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Diagnosing Cushing’s Syndrome: Not as Easy as it Seems Theodore C. Friedman, M.D., Ph.D. Professor of Medicine-Charles Drew University Professor of Medicine-UCLA.

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Presentation on theme: "Diagnosing Cushing’s Syndrome: Not as Easy as it Seems Theodore C. Friedman, M.D., Ph.D. Professor of Medicine-Charles Drew University Professor of Medicine-UCLA."— Presentation transcript:

1 Diagnosing Cushing’s Syndrome: Not as Easy as it Seems Theodore C. Friedman, M.D., Ph.D. Professor of Medicine-Charles Drew University Professor of Medicine-UCLA Magic Foundation Symposium on Cushing’s Syndrome February 22, 2009 Las Vegas, NV

2 States of Glucocorticoid Excess ACTH-dependent States a. Pituitary Adenoma (Cushing’s Disease) 90-95% b. Ectopic ACTH Syndrome ACTH-independent States a. Adrenal adenoma b. Adrenal carcinoma Exogenous Sources Glucocorticoid intake Psychiatric Conditions (Pseudo-Cushing Disorders) a. Depression b. Alcoholism Pregnancy

3 Pseudo-Cushing States High Cortisol Secretion Rate without Convincing Clinical Features of Cushing Syndrome

4 Eucortisolemic Cushing Syndrome Clinical Manifestations of Cushing Syndrome without evidence of increased cortisol levels Exogenous glucocorticoid administration Episodic (periodic) Cushing syndrome-common Recently cured Cushing syndrome

5 Need to Distinguish Early or Mild Cushing’s from Other Diseases Cushing’s is considered rare, but may not be that rare. It is vastly under diagnosed. Other diseases that have some symptoms/signs in common with Cushing’s (PCOS or Metabolic Syndrome) are more common, but present differently from Cushing’s. The treatment is different for these other diseases Thus, a strategy needs to be developed to diagnose Cushing’s syndrome.

6 Is Cushing’s Syndrome Rare Probably under-diagnosed Catargi et al. JCEM 2003, 88: consecutive overweight patients with type 2 diabetes, but no other stigmata of hypercortisolism. 4 (2%) patietns were found to have Cushing’s syndrome and another 7 are being evaluated. Kadioglu et al. Endo Society : P consecutive obese patients. Cushing’s syndrome was diagnosed in 11%. Nishikawa et al. Endo Society : P patients with hypertension. 11 had Cushing’s syndrome and 10 had subclinical Cushing’s syndrome (2%). These studies may have missed mild Cushing’s syndrome and may actually be low. Maybe Cushing’s syndrome is not so rare

7 Do all diseases progress from mild to severe? Rapid onset Delayed onset Linear

8 Should Cushing’s be Diagnosed Early? Cushing’s Patients are miserable. Effective treatment (surgery) exists Lack of medicine for it, less pharmaceutical funding. Most doctors are not familiar with Cushing’s syndrome and may only be familiar with severe cases.

9 How to Diagnose Cushing’s Syndrome Careful history and physical Change in weight and body habitus Look at old pictures Not all patients have all signs and symptoms, especially “early” and “periodic” patients. Most published data compared severe Cushing’s with normals. Important to diagnose early before devastating sequelae develop. Initial diagnosis most difficult aspect of Cushing’s syndrome. “Gestalt” with as much information as possible Periodic Cushing’s common, so one positive test may be worth more than 10 negative tests Make the diagnosis before proceeding to the differential diagnosis??

10 IMPORTANT SYMPTOMS Wired at night Trouble sleeping-trouble falling asleep or frequent awakenings Severe fatigue-new onset Abrupt weight gain-without other cause such as decreased activity or depression Decreased ability to exercise Menstrual abnormalities Cognitive changes- “brain fog” Decreased Libido Symptoms of adrenal insufficiency-joint pains, can’t get out of bed, nausea and vomiting Depression, anxiety, mood-swings

11 IMPORTANT SIGNS Central obesity Muscle atrophy Thin skin Buffalo hump Round, red face Bruising Extra hair growth Acne Loss of hair on head Stretch marks

12 Signs/Symptoms Most patients don’t have all these signs/symptoms Many doctors may have only seen 1 case of Cushing’s and textbooks may show only severe cases.

