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Cushing’s Syndrome A Clinical Approach

Cushing’s Syndrome A Clinical Approach. Stavroula Christopoulos, MD, FRCPC. Cushing’s Syndrome Outline. Definitions Clinical features Differential diagnosis Diagnostic approach Treatment Applied knowledge: a case presentation. Cushing’s Syndrome.

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Cushing’s Syndrome A Clinical Approach

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  1. Cushing’s SyndromeA Clinical Approach Stavroula Christopoulos, MD, FRCPC

  2. Cushing’s SyndromeOutline • Definitions • Clinical features • Differential diagnosis • Diagnostic approach • Treatment • Applied knowledge: a case presentation

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

  4. Cushing’s SyndromeDefinitions • Cushing’s syndrome • Cushing’s disease • Pseudo-Cushing’s syndrome

  5. Cushing’s SyndromeClinical features

  6. Cushing’s SyndromeClinical features

  7. Cushing’s SyndromeClinical features

  8. Cushing’s SyndromeClinical features • 63y.o M admitted on 7W with L/E muscle weakness and a T6 sensory level • Diagnosis?

  9. General Central obesity Proximal muscle weakness HTN Headaches Dermatologic Wide purple striae Spontaneous ecchymoses Facial plethora Hyperpigmentation Acne, hirsutism Fungal skin infections Endocrine/Metabolic Hypokalemic alkalosis Hypokalemia Osteopenia Hypogonadism Glucose intolerance Hyperlipidemia Hyperhomocysteinemia Kidney stones Polyuria Hypercoagulability Neuropsychiatric Insomnia Depression, frank psychosis Impaired cognition and short-term memory Cushing’s SyndromeClinical features

  10. Reversibility of Anatomic, Neuropsychological, and Metabolic Brain Disturbances Following Treatment of Endogenous Cushing’s Syndrome: A 3-Year Prospective Study • 23 patients with endogenous CS Post-operative Eucortisolism Curative Surgery 36 months 6 months 12 months 24 months Baseline MRI MRI MRI MRI MRI Psych Psych Psych Psych 1H-MRS 1H-MRS 1H-MRS

  11. Results Pre-operative MRI MRI 36 mo post eucortisolism

  12. *p value versus preceding value <0.05 *p value versus controls <0.05 Results Anatomic Evaluation: Subjective Grading of Cerebral Atrophy * * Grade3 Grade2 Grade 1 Controls Baseline 24mo 36 mo 6 mo 12 mo

  13. Discussion Excess GC enter the brain and act on MR and GR Dendritic atrophy Cell membrane dysfunction Decreased cell excitability Pathophysiologic Mechanisms Neuronal cell death Brain volume loss on MRI Neuropsychological and Cognitive Dysfunction Neurometabolic Abnormalities on 1H MRS Measurable Clinical Parameters

  14. Cushing’s SyndromeClinical features • Most reliable differentiating signs from obesity are those of protein wasting: • Thin skin • Easy bruising • Proximal weakness

  15. Cushing’s SyndromeEtiology

  16. ACTH-independent (Factitious) Unilateral Adrenal adenoma (10%) Adrenal carcinoma (5%) Bilateral Macronodular Hyperplasia (AIMAH) (<2%) Primary pigmented Micronodular Adrenal disease (PPNAD) (<2%) McCune Albright Syndrome (<2%) ACTH-dependent (Pseudo-CS) Pituitary (CD) (70%) Microadenomas (95%) Macroadenomas (5%) Ectopic ACTH or CRH (10%) Small cell lung ca Carcinoids: lung, pancreas, thymus Cushing’s SyndromeEtiology

  17. Cushing’s SyndromeAIMAH • Adrenal cortisol hypersecretion with radiological evidence of massive adrenal macronodules • “ACTH-independent macronodular adrenal hyperplasia” • “Massive macronodular adrecortical disease” • “Autonomous macronodular adrenal hyperplasia” • “Macronodular adrenal hyperplasia”

  18. Cushing’s SyndromeAIMAH • Presents 5th-6th decade • Radiological features • Bilateral adrenal masses measuring up to 5 cm of soft tissue density • Pathological features • Combined adrenal weight >60 g200g • Cut section: nodules yellow (high lipid content) • Inter-nodular hyperplasia

  19. Cushing’s SyndromeAIMAH • Lacroix et al. NEJM 1992 • First description of a patient with post-prandial hypercortisolism • Cortisol levels were correlated post-prandially with GIP levels • The presence of ectopic GIP receptors on the adrenal gland was further supported by adrenal imaging following the injection of [123I] GIP • Shown to be ectopically expressed at the cell membrane in a non-mutated form • Transfection of bovine adrenal cells with the GIP receptor leads to hyperplastic adrenals and hypercortisolism

  20. Cushing’s SyndromeAIMAH • Lacroix et al. NEJM 1999 • Patient with AIMAH who had transient CS during pregnancy and persistent CS following menopause • Cortisol secretion was stimulated by the exogenous administration of GnRH, h CG, or LH. • Treated succesfully with GnRH agonist

