1. Should we treat Subclinical Cushing’s syndrome? The case against
Paul M Stewart MD FRCP FMedSci Dean of Faculty of Medicine & Health, University of Leeds, Consultant Physician & Endocrinologist, Leeds Teaching Hospitals Trust

2. Disclosures
Speaker fees from Shire, Novartis on adrenal insufficiency MRC-Astra Zeneca grant on selective 11b-HSD1 inhibitor

3. Definition of Cushing’s syndrome
Untreated 5 years survival 50% - CVS mortality
Hypertension 95%
Obesity 80%
Glucose intolerance 50%
Osteoporosis 50%
Florid clinical features
Correlates with degree of hypercortisolism
“A constellation of symptoms and signs that reflect prolonged and inappropriately high exposure of tissues to glucocorticoids”
Nieman LK et al. J Clin Endocrinol Metab 2008;93:1526–1540

4. How to diagnose? Clinical acumen important
Test for Cushing’s syndrome in:
Patients with unusual features for age
Patients with multiple and progressive features, particularly those more predictive of Cushing’s syndrome
Children with decreasing height percentile and increasing weight
Patients with adrenal incidentaloma compatible with adenoma
Widespread testing for Cushing’s syndrome in any other patient group not recommended
Employ 2 of 3 high sensitive tests – UFC, late night salivary cortisol, low dose dexamethasone suppression test
Nieman LK et al. J Clin Endocrinol Metab 2008;93:1526–1540

5. Diagnosis – Guidelines Use two of three high sensitive tests
Sensitivity: Ability of test to identify Cushing’s syndrome
True positives/(true positives + false negatives)
Specificity: Ability of test to exclude Cushing’s syndrome
True negatives/(true negatives + false positives)
Suppressed ACTH confirms autonomous adrenal source
*27 studies, 8631 patients; Cushing’s syndrome prevalence: 9.2%
UFC
DST
LNSC
Sensitivity*
80–90%
80-95%
95%
Specificity*
~80%
85%
Nieman LK et al. J Clin Endocrinol Metab 2008;93:1526–1540
Elamin MB et al. J Clin Endocrinol Metab 2008;93:1553–1562

6. Hypercortisolism without Cushing’s syndrome
Some clinical features of Cushing’s syndrome may be present:
Pregnancy
Depression and other psychiatric conditions
Alcohol dependence
Glucocorticoid resistance
Morbid obesity
Poorly controlled diabetes mellitus
Unlikely to have any clinical features of Cushing’s syndrome:
Physical stress (hospitalization, surgery, pain)
Malnutrition, anorexia nervosa
Intense chronic exercise
Hypothalamic amenorrhea
CBG excess (increased serum but not urine cortisol)
Nieman LK et al. J Clin Endocrinol Metab 2008;93:1526–1540
CBG, corticosteroid-binding globulin

7. Subclinical Cushings, 9.2% adrenal incidentalomas
A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology.
J Clin Endocrinol Metab. 2000;85:
Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Alì A, Giovagnetti M, Opocher G, Angeli A.
Subclinical Cushings, 9.2% adrenal incidentalomas
A new “Italian” endocrine diagnosis

8. Cushing’s without overt clinical features and mild Cushing’s
Autonomous adrenal
Adenoma
Severe, Mild
?? Sub-clinical
“Because severe hypercortisolism is associated with a worse outcome than milder forms, it is likely that early recognition and treatment of mild disease would reduce the risk of residual morbidity. However, no data addressing this assumption have been reported.”
Tomlinson et al, JCEM; 2002; 87:57
Nieman L, et al, JCEM 2008; 93:

9. Major headache 1: I don’t really know what subclinical Cushing’s is?
Hugely variable diagnostic criteria
dexamethasone suppression tests
variable cortisol cut-offs, e.g. <50, <140 nmol/L, variable doses
urinary free cortisol, random cortisols, loss of CCR
late night salivary cortisol
DHAS, ACTH (or blunted response after CRH)
Unilateral uptake on scintigraphy
Any “2” abnormal tests to secure a diagnosis
Shen EJE 2014; 171:
“there is generally poor guideline quality among different organisations and remarkable differences exist in the recommendations for the same clinical subject” ….
“based on AGREE-II and Institute of Medicine criteria none of the guidelines were satisfactory”