13 The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab. May 2008, 93(5):1526–1540 Lynnette K. Nieman Beverly M. K. Biller James W. Findling John Newell-Price Martin O. Savage Paul M. Stewart Victor M. Montori

14 The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab. May 2008, 93(5):1526–1540 1st line recommended tests –UFC –Low dose or overnight dexamethasone test –Night-time salivary cortisols Testing for Cushing’s syndrome in patients with multiple and progressive features compatible with the syndrome Patients with an abnormal result see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone-CRH test.

15 The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab. May 2008, 93(5):1526–1540 Patients with 2 or more normal results should not undergo further evaluation. Recommend additional testing in patients with discordant results, normal responses suspected of cyclic hypercortisolism, or initially normal responses who accumulate additional features over time.

16 The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab. May 2008, 93(5):1526–1540 We recommend against any further testing for Cushing's syndrome in individuals with concordantly negative results on two different tests (except in patients suspected of having the very rare case of cyclical disease) Rarely patients have been described with episodic secretion of cortisol excess in a cyclical pattern with peaks occurring at intervals of several days to many months. Because the DST results may be normal in patients who are cycling out of hypercortisolism, these tests are not recommended for patients suspected of having cyclic disease. Instead, measurement of UFC or salivary cortisol may best demonstrate cyclicity. In patients for whom clinical suspicion is high but initial tests are normal, follow-up is recommended with repeat testing, if possible to coincide with clinical symptoms.

17 FIG. 1. Algorithm for testing patients suspected of having Cushing's syndrome (CS)

18 Hypothesis Patients with full-blown Cushing’s syndrome started out with mild Cushing’s syndrome. –It would be advantageous to diagnose these patients when they have mild disease before they are affected by hypercortisolemia. There are many case reports of patients with periodic Cushing’s syndrome. Some of these patients have hypercortisolism at regular intervals as documented by symptoms and laboratory measurements. Many patients report “highs” and” lows”even if not regular. There has been no series examining the frequency of mild or periodic/episodic Cushing’s syndrome. Thus, we hypothesized that a high percentage of consecutive patients presenting with signs and symptoms of hypercortisolism have episodic and/or mild Cushing’s syndrome.

19 Episodic, Cyclical, Periodic Periodic and cyclical refer to changes in cortisol levels that occur on a regular predictable basis. Episodic refers to high cortisol levels that are random. Most of my patients are episodic.

20 WEB AGE MOST FOUND ME FROM THE INTERNET Cushing’s-help.com (I hosted several “chats” including Jan 2009) Most went to numerous other Endocrinologist, including Cushing’s specialists Told “Your arms aren’t thin enough for Cushing’s” or were dismissed with 1 normal test In most cases, patient suspected Cushing’s, in spite of doctor telling them its unlikely

21 Confirmed Cushing’s Patients –66 patients –61 females, 5 males –62 Caucasians, 2 Hispanic, 1 Black, 1 Pacific Islander –Median age 38.5 years –BMI was 35.9 ±8.5 kg/m 2 (mean ± SD) –Average weight gain was 67.7 ±40.2 pounds –Patients were considered for Cushing’s syndrome if they had a rapid, unexplained weight gain and associated symptoms of hypercortisolism including adult-onset hirsutism and acne, menstrual irregularities and proximal muscle weakness. –All subjects reported that their symptoms were more severe at certain times suggesting episodic hypercortisolism

22 Cushing’s excluded –54 subjects –52 females, two males –All Caucasians –Median age 36 years –BMI was 32.9 ±8.0 kg/m 2 –Average weight gain was 48.3 ±35 pounds –Cushing’s syndrome was excluded by lack of progression of symptoms and lack of biochemical evidence. –Many were diagnosed with other conditions, including growth hormone deficiency

23 Symptoms/ Signs

24 24-Hour Urinary Free Cortisol (UFC) Integration of plasma cortisol throughout the day “Good” assays (using HPLC or mass spectroscopy) have a normal range of  g, with higher levels for men. Normal range of many older assays is  g /day indicating some non-specificity or interference of the assay PseudoCushings patients may have normal values in newer assays, but elevated levels in older assays. Many Cushing’s patients have normal values in the new assay My data demonstrates that most Cushing’s patients are periodic, therefore patients need to collect multiple collections hopefully when they have high cortisol. May be normal if subject is high at night and low during the day.

