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Cushing’s Syndrome

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

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  1. Cushing’s Syndrome Issues in diagnosis

  2. Overview of presentation • Introduction to CS • How is CS diagnosed? • What are the main problems surrounding diagnosis? • Psychological implications and patient perspective • Conclusion

  3. 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.)

  4. Classification of CS

  5. How is CS diagnosed?

  6. What are the main problems surrounding diagnosis of CS?

  7. 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.

  8. Atypical presentations • INTERMITTENT HYPERCORTISOLISM (or Cyclical Cushing’s): • Cortisol levels vary from few days to months. • Episodes of active hypercortisolism inbetween periods of normal pituitary-adrenal function. • PITUITARY INCIDENTALOMAS - 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. • ADRENAL INCIDENTALOMAS • 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.

  9. Pseudo-Cushing’s states • Pts without true CS may have symptoms and clinical features which suggest it. • Main conditions are OBESITY DEPRESSION ALCOHOL - Need to be ruled out by clinician in borderline cases.

  10. Pseudo-Cushing’s states cont…

  11. 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.

  12. Reliability of lab tests in diagnosis of CS SCREENING 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.

  13. 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.

  14. 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.

  15. Defining the aetiology • 1st step= ascertain whether ACTH dependent or independent. ACTH • 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. Disadvantages: • Fails to recognise some ectopic sources. • Results may be affected by quality of blood samples

  16. Defining the aetiology cont… • ACTH independent CS HIGH DOSE DEXAMETHASONE SUPPRESSION TEST (HDDST) • 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. ADRENAL IMAGING • 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.

  17. Defining the aetiology cont… ACTH DEPENDENT CS (1) CRH STIMULATION TEST • 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. (2) INFERIOR PETROSAL SINUS SAMPLING • 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. (3) PITUITARY IMAGING • 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.

  18. Psychological implications and patient perspective • CS can present with psychiatric features or the diagnosis itself can contribute to them. PSYCHIATRIC FEATURES ASSCOCIATED WITH CS • 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.

  19. 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?

  20. Conclusion • 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.

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