2. Cushing ’s syndrome Anwar Ali Jammah PGY4

5. Hypothalmus-Pituitary-Adrenal Axis

6. ACTH ( +) ( -) Cortisol CRH ( +) ( -)

7. Cortisol Circadian Rhythm

8. Clinical findings I Central obesity with insulin resistance, & Weight gain. Diabetes mellitus or Impaired glucose tolerance and their sequelae of atherosclerosis and cardiovascular disease. Dyslipidemia Osteoporosis Nephrolithiasis Neuropsychiatric problems Polycystic ovary syndrome is common in women with the Cushing syndrome. –Pt. with PCOD should be tested to exclude endogenous hypercortisolism Kaltsas Clin Endocrinol 2000

9. Hypertension Coetaneous wasting Cervical (dorsal) fat pad fat pads. Facial rounding with plethora Supra-clavicular fullness Proximal myopathy Striae Thin skin Clinical findings II

11. + Likelihood ratio’s –Ecchymoses 10 - 11.3 –Osteopenia or fracture 8 - 13.8 –Weakness, prox muscles 8 - 12.6 –Hypertension 4.35 – 5.29 –Edema 2.82 – 3.88 –Striae (purple; > 1 cm)2.72 – 2.91 –Plethora2.51 – 3.03 –Hirsutism2.21 – 2.90 –Gen. Obesity/weight  1.75 - 3.10 –Headache1.27 - 1.57 L. Nieman, Handbook of Diagnostic Endocrinol

12. Cushing’s Syndrome Causes ACTH-dependent (bilateral adrenal hyperplasia) –Pituitary ACTH-dependent Cushing’s syndrome (Cushing’s disease) –Ectopic ACTH syndrome –Ectopic CRH syndrome ACTH-independent –Adrenal Adenoma or Carcinoma –Adrenal hyperplasia (Micro- and macro-) –Glucocorticoids administration

13. Causes of Cushing's syndrome The most common cause of hypercortisolism is ingestion of prescribed medication, usually for Non-Endocrine disease. –Oral –Injected –Topical (intra-articular, epidural, nasal, & dermal) –Inhaled glucocorticoids Cizza J Clin Endocrinol Metab. 1996 Raff H. The Endocrinologist. 1998

14. Frequency of causes of Cushing's syndrome Diagnosis Percent of patients ACTH-dependent Cushing's syndrome –Cushing's disease 68% –Ectopic ACTH syndrome 12% –Ectopic CRH syndrome <<1% ACTH-independent Cushing's syndrome –Adrenal adenoma 10% –Adrenal carcinoma 8% –Micronodular hyperplasia 1% –Macronodular hyperplasia <<1% Pseudo-Cushing's syndrome –Major depressive disorder 1% –Alcoholism <<1% 630 patients Vanderbilt University Medical Center

16. 200 400 600 800 1000 1200 1400 1600 1800 -1501530456090120 CD [n=101] ECTOPIC [n=14] Serum cortisol (nmol/l) Time (min) (Newell-Price, Morris et al., 2002)

17. Sederberg-OlsenJ Clin Endocrinol Metab 1973.

18. ACTH ( - ) CRH ( +) Exogenous Hydrocortisone (-) Cortisol Iatrogenic Cushing’s Syndrome (-)

19. ACTH ( +) ( -) Cortisol CRH ( +) ACTH-dependent Cushing’s disease Autonomous ACTH secreting tumour

20. ACTH (-) (+) Cortisol CRH ( +) Adrenocortical tumour Autonomous cortisol secreting tumour

21. ACTH (+) (+) Cortisol CRH ( +) Ectopic ACTH syndrome Ectopic ACTH secreting tumour

22. ACTH (+) (+) Cortisol CRH (+) Ectopic CRH producing tumour Ectopic CRH secreting tumour

24. Diagnosis of Cushing syndrome Does the patient have Cushing's syndrome? Determining if the Cushing's syndrome is corticotropin (ACTH)-dependent or (ACTH)-independent. Determining the source of the ACTH in ACTH-dependent Cushing's syndrome.

25. Dennis A. Ann Intern Med. 2003

27. Urinary free cortisol (UFC) Free cortisol may be detected by –Structurally-based techniques (eg, high performance liquid chromatography). –Antibody-based techniques (immunoassays): less specific since antibodies may cross-react with other steroids.

28. When several UFC collections are normal, CS is unlikely. May use early morning UFC/creatinine (nmol/l:mmol/l) ratio of greater than 50 is suggestive of CS. Four-fold greater than the upper limit of normal, is considered diagnostic test.