25 UFC: Cushing's UFC> 34 micrograms/day=(50/66) UFC< 34 micrograms/day=(57/66) Cushing's Patients micrograms/day Women Men

26 UFC: non-Cushing's One UFC > 34 micrograms/day= (13/51) One UFC < 34 micrograms/day= (50/51) non-Cushing's Patients micrograms/day Women Men

27 10 hr urine Cortisol/Cr Corcuff, et al. Clinical Endocrinology 48:1998, Night-time (from 10 PM to 8 AM) UFC excretion (correct for g of creatinine) 16 nmol/umol was the cutoff Helpful in subjects with high night time cortisol excretion and low daytime cortisol excretion Correcting for US units 16 ug/g is a reasonable cut-off I need to tabulating our data, but this is a reasonable approach.

28 Urinary 17-OH Corticosteroids (17-OHS) One of the earliest tests Went out of favor about 10 years ago and has been (incorrectly) replaced by UFC. UFC is probably better for full-blown Cushing’s compared to obese and normal subjects. 17-OHS may be better for picking up mild cases. Can use the same collection for both, so its worthwhile to measure 17- OHS in addition to UFC. Can also express results per gram of creatinine to correct for obesity

29 17 OHS: Cushing's One 17 OHS > 6mg/day=(52/63) One 17 OHS < 6mg/day=(53/63) Cushing's Patients mg/day Women Men

30 17 OHS: non-Cushing's One 17 OHS > 6mg/day= (15/50) One 17 OHS < 6mg/day= (48/50) non-Cushing's Patients mg/day Women Men 16-32

31 17 OHS/g Cr: Cushing's One 17 OHS/g Cr > 3.6 micrograms/g=(45/61) One 17 OHS/g Cr < 3.6 micrograms/g=(45/61) Cushing's Patients micrograms/day Women Men

32 17 OHS/g Cr: non-Cushing's One 17 OHS/g Cr > 3.6 micrograms/g= (15/50) One 17 OHS/g Cr < 3.6 micrograms/g= (46/50) non-Cushing's Patients micrograms/day Women Men

33 Diurnal Plasma Cortisol Test Normal individuals and patients with pseudo-Cushing states have a pronounced diurnal rhythm of cortisol with the highest values in the morning and lower values at night. Patients with Cushing syndrome lack their diurnal variation of cortisol. Papanicolaou et al. (JCEM, 1998, 83: ) compared morning and nighttime plasma cortisol in 97 patients with proven Cushing syndrome and 31 patients with pseudo- Cushing states. A midnight plasma cortisol greater than 7.5  g/dL makes Cushing’s syndrome likely. Patients taking oral estrogens (or birth control pills) will have an increase in their CBG and a falsely high serum cortisol level. Pretty good test, but hard to arrange.

34 Midnight plasma cortisol Papanicolaou et al. (JCEM, 1998, 83: )

35 Night Cortisol: Cushing's Night cortisol > 7.5 micrograms/dL= (26/57) Night cortisol < 7.5 micrograms/dL= (31/57) Cushing's Patients micrograms/dL Women Men

36 Night Cortisol: non-Cushing's night cortisol > 7.5 micrograms/dL=(11/44) night cortisol < 7.5 micrograms/dL=(33/44) non-Cushing's Patients micrograms/dL Women Men

37 Diurnal Salivary Cortisol Test Salivary cortisol levels reflect plasma cortisol levels. Midnight plasma cortisol measurement requires blood- drawing and may be difficult to obtain in an outpatient setting. Measured by a company in Wisconsin called ACL. Also Esoterix Uses a "Salivette" in which the patient chews on a cotton tube for 2-3 minutes. The samples are stable for a week at room temperature and salivary cortisol is independent of the rate of saliva production.

