Cushing’s Syndrome

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.