29. Sensitivity of 94.4%, false negative 5.6% and a false positive 3.3% –315 patients with Cushing's syndrome and 479 lean, obese, or chronically ill patients who did not have Cushing's syndrome Crapo L, Metabolism 1979 Diagnostic sensitivity 100% and specificity 98% –48 patients with Cushing's syndrome, 95 obese, and 94 normal subjects Mengden Clin Invest 1992

30. Sensitivity problem In patients with mild CS, UFC levels may be consistently normal,. Trainer Lancet 2000 10% to 15% of patients with the Cushing syndrome, at least one of four 24-hour determinations of urine free cortisol level are within the normal range Nieman Endocrine Soc; 1990 Specificity problem Elevated UFC levels may also be found in: –ETOH, Phenytoin, Phenobarbital, primidon –Pregnant women –40-60% of depressed inpatients –Patients with Polycystic Ovarian Syndrome (PCOS) Carroll 1976, Cizza 1996, and Yanovski 1993

31. Salivary cortisol levels Many studies have demonstrated great promise In the use of this test as a screening test for CS –More than 140 patients found an Increased bedtime salivary cortisol levels yield both a Sensitivity of 93% Specificity of 100% Papanicolaou J Clin Endocrinol Metab. 2002

32. Low-Dose Dexamethasone Suppression Test 1mg of dexamethasone at 2300 hours and measurement of plasma cortisol at 0800 or 0900 hours the next morning. –High diagnostic accuracy with a sensitivity of 98% using a post-dexamethasone serum cortisol value of less than 50nmol/l (1.8µg/l) Consensus opinion in the United Kingdom: value of less than 50nmol/l (1.8µg/l) effectively Excludes the Cushing syndrome Wood Ann Clin Biochem1997

33. False positive results can occur because: –Failure to take dexamethasone as prescribed. –Accelerated hepatic metabolism Phenytoin, Carbamazepine, Barbiturates, Aminoglutethimide or Rifampicin), and ETOH. –Increased concentration of cortisol binding globulin (CBG) Pregnancy or Estrogen treatment.

34. Dexamethasone-CRH Test Dexamethasone (0.5 mg Q 6 hours) is given X8, the first dose at noon and the last dose at 6:00 a.m. Corticotropin-releasing hormone CRH (1µg/kg) is then administered IV at 8:00 a.m., and plasma cortisol and ACTH levels are obtained at 15-minute intervals for 1 hour. Cortisol level greater than 39 nmol/L (1.4 g/dL) measured 15 minutes after the administration of CRH correctly identifies patients with the Cushing syndrome, and levels of 39 nmol/L or less (1.4 g/dL) are considered normal. ??Normal ACTH response. –Patients with the Cushing syndrome usually have a peak ACTH response exceeding 3.3 pmol/L (15 pg/mL) during the test.

35. The dexamethasone-CRH test is usually reserved for patients with equivocal results on other diagnostic tests and a high index of suspicion for the Cushing syndrome.

37. Measurement of ACTH IRMA (Immunoradiometric assay) is more sensitive and specific assay than RIA (radioimmunoassay) for ACTH. Some tumors secrete active Large ACTH fragments not detected by IRMA; therefore RIA is preferred for initial evaluation. Wallach, 7 th edi, 2000

38. Measurement of ACTH A suppressed ACTH concentration <10pg/ml at 0900 hours, with concomitant increased cortisol production indicates adrenal-dependent Cushing syndrome (ACTH-Independent) caused by classic negative feedback both at the hypothalamus (to decrease CRH release) and at the pituitary (to decrease ACTH release). Plasma ACTH levels greater than 4.4 pmol/L (20 pg/mL) imply an ACTH-dependent cause

40. Values between 1.1 and 4.4 pmol/L (5 to 20 pg/mL) usually require a CRH stimulation test. –Patients with ACTH independent Cushing syndrome usually have a subnormal peak ACTH response to CRH stimulation (usually < 6.6 pmol/L [30 pg/mL]).

42. DIFFERENTIATION OF PITUITARY AND ECTOPIC ACTH-DEPENDENT CUSHING SYNDROME

43. 1-Serum potassium Serum potassium is usually low in the ectopic ACTH syndrome; therefore, this may be a discriminator. –Hypokalemia has high sensitivity for the ectopic ACTH syndrome (almost all), but up to 10% of patients with Cushing’s disease exhibit hypokalemia ??? Saturation of 11ß-hydroxysteroid dehydrogenase by excessive cortisol, which under normal physiological circumstances protects the mineralocorticoid receptor from the effects of cortisol. Endocrine Reviews 19 (5): 647-672 1998

44. 2-Ectopic co-secretion In up to 70% of cases, occult ectopic tumors may express and co-secrete one or more additional peptides ie. calcitonin, somatostatin, gastrin, pancreatic polypeptide, vasoactive intestinal peptide, glucagon, hCG-ß, GHRH, CRH, and carcinoembryonic antigen. measurement of these specific peptides may sometimes be useful Endocrine Reviews 19 (5): 647-672 1998

