Testing in Cushing’s Syndrome and pheochromocytoma

1. Tamara Spaic, R4 Testing in Cushing’s Syndrome and pheochromocytoma

2. Adrenal cortex and HPA axis • Testing in Cushing’s syndrome • Review of the Endocrine Society Clinical Practice Guidelines (JCEM, May 2008) • Assessment of adrenal medullary function and disorders • Which test is the best? Objectives

3. 4 g weight 2x5x1 cm Posteromedial surface of the kidney Retroperitoneal Adrenal Gland

4. Cross sectional anatomy

6. L adrenal metastasis Unenhanced CT PET scan

7. Figure 28.   Adrenal lymphoma in a 74-year-old woman with biopsy-proved non-Hodgkin lymphoma. Contrast-enhanced CT scan demonstrates bilateral adrenal masses (straight arrows). The patient also has a destructive lesion from the lymphoma in the right rib (curved arrow)

8. Bilateral adrenal hyperplasia

9. Nodular hyperplasia

10. Adrenal Cortex

12. Histology

13. zona glomerulosa lacks Only zona glomerulosa

14. Steroid synthesis

15. Trophic hormone of zonae fasciculata and reticularis • Major regulator of adrenal androgen and cortisol production • Regulated by CRH (whose action is also potentiated by AVP -arginine vasopressin, and β adrenergic catecholamines) • Rapid synthesis and secretion of steroids (hormone levels rise within minutes) ACTH

16. POMC (proopiomelanocortin) - precursor ACTH biosynthesis

17. ACTH circadian rhythm generated in suprachiasmatic nc (signals CRH release) Secreted with both circadian periodicity and ultradian pulsatility Periodic secretory bursts at frequency of ~ 40 pulses/day Entrained by visual cues, light –dark cycle Continuous CRH administration desensitizes the ACTH response Prolonged pulsatile CRH administration restores cortisol secretion Corticosteroids directly suppress basal or stimulated ACTH pulse amplitude ACTH secretion

18. Circadian rhythm

19. Episodic secretion and circadian rhythm of ACTH Stress responsivness of the HPA Feedback inhibition by cortisol of ACTH secretion Neuroendocrine Control

20. Physical stresses (major illness, surgery, trauma, starvation) • Psychological stress (anxiety, depression, manic-depressive psychosis) • CNS and pituitary d/s • Cushing’s syndrome • Liver d/s • CRF • Alcoholism Rhythm changes

21. ACTH and cortisol secreted within minutes (Sx, hypoglycemia) Abolish circadian periodicity (prolonged stress) Stress →↑CHR → ↑ACTH Stress response abolished by proior high dose glucocorticoids/Cushing’s syndrome Enhanced following adrenalectomy Stress responsivness

22. FAST feedback inhibition – depends on the rate of increase of GC (not the dose) Rapid (within minutes) and transient (up to 10 minutes) DELAYED feedback inhibition is both time and dose dependent Feedback Inhibition

23. Ideally nonstressed resting subject should have venous sample drawn 6-9 am Unstable on room temperature (must immediately go on ice, -20° C) Siliconized glass tube containing EDTARandom ACTH values do not on their own provide an accurate assessment of HPA function ACTH measurement

24. Under basal (non stressed) conditions 8-25 mg/day (22-69 μmol/day) Mean 9.2 mg/day (25 μmol/day) – less than thought before (?20 mg/day) Cortisol secretion

25. Circulate bound to plasma proteins (bound – biologically inactive • t½ (60-90 minutes) is determined extend of plasma binding and rate of metabolic inactivation • 10% - free • 75-90% - CBG (corticosteriod binding globulin) • 15% - albumin (dexamethasone -75%) Cortisol circulation

26. Produced by the liver Progesterone in late pregnancy Synthetic steroids – do not significantly bind (except prednisolone) CBG

27. High estrogen states (pregnancy, OCP) ↑T4 Diabetes Hematologic d/s Chronic active hepatitis ↑CBG

28. Familial CBG deficiency ↓ T4 Protein deficiency states (nephrotic syndrome, liver failure) ↓CBG

29. Metabolism – liver (conjugation) Excretion – kidney (<1% in urine unchanged – “free”) 11β-hydroxysteriod dehydrogenase (inhibited by IGF-1) Cortisol metabolism

