1. INVESTIGATION OF GLUCOCORTICOID EXCESS Dr. Umar M.T

2. Outline  Introduction  Physiology of glucocorticoid  Causes of glucocorticoid excess  Brief clinical features  Investigations -Specific -Supportive  Conclusion

3. Introduction  Cushing’s syndrome (hypercortisolism) is a hormonal disorder caused by prolonged exposure high levels of steroid hormones called glucocorticoids.  Exogenous Cushing’s syndrome: caused by taking excessive amounts of steroids e.g. prednisone, dexamethasone  Endogenous Cushing’s syndrome: excess cortisol produced by the adrenal glands. This is far rarer, but if left undiagnosed & untreated it can result in a shorter lifespan.

4. Cushing’s Syndrome  1932: Harvey Cushing described a series of seven pts with basophilic adenomas of the pituitary --- CD

5. Physiology

6. Physiology cont’d

8. Terminologies  Cushing’s syndrome  Cushing’s disease  Pseudo-Cushing’s syndrome

9.  ACTH-independent  (Factitious)  Unilateral  Adrenal adenoma (10%)  Adrenal carcinoma (5%)  Bilateral  Macronodular Hyperplasia (<2%)  Micronodular (<2%)  McCune Albright Syndrome (<2%) Causes of glucocorticoid excess (Cushing’s syndrome)  ACTH-dependent  Pituitary (CD) (70%)  Microadenomas (95%)  Macroadenomas (5%)  Ectopic ACTH or CRH (10%)  Small cell lung ca  Carcinoids: lung, pancreas, thymus  (Pseudo-CS)

10. Clinical features

11. Investigations Aims  To confirm diagnosis  Rule out diff. diagnosis  Rule out complications  Facilitate appropriate treatment  Prognosis

12. Investigations cont’d  Specific  Supportive

13. Specific investigations 1. Establishing the diagnosis of CS 2. Establishing the cause of CS a. ACTH-dependent vs independent b. Identifying the source in ACTH-dependent 3. Imaging

14. Diagnostic algorithm

15. Specific investigations cont’d Establishing the diagnosis of CS 1. 24-hr urinary free cortisol 2. Late-night salivary free cortisol 3. Midnight plasma cortisol 4. Low-dose dexamethasone suppression tests

16. Specific investigations cont’d  24-hr urinary free cortisol  Direct assessment of circulating free (biologically active) cortisol  Up to 3 collections if high suspicion  UFC>4X normal -- diagnostic  False negative rate <6%  Assess whether collection is complete with urinary volume and creatinine  If GFR<30cc/min, UFC may be falsely low

17. Specific investigations cont’d  Late-night salivary free cortisol  Increasing interest in recent years  Pts collect saliva by chewing on cotton  Excellent sensitivity and specificity—but exact cutoffs not established  Midnight plasma cortisol  Most studies with inpatients, sleeping, and installed venous catheter—may be impractical and expensive  Level <50nmol virtually R/O the dx  Level >207 nmol/L virtually rules in the dx

18. Midnight plasma cortisol Papanicolaou et al. (JCEM, 1998, 83:1163-1167)

19. Specific investigations cont’d  Low-dose DST (Overnight & 48-hr DST)  Am cortisol <50nmol/L (traditionally <138nmol/L)  Excellent sensitivity but borderline specificity— false positives  Pseudo-Cushing’s  Pt’s error in taking medication  Decreased dexamethsone absorption  Drugs accelerating dexamethasone metabolism (eg: dilantin, tegretol, rifampin…)  Elevated CBG (pregnancy, OCP)

20. FALSE POSITIVES  Severe depression  Severe stress  Phenytoin/phenobarbital/rifampin (accelerated metabolism of dex)  Estrogen (pregnancy or OCP)  Morbid obesity

21. Differentiating between pseudo-Cushing’s and Cushing’s syndome  Very difficult with coexisting depression, alcoholism, obesity  Recently discovered and validated test at the NIH: Combined low dose DST-CRH test  Cortisol >38nmol/L had 100% sensitivity, specificity, and diagnostic accuracy

22. Establishing the cause of Cushing’s Syndrome  High dose DST  CRH stimulation test  Inferior Petrosal Sinus Sampling (IPPS)  Imaging

23. Establishing the cause of Cushing’s Syndrome cont’d High-dose DST  Two-day test (2mg q6hrs) with baseline and final cortisol value— suppression >50 % suggestive of CD  Principle that pituitary tumors are only partially autonomous, retaining feedback inhibition at a higher set point (80% of CD are suppressible)  In contrast, adrenal and ectopic tumors are usually autonomous, and cortisol production will normally not be suppressed by dexa

24. Establishing the cause of Cushing’s Syndrome cont’d CRH stimulation test  Principle that pituitary tumors are responsive to an exogenous dose of CRH whereas ectopic and adrenal tumors are not  Ovine CRH administered as an IV bolus and ACTH and cortisol drawn at baseline at 30, 60, 90, and 120 min.  Side effect facial flushing (20%)  CD: >50% rise in ACTH, >20% rise in cortisol---91% sensitivity and 95% specificity  In ectopic CS, levels are usually not altered. However, some reports of ACTH rise but not cortisol

25. Establishing the cause of Cushing’s Syndrome cont’d Inferior Petrosal Sinus Sampling (IPPS)  The most direct way of knowing if the pituitary is making excess ACTH  The inferior petrosal sinuses receive the drainage of the pituitary gland without admixture of blood from other sources  Each half of the pituitary drains in the ipsilateral petrosal sinus

27. IPPS  INTERPRETATION  Localization  If pituitary/periphery ratio >2 (>3 with CRH), the pt has CD  If pituitary/periphery ratio <1.5 (<2 with CRH), the pt has ectopic CS --- 94% sensitivity and specificity with CRH  Lateralization  If the higher side/lower side >1.4/1, the tumor is on the side with higher ACTH levels --- accuracy only 70%

28.  Complications  Very uncommon  Most common:  Hematoma at the groin  Transient ear pain  Several cases of DVT reported  Neurological complications and SAH reported but extremely rare

29. Imaging  CXR and CT chest  In cases suggesting ectopic source  If negative, CT abdo, +/-pelvic, +/-neck  Head MRI  In cases suggesting pituitary source  >40% of CD have normal MRI (have size 5mm)  3-27% have pituitary incidentalomas  Adrenal CT  In cases of ACTH-independent CS  20% of CD have at least 1 nodule

30. Cushing’s Syndrome Imaging

31. Supportive investigations  E/U/Cr  Blood sugar  FLP  FBC  ECG, ECHO

32. Conclusion  Diagnosis and management of CS remains a considerable challenge  Diagnostic algorithm (biochemical confirmation followed by localization) should be closely followed to avoid major pitfalls and misdiagnosis  Our understanding of the pathogenesis has evolved, but mainly with respect to the very rare causes of CS

33. THANKS NAGODE