45. 3-High-Dose Dexamethasone Suppression Testing HDDST has a sensitivity of 81% and a specificity of 67% –(112 patients & BIPSS as gold standard) ?? less accurate than the pretest likelihood of Cushing’s disease (70%). Findling et al, Endocrinol Metab Clin North Am. 1999 & 2001, and Aron DC, J Clin Endocrinol Metab. 1997. Some authors have suggested: the HDDST provides little diagnostic advantage in the differential diagnosis of ACTH-dependent CS in relation to other tests both in adult and paediatric patients. Dias Horm Res 2006

46. 4-Other tests CRH or Desmopressin Stimulation Test Pituitary adenomas, express the CRH receptor, ectopic tumors are not pituitary cells and would not be expected to respond to CRH. –Some occult ectopic tumors express the CRH receptor and do respond to CRH Becker M Endocrinol Metab Clin North Am. 1994 –Desmopressin, the vasopressin V2 agonist has the same effect. Neither (CRH & Desmopressin) test provides adequate information to justify its use in the differential diagnosis of ACTH-dependent Cushing syndrome. Dennis A. Ann Intern Med. 2003

47. Bilateral simultaneous inferior petrosal sinus sampling Blood samples are obtained from each inferior petrosal sinus and a peripheral vein in the basal state and at 2 or 3, 5, and 10 minutes after CRH (1 g/kg) is administered intravenously. Ratios of right and left inferior petrosal sinus to peripheral ACTH are then calculated at each time point

48. Pituitary (Central) and Peripheral values C/P ACTH ratio Cushing disease: ratio greater than 3.0 after the administration of CRH with about 100% sensitivity and specificity Ectopic ACTH: will have a ratio less than 2 before and after CRH. Polyzois, HORMONES 2006 The rate of Localization has been reported to range from 70% to 90%. –Tumor localization by IPSS, in experienced hands, shown to be ?more reliable than pituitary MRI. Dennis A. Ann Intern Med. 2003

49. (Kaltsas et al, 1999)

50. IPSS has been associated with co-morbid and fatal complications, including: –Deep venous thrombosis. –Pulmonary emboli. –Brain Stem vascular damage. In a series of more than 300 patients, IPSS was associated with one episode of DVT –The use of intravenous heparin during the procedure to help prevent thrombosis is recommended. Dennis A. Ann Intern Med. 2003

51. RADIOLOGICAL DIAGNOSIS OF CUSHING'S SYNDROME Imaging of the pituitary is essential. MRI of the pituitary with gadolinium exhibits a sensitivity of 60-70% in identifying a microadenoma and should be the imaging modality of choice. 10% of the population may have co-incidental tumors of the pituitary shown on MRI (Not always indicative of significant pathology). Polyzois, HORMONES 2006

53. A correlation between biochemical DX of CD and a tumour on MRI, is about 75-98% Others reports have demonstrated a correlation of only of 52%. –Therefore If pituitary microadenomas are not visualized on MRI further studies, i.e. IPSS, are necessary. Polyzois, HORMONES 2006

54. CT scan of the chest and mediastinum. –When the investigations are indicative of Ectopic CS. CT of the abdomen. –In order to exclude more rare causes of CS (e.g.pancreatic islet cell tumours, intestinal carcinoids tumours, and pheochromocytomas). imaging with 111In-DTPA-octreotide –High suspicion for Ectopic CS and the conventional imaging has failed to localize an ACTH secreting tumor. –Can identify bronchial carcinoids of a size greater than 5mm with a sensitivity of approximately 70% Polyzois, HORMONES 2006

56. Adrenal CT –If CS is due to an autonomously functioning adrenal tumor, a unilateral mass, 2cm or larger in diameter, is usually seen on adrenal and the remaining ipsilateral and contra-lateral adrenal gland should be atrophic or of normal size. –CT scan of the adrenal glands in patients with ACTH- dependent hypercortisolism reveals bilaterally hyperplastic adrenal glands, with and without nodules. Polyzois, HORMONES 2006

57. SUMMARY I Repeated measurements of cortisol secretion (urine free cortisol or late-night salivary cortisol levels) over an extended period may be needed to establish a diagnosis. The low-dose dexamethasone suppression test (overnight 1-mg test) may be useful in some patients. Finally, the dexamethasone-CRH test is a reasonable approach in patients with equivocal data.

58. SUMMARY II If CS diagnosed the next step is a plasma ACTH measurements. Inferior petrosal sinus ACTH sampling with CRH stimulation have provided the diagnostic tools to establish the cause of the Cushing syndrome. Radiological modality then chosen according to clinical and biochemical diagnosis

59. THANKS