30. ↓ clearance in starvation/anorexia nervosa and pregnancy (↑CBG) ↓ metabolism and excretion – hypoT4 ↑metabolism – OCP, liver disease Also drugs : dilantin, barbiturates, mitotane, rifampin Altered metabolism

31. ACTH Dependent ACTH Independent Pseudo-Cushing’s Syndrome Cushing’s Syndrome

32. Etiology Pseudo-Cushing’s Syndrome Etoh Obesity Depression

34. Sign/symptom Frequency (%) Truncal obesity 96 Facial fullness 82 Diabetes or glucose intolerance 80 Gonadal dysfunction 74 Hirsutism, acne 72 Hypertension 68 Muscle weakness 64 Skin atrophy and bruising 62 Mood disorders 58 Osteoporosis 38 Oedema 18 Polydipsia, polyuria 10 Fungal infections 6 The mean age of the 239 female and 63 male patients was 38·4 years (SD 13·5; range 8–75). Sign and symptoms

36. Answer 2 questions: • Does this patient have Cushing’s Syndrome? • Having confirmed Cushing’s syndrome clinically and biochemically – What is the cause? Investigations

37. Options for investigation • Diagnosis • UFC • Circadian Rhythm of plasma cortisol • Low dose dexamethasone • Salivary cortisol • Differential Diagnosis • Plasma ACTH • Plasma K, HCO3 • High dose dexamathasone suppression • Metyrapone test • CRH • IPSS • CT/MRI pituitary, adrenals • Scintigraphy

38. Obesity epidemics Aging population Suspicion - common Rare diagnosis (5-10 cases/million population/year) – Cushing’s disease – (70% of all cases) 0.5% of lung cancer patients have ectopic ACTH syndrome False positive tests Accuracy

39. 2-5% prevalence of unsuspected Cushing’s syndrome in pts with poorly controlled DM 0.5-1% in HTN 10.8% of pts with osteoporosis/vertebral # 3% in osteoporosis Overlap with PCOS (5.8%) 9% pts with incidental adreanal nodules (>2 cm) have evidence of hypercortisolism Suspicion

40. To reduce FP rate (high pretest probability) • Pts with unusual features for age (osteoporosis, HTN) • Pts with multiple and progressive features 9especially those predictive of Cushing’s • Children with decreasing height ‰ and increasing wt • Adrenal incidentaloma compatible with adenoma Who should be tested?

42. <1% of secreted cortisol unchanged in urine Cushing’s – CBG binding capacity exceeded, so plasma free cortisol ↑ - ↑UFC N range 50-250 nmol/24 h (80-120) Not affected by conditions and meds that alter CBG Use the upper limit of normal as cut-off point Should do 2 or 3 complete consecutive collections (with 24 hr Cr) Can not do in RF (falsely low) False + if fluid intake >5 L /day UFC

43. Am cortisol often not elevated in Cushing’s syndrome (late night usually increased) • Small increases in cortisol at circadian nadir may not be detected as ↑ UFC • Sn 45-71% (although most studies show excellent sn, sp is the problem) • Pseudo vs Cushing’s – ? Useful (also anxiety, starvation, AN) • To avoid overlap 4-fold increase • Levels elevated during stress Issues UFC

46. Abnormal circadian rhythm (absence of late night nadir) Same as in midnight serum cortisol (but impractical) Sn 100%, Sp 77% CBG absent in plasma (measures free, not dependent on CBG) Not affected on saliva amount or composition Stable on room temperature Can be sampled at home by the pt At least 2 measurements Late-night salivary cortisol

47. N(bedtime or 2300-2400) <4 nmol/L • Sn 92-100% • Sp 93-100% (highly accurate for differentiating from pseudocushing’s) • Circadian rhythm is blunted in depression, shift workers • May be absent in critically ill • Chewing tobacco or licorice may have falsely elevated result (inhibits which enzyme?) • ?Smokers • Different time zones Late- night salivary cortisol

48. 11 β hydroxysteriod dehydrogenase type 2 Cortisol → cortisone (inhibits) Answer

50. Assessing feedback inhibition of HPA axis Suppresses pituitary ACTH ↓plasma and urinary cortisol Cushing’s – fails to suppress Dexamethasone does not interfere with the measurment of cortisol Measure simultaneously daxamethasone level (to assess compliance, etc) 1-mg DST