38 Diurnal Salivary Cortisol Test (2) 36/39 patients with Cushing syndrome had a salivary cortisol > 3.6 nmol/L (0.13  g/dl). 38/39 normal volunteers had a value ≤ 3.6 nmol/l (mean 1.2 nmol/L) and 37/39 patients with rule/out Cushing syndrome had a value ≤ 3.6 nmol/l (mean 1.6 nmol/L).

39 Salivary Cortisols: Cushing's salivary cortisol > 4.3 nmol/L=(43/64) salivary cortisol < 4.3 nmol/L=(58/64 ) Cushing's Patients nmol/L Women Men

40 Salivary Cortisols: non-Cushing's One salivary cortisol> 4.3 nmol/L=(9/53) One salivary cortisol< 4.3 nmol/L=(53/53 ) non-Cushing's Patients nmol/L Women Men 16-22

41 Both UFC and Salivary Cortisol are unlikely to pick- up mild Cushing’s Serum cortisol less than 20  g/dl (lower in evening when CBG is lower) is mainly (but not exclusively) bound to CBG and therefore little free cortisol is present in the blood. This results in little increase in salivary cortisol or UFC. At serum cortisol concentrations exceeding this cut-off, then salivary cortisol and UFC will rise dramatically.

42 Salivary cortisol: Conclusions Convenient for periodic patients as the patient can collect many samples easily Try to have the patient collect when high symptoms, but I’m finding that multiple collections (up to 8) is probably the best approach No better or worse than UFC for picking up mild cases.

43 Overnight dexamethasone test Give 1 mg of dexamethasone at midnight- collect 8 am plasma cortisol Cushing’s patients resistant to glucocorticoid feedback. Old cut-off 5 mg/dL, new cut-off 1.8, 2 or 3 mg/dL. Value greater than that consistent with Cushing’s syndrome. Cortisol assay isn’t that good at low values May get falsely high values if on oral estrogens. Only half of classic Cushing’s patients have the genetic defects leading to resistance to dexamethasone-probably lower in mild/episodic patients (Bilodeau et al : Genes & Dev.) Friedman, T.C. (2006) An Update on the Overnight Dexamethasone Suppression Test for the Diagnosis of Cushing’s Syndrome: Limitations in Patients with Mild and/or Episodic Hypercortisolism. Experimental and Clinical Endocrinology and Diabetes 216:

44 Overnight dexamethasone test Patient # 0800 h cortisol (  g/dL)

45 Overnight dexamethasone test Conclusion: test useless for excluding Cushing’s syndrome. If someone has a high value after dexamethasone, may help with the diagnosis of Cushing’s syndrome, but those patients usually are severe and can be diagnosed anyway If patient suppresses to overnight dexamethasone, adrenal adenoma or ectopic is unlikely. I am now doing a prospective study using 0.25 mg of overnight dexamethasone, 1 mg of dexamethasone and the 2 mg/2 day dexamethasone test. All my patients suppress on the 2 mg/2 day test 0.25 mg may be helpful, but so far a lot of overlap between Cushing’s and Cushing’s excluded.

46 Dexamethasone-CRH test Patients with pseudo-Cushing’s states show a diminished response to exogenous CRH and a greater inhibition of cortisol production by glucocorticoids than patients with Cushing’s syndrome. Yanovski et al. (JAMA 1993, 269: ) studied 39 patients with surgery confirmed Cushing’s syndrome and 19 patients with pseudo-Cushing states. Both groups of patients had UFC between ug/day (nl ug/day). Dexamethasone (0.5 mg) is given every 6 hours for 8 doses, starting at noon. The last dose is given at 6 A.M, 2 hours before the CRH test. Ovine CRH (1 mg/kg) is then given at 8 A.M. Plasma samples were analyzed for cortisol and ACTH at 4 basal time points (-15, -10, -5 and 0) and at 5, 15, 30, 45 and 60 minutes after oCRH.

