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Cushing’s Syndrome. Issues in diagnosis. Overview of presentation. Introduction to CS How is CS diagnosed? What are the main problems surrounding diagnosis? Psychological implications and patient perspective Conclusion. What is Cushing’s syndrome?.

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cushing s syndrome

Cushing’s Syndrome

Issues in diagnosis

overview of presentation
Overview of presentation
  • Introduction to CS
  • How is CS diagnosed?
  • What are the main problems surrounding diagnosis?
  • Psychological implications and patient perspective
  • Conclusion
what is cushing s syndrome
What is Cushing’s syndrome?
  • Excessive, inappropriate, endogenous cortisol secretion.
  • Loss of normal circadian rhythm of cortisol and negative feedback of HPA axis.
  • ACTH independent and ACTH dependent causes ( Cushing’s Syndrome, Cushing’s Disease.)
1 clinical presentation symptoms
1) Clinical presentation- symptoms
  • Symptoms of CS highly variable & include:
  • Weight gain, lethargy, weakness, menstrual irregularities, loss of libido, acne, & skin striae.
  • Some pts present with only isolated symptoms; one feature alone not enough to make a diagnosis.
  • Presence of symptoms common to other diseases –
  • Allows room for misdiagnosis
  • Long anxious waiting times for patients
  • May be seen in non –endocrine clinics.
atypical presentations
Atypical presentations
  • Cortisol levels vary from few days to months.
  • Episodes of active hypercortisolism inbetween periods of normal pituitary-adrenal function.

- Pts with ectopic ACTH production may show biological characteristics similar to those with pituitary-dependent Cushing’s syndrome.

  • Incidental tumours discovered routinely in 10-20% of pts.
  • 1-8% of healthy subjects harbour non-functioning adrenal tumours.
  • Many pts with CS found to have an incidentaloma with no relevance to increase in cortisol.
pseudo cushing s states
Pseudo-Cushing’s states
  • Pts without true CS may have symptoms and clinical features which suggest it.
  • Main conditions are OBESITY



- Need to be ruled out by clinician in borderline cases.

laboratory tests and shortcomings
Laboratory tests and shortcomings
  • Adding to difficulty of diagnosis of CS is the efficacy of lab tests.
  • Normal protocol for investigation of CS

Screening - Standard overnight dexamethasone suppression test

24 urinary cortisol

Confirming - 48 hour dexamethasone suppression test

the diagnosis

Defining the - Basal ACTH,

Aetiology ACTH independent – HDDST/ Adrenal Imaging

ACTH dependent - CRH stimulation test/ Inferior

petrosal sinus sampling/ Pituitary imaging

  • At each point, inaccuracies can occur and factors increasing false- positives can play a role.
reliability of lab tests in diagnosis of cs
Reliability of lab tests in diagnosis of CS


24 hour urinary free cortisol

  • Involves collection of urine over 24 hrs to measure free urinary cortisol.
  • 3 measurements normally taken with creatinine
  • Been shown to have good sensitivity in cortisol overproduction

(Barrout et Al. ).

Disadvantages to test

  • Cumbersome and potentially unreliable ( collecting over 24 hrs )
  • Collecting for < 24 hrs more reliable?
  • Not always useful in pseudo-Cushing’s states.
  • Not necessarily useful in cyclical Cushing’s.
  • Variability of normal ranges between labs.
  • No validity in pts with RF and GFR < 30mL/min.
screening tests cont
Screening tests cont…