10. Major headache 2: The false positive
phenomenon: in-built hazards of testing
The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome with a threshold at 138 nmol/l. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l.
Terzolo M, Italian Association of Clinical Endocrinologists, EJE, 2011;164:
Sensitivity
Specificity
80% – more cases missed % – fewer false positives
95% – fewer cases missed % – more false positives
138 nmol/L (5 µg/dL)
50 nmol/L (1.8 µg/dL)

11. Major headache 3: The effect of age
AI: % incidence
Age (yrs)
Autopsy data 57,262 subjects

12. Age-related “cushingoid features” in the normal population
Osteoporosis 6.3% male and 21.2% female aged 50-70, 16.6% males and 47.2% females >70yr (International Osteoporosis Foundation)
Diabetes 9.3% USA population has diabetes, 25.9% in subjects >65yr (ADA)
Obesity (USA CDC data) 30.3% aged 20-39, 35.4% in > 65 years
Hypertension 7.3% aged 18-40yr, 65% in patients >60 years (NCHS)

13. Time to clear the head? High false positive test rate
Increased further in patients with “physiological hypercortisolism” in diabetes, obesity, depression
“Ageing”
High prevalence adrenal incidentalomas
High prevalence of coincidental “cushing’s features”
Cawood et al EJE 2009; 161:
Literature search 110 studies
Considerable bias in published series
Incidence of functionality grossly over estimated
False positive rates at least 50x greater than true positives

14. Is adrenalectomy effective?
Early series, small numbers
Ref
Design N BP
Weight
Glucose
Bone
Rossi, 2000
Prosp 5 +
Midorikawa, 2001 4
+/- -
Emral, 2003 3
Bernini, 2003 6
Erbil, 2006
Retro 11
Mitchell, 2007 9
Sereg, 2009
Chiodini, JCEM 2011; 96:

15. Is adrenalectomy effective? Systematic review
Ref
Design
Diagnostic criteria N BP
Weight
Glucose
Perysinakis 2013
Retro no control
DST > of ACTH, UFC, CCR 29
12/17
6/14
5/12
Iacobone, 2012
Retro
DST >138 + ACTH + high UFC 20
8/15
6/15
5/10
Maehana, 2012
Retro non func control
DST > of ACTH, scintig, DHAS 13
5/7 --
2/2
Guerrieri, 2010
2 of DST >50, UFC, ACTH 19
12/12
Chiodini, 2010
2 of DST >83, UFC, ACTH 25
Next slide
Toniato, 2009
Prosp randomized
DST > of ACTH, CCR, DHAS 23
12/18
3/6
5/8
Tsuiki 2008
DST (8mg) >28 +1 of ACTH, CRH, DHAS, scintig 10
5/6
0/3
2/9
Iacobone M, et al, BJS; 2015: 102:

16. Any Rx effect independent of presence/ absence of SCS
Chiodini et al, JCEM 2010
108 patients, four quadrants SCS+/-, Rx +/-, latest f/u
Group n
Weight kg
BP mmHg
Lipids (LDL) mg/dl
Fasting glucose mg/dl
Treated SCS+ 25 75
124/76
125 90
Treated SCS - 30 70
120/78
123
Untreated SCS+ 16 76
139/83
114
Untreated SCS- 37 72
131/79
138 95
No consistent changes
Any Rx effect independent of presence/ absence of SCS

17. Is adrenalectomy effective? Bone
Ref
Design
Diagnostic criteria N BP
Weight
Glucose
Salcuni et al
EJE 2016
Retro
23 controls refused Sx
DST >138 or
2 of DST >83 + ACTH + UFC 32
No change --
Follow-up months
Lumbar spine BMD Z score
0.14 to 0.12 in “controls”
-0.86 to in Sx treated
But surgical group ….
higher post DEXA cortisol,
higher UFC
lower ACTH (all p<0.01)
Antonio Stefano Salcuni, EJE; 2016:174:

18. Final “nail in coffin” ….
In a patient with tests indicating prolonged and inappropriate hypercortisolism what is “subclinical” about hypertension, low BMD, diabetes, central adiposity? Why would we Rx/ operate unless features of Cushing’s? = mild Cushing’s not “subclinical”

19. So with a clear head …….
As described in literature SCS is almost certainly a “false positive” phenomenon
Many conditions result in hypercortisolism
beware ascribing features of ageing
Need for better biomarkers of “cortisol excess”
ACTH for autonomy, not diagnosis
A cortisol >138 nmol/l post DST in isolation is NOT autonomy
Real effort/ debate should focus on establishing an evidence base for treating “mild disease”