47 Dexamethasone-CRH test Using a cutoff of 1.4 mg/dL, a plasma cortisol drawn 15 minutes after oCRH administration (following dexamethasone suppression) was able to completely separate patients with pseudo-Cushing states from those with Cushing syndrome. This was much better than just performing a oCRH test or dexamethasone test alone. Subsequently, many articles have shown the test is not full-proof Timing is crucial. Has not been tested in mild or periodic patients. The dex-CRH test is expensive and time consuming. I found that most of my patients with mild Cushing’s syndrome had low cortisol values following the test.

48 Pituitary MRI In literature approximately 50% of patients with Cushing disease have a visible tumor on MRI (older, non-dynamic, lower power MRIs). 10% of normal volunteers have MRIs consistent with a pituitary adenoma (Hall et al. Ann. Intern. Med., 1994, 120: ). Now 3 Tesla doing dynamic MRIs can pick up small tumors are done. Patients without Cushing’s syndrome or with adrenal/ectopic Cushing’s can have a pituitary incidentaloma. Friedman, T.C., Zuckerbraun, E., Lee, M.L., Kabil, M.S., Shahinian, H.K. (2007) Dynamic Pituitary MRI Has High Sensitivity and Specificity for the Diagnosis of Mild Cushing’s Syndrome and Should be Part of the Initial Workup. Hormone and Metabolic Research 39:

49 Pituitary MRI 23 of 24 patients had had a MRI consistent with a pituitary lesion Pt # Tumor size (mm)

50 Pituitary MRI-Cushing’s Syndrome-excluded Tumor size (mm) Pt #

51 Pituitary MRI 23 of 24 patients had had a MRI consistent with a pituitary lesion (21 with a microadenoma, two with pituitary asymmetry). Only 3 of 20 patients (2 patient did not have MRIs) in the Cushing’s excluded group had a pituitary lesion on dynamic MRI. Dynamic pituitary MRI had the highest sensitivity and negative predictive value of any testing modalities and its specificity and positive predictive value were similar to that of other tests. A negative MRI goes a long way in excluding Cushing’s syndrome, except in the patient with adrenal or ectopic Cushing’s syndrome, who usually has more severe hypercortisolism and is usually easy to diagnose. Positive MRI is helpful, but still needs biochemical evidence for hypercortisolism.

52 Dynamic Pituitary MRI Coronal T1-weighted Static MRI (Contrasted) Coronal T1-weighted Dynamic MRI (Contrasted)

53 Pituitary MRI 3T MRI with dynamic is the best-picks up small tumors and gives more specificity Need to send MRI to neurosurgeons as radiologists often miss small tumors. Still no way to distinguish between Cushing’s tumors and incidentalomas on MRI. Size is not helpful. Cushing's tumors are often very small:1-3 mm. Do not have to perform during a high Quality of MRI’s still vary, make sure yours is a good one I think the test is very helpful as it adds useful information to the clinician. Goes against dictum of diagnose Cushing’s syndrome before performing tests previously reserved for determining type of Cushing’s.

54 Adrenal Imaging Patients with severe pituitary Cushing’s can have adrenal enlargement. I hypothesized that adrenal MRIs or CTs would show adrenal enlargement that would help with the diagnosis. Did not find adrenal imaging helpful for the diagnosis of hypercortisolism Helpful for determining the type of Cushing’s syndrome (discussed later)

55 Unhelpful tests Morning cortisol (Friedman, T.C. and Yanovski, J.A. (1995) Morning Plasma Free Cortisol: Inability to Distinguish Patients with Mild Cushing Syndrome from Patients with Pseudo-Cushing States. J. Endocrinol. Invest. 18: ) Morning ACTH Late afternoon cortisol Insulin tolerance test CRH test

56 Periodic Cushing’s Data shows that all patients are periodic to some degree May account for many patients incorrectly diagnosed as normal. Marked by mostly normal (or low) cortisol levels with some high values accounting for the signs and symptoms of Cushing’s syndrome Can be all types of Cushing’s syndrome, but in my hands, its pituitary. Very difficult to diagnose and exclude

57 Periodic Cushing’s (2) My approach is to measure 3-8 UFCs and 17-OHS and 3-8 salivary cortisols in patients with a high degree of suspicion and symptoms of periodicity. Multiple serum midnight cortisols and 10 hr urine cortisols can also be done The patient should keep a diary of symptoms to correlate with cortisol values. Patients should try to collect urines/saliva when high symptoms. If all urines /saliva are normal, it makes active Cushing’s syndrome unlikely at that time. Patients should be followed and re-examined at a future time.

