cortisol. Excess cortisol production can be secondary to an ACTH secreting pituitary tumour (Cushing’s disease, 70% of cases), ectopic secretion of ACTH (12% of cases) or an adrenal adenoma/carcinoma (18% of cases).

Indications

Testing for Cushing’s syndrome in adults, after excluding exogenous glucocorticoid use, is recommended with:

  • Multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value (e.g. facial plethora, easy bruising, striae, and proximal myopathy)
  • Unusual features for age (e.g. osteoporosis, hypertension, and type 2 diabetes);
  • Adrenal incidentaloma;

First line screening tests

Random cortisol is not an effective screening tool Those that may be used are:

  1. Overnight dexamethasone suppression test (see BS/CB/DCB/EN/10)
  2. At least two 24 hour urinary free cortisol
  3. At paired midnight and waking salivary cortisol

In general, these tests have equal accuracy in detecting Cushing’s syndrome but 24 hour urine free cortisol can be increased by high fluid intake, stress and medications, whilst midnight salivary cortisol may be affected in shift workers, depression and the critically unwell. There are also difficulties with collecting saliva and 24 hour urine so the local policy is to recommend an overnight dexamethasone suppression test which is more appropriate in morbid obesity, depression, alcohol excess and diabetes.

There are some special circumstances that apply;

  • Pregnancy – Advise 24 hour urinary cortisol
  • Women on the combined contraceptive should ideally stop 6 weeks prior to dexamethasone suppression test or use 24 hour urinary free cortisol.
  • Enzyme inducing medication, e.g. anticonvulsants, can increase dexamethasone clearance therefore 24 hour urinary cortisol advised.
  • Chronic kidney disease- dexamethasone suppression test should be used rather than 24h hour urinary cortisol.

DEPARTMENT OF CLINICAL BIOCHEMISTRY

Title of Document: Investigation of Cushing’s Syndrome Q Pulse Reference No: BS/CB/DCB/EN/11 Version NO 6 Authoriser: Paul Thomas Page 1 of 3

  • Adrenal Incidentaloma – Either dexamethasone suppression test or salivary cortisol should be used.
  • Urine and salivary cortisol should be used in suspected cyclic Cushing’s syndrome

Second line investigation

The endocrinologist has to choose second-line tests:

  1. Either one or two of the above
  2. Low dose dexamethasone test (+/- CRH)
  3. High dose dexamethasone suppression test.
  4. ACTH (EDTA sample, to reach lab within 10 minutes and on ICE)

Principle of the tests

Low dose dexamethasone Suppression test (LDDST)

  1. 9 a.m cortisol (serum) and basal ACTH (EDTA) prior to the test on day 1.
  2. 0.5 mg dexamethasone 6 hourly for 48 hrs, (09.00, 15.00, 21.00, 03.00 both days)
  3. 9 a.m cortisol (serum) at the end of the test on day 3 (6 hrs after last Dexamethasone dosage)

Failure to suppress cortisol to <50nmol/L suggests the diagnosis of Cushing's Syndrome. False positives can still occur, however there are fewer false positives compared to the overnight dexamethasone suppression test.

Yanovski test, using ovine CRH

Similar to low dose dexamethasone test; it is used to try and differentiate pseudo-Cushing’s syndrome from true Cushing’s syndrome.

There is controversy regarding its specificity. Note that usually ovine CRH is used in the USA, and human CRH is used in Europe. The cut-off currently applied to the test derives from work carried out with ovine CRH and cannot be automatically superimposed for those employing human CRH. European Endocrine guidelines suggest that it is not as specific as LDDST but is included here as it is occasionally used.

  1. Start at 12:00hrs and take basal cortisol(serum) and ACTH (EDTA).
  2. Give 0.5mg dexamethasone at 12:00, 18:00, 24:00 and 06:00 hrs for both days.
  3. Cortisol at 08:00 on third day – 2 hours after last dose.
  4. IV 100mcg CRH at 08:00 then cortisol at 15, 30, 45 and 60 minutes afterwards.

Cushing’s syndrome is excluded by suppression of cortisol < 50nmol/l after the LDDST and cortisol < 38nmol/l 15 minutes after CRH