Approach to the Patient with Possible Cushings Syndrome

Jindaprasert, J.

Recognize and Confirm Cushings Syndrome

Classic phenotype
Cardiovascular Metabolic Dermatological Musculoskeletal Psychiatric

Some- isolated symptoms Atypical- mild and cyclic hypercortisolism

Ophthalmology
Increase intraocular pressure---- glaucoma Posterior subcapsular cataract

Cardiovascular
Hypertension

Metabolic
Central or truncal obesity Moon face, Buffalo hump, Supraclavicular fat pad BS, VLDL, LDL, chol, TG Amenorrhea Hypokalemia Metabolic alkalosis

Dermatological
Bruise, ecchymosis, thin skin Purplish striae > 1 cm
Abdomen, axilla, breast, groin

Acanthosis nigricans Facial plethora Oily skin, acne, hirsutism panniculitis

Musculoskeletal
Proximal muscle weakness Muscle fiber atrophy Inh. Muscle protein synthesis Increase muscle protein catabolism Osteopenia Osteoporosis Avascular necrosis

Psychiatry
Fatigue Depression Agitation, irritability Insomnia Impaired memory Decrease libido

Features the best discriminate Cushings syndrome

Easy bruising Facial plethora Proximal myopathy Children: weight gain with decreasing velocity of growth Reddish-purple purpura, > 1 cm wide

Pseudocushings syndrome
Pregnancy Depression and other psychiatric conditions Alcohol dependence Glucocorticoid resistance Morbid obesity Poorly controlled DM

Who should be screened?

Signs & symptoms of cushings Unusual features for age (HT, osteoporosis) Adrenal incidentaloma Children: decreasing height and increasing weight Pituitary incidentaloma Metabolic syndrome: young Obese womenwith polycystic ovary syndrome Males with hypogonadotropic hypogonadism

Guideline for Diagnosis of CS

Exclude exogenous Cushing Confirm abnormal cortisol production Differential diagnosis of CS
ACTH-dependent vs. ACTH-independent

Differential diagnosis of ACTH-dependent CS

Exogenous vs. Endogenous

Questions about exogenous steroid
Symptom : : :

Cushingoid appearances are generally not full blown

Initial tests
24-h urinary free cortisol: 2 measurements Late night salivary cortisol: 2 measurements 1- mg overnight DST Standard low-dose DST

24-h urinary free cortisol

Measure total volume and creatinine levels First morning void- discarded Include first morning void on 2nd day Refrigerated (not frozen) NOT to drink excessive amount of water AVOID use of glucocorticoid preparations

> 4 times UNL ; most likely Cushings

24-h urinary free cortisol

False positive
Severe obesity Depression Anxiety Alcoholism Drugs; Carbamazepine, fenofibrate High fluid intake

False negative
CrCl< 60 ml/min Cyclic disease Mild cushing

Late night salivary cortisol

Saliva sample on two separate evenings 23.00- 24.00 Passive drooling into a plastic tube or placing a cotton pledget (salivette) in the mouth and chewing for 12 min Normal 0.14 g/dl Very useful in investigating patients with cyclical Cushings syndrome

False positive
Poor diabetic control Obesity Depression, stress Shiftwork Behavior (variable bedtime, licorice, cigarettes, and chewing tobacco)

Low dose DST

Overnight
Dexamethasone (0.5) 2 tab at 23.00 then Cortisol level at 8.00

Standard
Dexa 0.5 mg q 6 hr for 8 times 12.00, 18.00, 24.00, 6.00, 12.00, 18.00, 24.00, 6.00 . Morning serum cortisol at 8.00-9.00 . (after last dose for 2-6 hr)

Cutoff point > 1.8 g/dl Sensitivity 95-98%

False positive
Reduced dexamethasone absorption Drugs enhancing CYP3A4 Liver and renal failure Pseudo-cushing state Drugs that increase CBG- Estrogen

Drugs interfering tests

Special population
Pregnancy: 24 h UFC Epilepsy: 24 h UFC, salivary cortisol Renal failure: 1 mg overnight DST Cyclic: 24 h UFC Incidentaloma: 24 h UFC

Identifying the cause

Measuring plasma ACTH levels 2 times Prechilled EDTA tubes <10 pg/ml ACTH independent cushing >20 pg/ml ACTH dependent >200 pg/ml Ectopic ACTH

Classifications of Cushings Syndrome

Classifications of Cushings Syndrome

Cushings disease Adrenal tumor Ectopic ACTH syndrome

Ectopic ACTH

ACTH independent cushing CT/MRI adrenals

Unilateral
Adenoma Carcinoma

Bilateral
Macronodular Micronodular hyperplasia

AIMAH
ACTH independent bilateral macronodular adrenal hyperplasia Multiple nodules up to 5 cm 6th decade of life Aberrantly expressed receptors in adrenal cortex Ectopic membrane receptors: gastric inhibitory peptide, catecholamines, LH/ hCG, vasopressin

GIP receptor Vasopressin receptor Beta adrenergic receptor Angiotensin II receptor LH / hCG serotonin

Ectopic receptor

PPNAD
Small to normal-sized adrenal glands nodules do not normally exceed 5mm children and young adults multiple small cortical pigmented nodules sporadic or asso. with Carney complex
Autosomal dominant spotty skin pigmentation,myxomas, and nonendocrine and endocrine tumors

CRH test
1g/kg or the 100-g fixed dose, The wide range of response parameters Increase above baseline in peak ACTH 3050%, vs. peak cortisol 1420%

High dose DST

48 hr: 2 mg q 6 hr x 2 days 24 h UFC at baseline& during last 24 h Overnight HDDST: 8 mg at 11 pm 9 am serum cortisol Do not recommend the routine use of HDDST alone

MRI pituitary
All patients with ACTH-dependent Cushings syndrome Fails to identify the tumor in up to 50% pituitary lesion >6 mm + classical presentation + concordant dynamic results Definite diagnosis of Cushings disease!!

BIPSS
Bilateral inferior petrosal sinus sampling Gold standard All pt- negative MRI, discordant test

Inferior Petrosal Sinus sampling

ACTH central/ peripheral Basal

right

left

>2

>2

CRHinduced

>3

>3

No LEFT RIGHT ??? ORbenefits ??? in predicting sides of tumor

References
J Clin Endocrinol Metab, September 2009, 94(9):31213131 The Endocrine Societys Clinical Guidelines Harrisons principles of internal medicine