58 Periodic Cushing’s (2) I agree with the Endocrine Society recommendations and like to see 2 different tests high. The higher the test, the more likely Cushing’s is Patients with mild/episodic Cushing’s seem to have as many symptoms and as poor a quality of life as full-blown- may be due to daytime lows.

59 Conditions with Normal Cortisol Levels which May Mimic Cushing’s Syndrome- What else gives you a rapid weight gain, striae, trouble sleeping, fatigue, acne, irregular periods?? Obesity-not associated with other stigmata Syndrome X (Insulin Resistance) Polycystic Ovary Syndromes Growth Hormone Deficiency (different symptoms and testable)

60 Cushing’s vs Metabolic Syndrome/Polycystic Ovary Syndromes Rapid new onset weight gain in Cushing’s Sleep disturbances, depression, striae, fatigue, bruising Measure testosterone level (low in Cushing’s)-Pall et al. (2008) Testosterone and Bioavailable Testosterone Help to Distinguish Between Mild Cushing’s Syndrome and Polycystic Ovarian Syndrome. Hormone and Metabolic Research. 40: Measure fasting insulin level-low value argues against metabolic syndrome

61 Cushing’s vs Syndrome X/Polycystic Ovary Syndromes Rapid new onset weight gain in Cushing’s Sleep disturbances, depression, striae, fatigue, bruising Measure testosterone level (low in Cushing’s) Measure fasting insulin level-low value argues against metabolic syndrome Total Testosterone nmol/L 95% Sensitivity 70% Specificity Cushing's Syndrome PCOS Upper limit of normal range 1.39 nmol/L cut-point

62 How to tell if you are in a high cortisol phase Trouble sleeping Worsening acne Worsening ‘brain fog” If diabetes-higher glucose (especially after carbohydrate meals) If hypertension-higher blood pressure Signs of low cortisol-joint pains, can’t get out of bed, nausea and vomiting-do not test!

63 How to tell if you are in a high cortisol phase In the future, hopefully we will have a cortisolometer. Like a glucometer-gives instant cortisol levels with a finger prick.

64 Mild Cushing’s-Conclusions Important to make the diagnosis of Cushing’s Syndrome early-before ravages of disease have affected the patient. Careful history and physical (patient may not have all the classic findings) Many tests may be normal Unclear which is the “earliest” test to be abnormal. Wait only until ample evidence for Cushing’s is obtained.

65 CONCLUSIONS Almost all patients are episodic Most patients are mild Less pseudoCushing’s with new UFC assay No single tests diagnoses everyone Overnight dex testing is not helpful 17-OHS may pick up some patients and should be done in conjunction with UFC Pituitary MRI helpful Difficult to diagnose

66 RECOMMENDATIONS Careful history and physical At least 3 UFC and 17-OHS At least 3 11 pm salivary cortisols Make diagnosis if two distinct values are high Have patient keep a diary and try to collect when “high” Be careful interpreting serum cortisols on birth control pills

67 On to Determining the Type of Cushing’s

68 Thanks to: Dianne Andrews Magic foundation All my patients Surgeons:Ian McCutcheon, M.D., Hrayr Shahinian, M.D., Hae Dong Jho, M.D., Ph.D., Sandeep Kunwar, M.D., Ed Phillips, M.D., Manfred Chiang, M.D. Assistants: Lynne Drabkowski and Erik Zuckerbraun, M.D.

69 For more help Chat with Dr. Friedman on Cushing’s: nterview-with-Dr-Ted-Friedman-DR-F National geographic show on Cushing’s Dr. Friedman’s website: Dr. Friedman’s or to schedule an appointment:


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