Overnight dexamethasone suppression test

  • Excludes CS if morning plasma cortisol levels < 50nmol/L (probably….)
  • 1mg dexamethasone given orally @ 10pm & blood taken at 8am the following day.
  • Factors increasing risk of false positives:
  • Type of assay undertaken e.g fluorometric assay (no longer a significant problem).
  • Many drugs (eg Anticonvulsants) accelerate catabolism of cortisol by inducing liver enzyme activities)
  • Oestrogen – increases corticosteroid-binding globulin, and total plasma cortisol levels. UFC will exclude hypercortisolism in these pts.
  • Stress – increases steroid requirements for suppressibility.
confirming the diagnosis
Confirming the diagnosis
  • Most difficult part of diagnosis?
  • Requires admission, pt should be used to hospital environment and not feel stressed.
  • Clinician must be aware of factors increasing false-positives at this stage.
  • The 48 hour dexamethasone suppression test
  • Administration of 0.5mg dexamethasone at intervals of 6 hrs from 9am on 1st day for eight doses
  • AM plasma cortisol level of <50nmol/L indicates a normal response.
  • This test has higher specificity and sensitivity than 1mg test ( only 2% chance of false-positives) ( Meier et Al.)
  • Same factors play a role as in 1mg suppression test.
defining the aetiology
Defining the aetiology
  • 1st step= ascertain whether ACTH dependent or independent.


  • If ACTH undetectable by assay on two 0900 samples- likely diagnosis = adrenal tumour. If detectable, likely to be a pituitary cause or ectopic production.
  • Accuracy of test improved if the 2 site immunoradiometric assay is used.


  • Fails to recognise some ectopic sources.
  • Results may be affected by quality of blood samples
defining the aetiology cont
Defining the aetiology cont…
  • ACTH independent CS


  • As 48 hr low dose test, 2mg instead of 0.5mg.
  • If Cushing’s Disease – 80-90% suppress cortisol to < 50% of baseline plasma conc.
  • A useful test to demonstrate functional autonomy- independent secretion of cortisol of adrenal adenoma or carcinoma.


  • Tumours seen as > 6cm in diameter on scanning- considered malignant.
  • MRI as sensitive as CT and neither has advantage.
  • Bilateral hyperplasia suggests ACTH effect secondary to Cushing’s Disease or ectopic ACTH production.
defining the aetiology cont1
Defining the aetiology cont…



  • Pituitary tumours show large ACTH responses to CRH administration unlike ectopic tumours.
  • Considered a good test when combined with HDDST to differentiate pituitary from ectopic ACTH sources.
  • Disadvantage – CRH deteriorates easily if not handled correctly.


  • May help to determine site of an ACTH secreting lesion. ( i.e pituitary or ectopic source)
  • Can get misleading results due to anatomical variations e.g between inferior petrosal sinuses and vertebral, basilar and epidural venous plexuses.
  • Expensive procedure and requires great skill.


  • MRI picks up pituitary tumours in 53-75% and CT in 48% ( Buchfelder et Al.)
  • If ectopic ACTH suggested, MRI AND CT of chest, mediastinum and abdomen should also be carried out.
psychological implications and patient perspective
Psychological implications and patient perspective
  • CS can present with psychiatric features or the diagnosis itself can contribute to them.


  • Major depression = most common co-morbid disorder.
  • Also, mania, anxiety disorders and cognitive dysfunction
  • Presence of depression = severe clinical presentation
  • Appears to be associated with older age, female sex, higher pretreatment urinary cortisol levels.
  • Studies have shown that when CS is biochemically cured, depression decreases.
cs from a patient s perspective
CS from a patient’s perspective.
  • Quality of life of people with CS is severely compromised.
  • Much anxiety experienced while waiting for diagnosis.
  • Patient will have undergone physical change which has psychological implications.
  • Presenting patients may be labelled as suffering from psychological rather than physical illness which is frustrating and can cause depression and anxiety in its own right.
  • Therefore- issue of depression- is it reactive? Or part of the disease process?
  • No single lab test is perfect, combinations used to build up an overall picture.
  • The 48hr 2mg/day dexamethasone test is considered to be the most accurate.
  • Many factors play a role in generating false positive results- variations in presentation, pseudo-Cushing’s states and influence of other hormones ( oestrogen) and drugs ( anticonvulsants)
  • Delay in diagnosis impacts on mental state of the patient who may already be depressed as part of the disease process.