  21. Cushing’s SyndromeAIMAH

  22. Cushing’s SyndromeAIMAH Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005

  23. Cushing’s SyndromeAIMAH Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005

  24. Cushing’s SyndromePPNAD • Adrenal CS caused by small nodules that may not be visualized on imaging • Adrenal glands contain multiple small cortical black pigmented micronodules (<4 mm) • Positive stain synaptophysin

  25. Cushing’s SyndromePPNAD • Sporadic or part of Carney’s complex: pigmented lentigines and blue nevi on the face, neck, trunk and multiple endocrine and non-endocrine tumors (atrial myxomas) • Second decade • PARADOXICAL increase of cortisol secretion during Liddle test (0.5mg q6 –2mg q6)– 100% increase in UFC at day 6 highly specific – study shown high expression of GR in PPNAD nodules

  26. Cushing’s SyndromePPNAD

  27. Cushing’s SyndromeDiagnostic approach 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

  28. Cushing’s SyndromeDiagnostic approach • Key physiological principles • Cortisol hypersecretion in most patients with CS is cyclical

  29. Cushing’s SyndromeDiagnostic approach • Key physiological principles • Loss of circadian rhythm in pts with CS

  30. Cushing’s SyndromeDiagnostic approach • Key physiological principles (cont.) • Pituitary tumors are partially autonomous—they retain feedback inhibition, but at a higher setpoint than the normal pituitary gland • Adrenal and ectopic tumors have autonomous hormone secretion and do NOT (usually) exhibit feedback inhibition

  31. Cushing’s SyndromeDiagnostic approach 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

  32. Cushing’s SyndromeDiagnostic approach • 1. Establishing the diagnosis of CS • 24-hour urinary free cortisol • Low-dose dexamethasone suppression tests • Midnight plasma cortisol or late-night salivary cortisol

  33. Cushing’s SyndromeEstablishing the dx • 24-hr urinary free cortisol • Direct assessment of circulating free (biologically active) cortisol • Up to 3 collections if high suspicion • UFC>4X normal -- diagnostic • FN rate <6% • Assess whether collection is complete with urinary volume and creatinine • If GFR<30cc/min, UFC may be falsely low • FP rate <4% • Recently shown with fluid intake >5L/day

  34. Cushing’s SyndromeEstablishing the dx • Low-dose DST (Overnight vs 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 dex absorption • Drugs accelerating dexa metabolism (eg: dilantin, tegretol, rifampin…) • Elevated CBG (pregnancy, OCP) • Assay error (interaction with reaction—atarax, librium…) • 3-8% of pts with CD will retain sensitivity to low-dose dex

  35. Cushing’s SyndromeEstablishing the dx • Midnight plasma cortisol • Most studies with inpatients, sleeping, and installed venous catheter—VERY impractical and expensive • Level <50nmol virtually R/O the dx • Level >207 nmol/L virtually rules in the dx • Late-night salivary free cortisol • Increasing interest in recent years • Pts collect saliva by chewing on cotton • However, a modified cortisol assay is required so not validated by all labs • Excellent sensitivity and specificity—but exact cutoffs not established

  36. Cushing’s SyndromeEstablishing the dx • Differentiating between pseudo-Cushing’s and CS • Very difficult with coexistant 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 • Recent literature not reproduced these results—midnight cortisol>256

  37. Cushing’s SyndromeEstablishing the dx Source: Newell-Price et al. Lancet 2006

  38. Cushing’s SyndromeDiagnostic approach 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

  39. Cushing’s SyndromeEstablishing the cause of CS • Clinical features may provide a clue • First step is to measure plasma ACTH to differentiate ACTH-dependent from ACTH-independent CS • If ACTH <1 pmol/L---adrenal CS • If ACTH >3.3 pmol/L—ACTH-dependent • If ACTH 1-3CRH stim

  40. Cushing’s SyndromeEstablishing the cause of CS • ACTH-dependent CS • Distinguishing between pituitary vs non-pituitary sources is a great challenge!! • Carcinoids can be clinically undistinguishable from CD and are difficult to identify by imaging • 40% of CD will have non-detectable AN on MRI • So, biochemical assessment rather than imaging used to differentiate between pituitary and non-pituitary causes

  41. Cushing’s SyndromeEstablishing the cause of CS • Two biochemical tests in ACTH-dependent CS • High dose DST • CRH stimulation test

  42. Cushing’s SyndromeEstablishing the cause of CS • High-dose DST • 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 • Two-day test (2mg q6hrs) with baseline and final cortisol value—suppression >50 % suggestive of CD

  43. Cushing’s SyndromeEstablishing the cause of CS • 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. • MC 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

  44. Cushing’s SyndromeDiagnostic approach 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

  45. Cushing’s SyndromeImaging • Adrenal CT • In cases of ACTH-independent CS • 8% of N have incidentalomas and 20% of CD have at least 1 nodule • CXR and CT chest • In cases suggesting ectopic source • If negative, CT abdo, +/-pelvic, +/-neck • SS receptor scintigraphy • Head MRI • In cases suggesting pituitary source • >40% of CD have normal MRI (ave size 5mm) • 3-27% have pituitary incidentalomas

  46. Cushing’s SyndromeImaging

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