CUSHINGS SYNDROME AND HYPOADRENALISM DIAGNOSIS

Cushings syndrome suspected Consider endocrinologist consultation

Exclude exogenous glucocorticoid exposure

Question 1 DOES THE PATIENT HAVE CUSHINGS SYNDROME?

Screening tests: 1.Circadian rhythm of plasma cortisol 2.Late-night salivary cortisol (2 measurements) 3.Urinary free cortisol (2 measurements) 4.The overnight 1-mg dexamethasone suppression tests (DST) 5.The 2-day 2 mg dexamethasone test

2 positive testsCushings syndrome

1. Circadian rhythm of plasma cortisol

Basal plasma cortisol - normal range 5-25g/dl NON DIAGNOSTIC!

Midnight cortisol level normal value < 3g/dl

>7.5g/dl Cushings syndrome

2. Midnight salivary cortisol

- 2 measurements - Passive drooling/salivette

- Normal value 1 ng/ml (2.8nmol/l) - value>2 ng/ml (5.5nmol/l)Cushings syndrome

3. Urinary free cortisol

- 2 measurements - 24 hour urine collection,
- refrigerated, not frozen

- Normal range 20-90 g/24 h

- (50-250 nmol/24 h)

- Elevated level (2-3X times) Cushings syndrome

4. 1-mg overnight DST

- 1 mg DXM administered at 11-12 P.M.
- Plasma cortisol level measured next morning 8 A.M.

- A value < 1.8 g/dl (50nmol/l) good suppression NO Cushings syndrome

5. Longer low-dose DST (2 mg/d for 48 h)

- 0.5 mg every 6 hours for 48 hours beginning 8 A.M. on day 0 - (2X2 mg)
- pl cortisol before first dose and 6 hours after last dose.

- A value < 1.8 g/dl (50nmol/l) good suppression NO Cushings syndrome

+ UFC on day 2 collected urine < 10g/24h + 17 HOCS <2.5mg/24h

Question 2 What is the cause of Cushings syndrome in this patient?

Tests
1. 2. 3. 4. 5. 6. 7. 8. ACTH level Plasma potassium, bicarbonate High-dose DXM suppression test CRH test Inferior petrosal sinus sampling CT, MRI pituitary, adrenal Scintigraphy Tumor markers

1. ACTH
- Serum ACTH - IRMA - Normal range 9-52 pg/ml (2-11 pmol/l)
- A value < 5 pg/ml ACTH independent cause

- A value > 20 pg/ml ACTH dependent disease

2. Potassium, bicarbonate
HYPOKALEMIC ALKALOSIS

Ectopic ACTH secretion

3. High-dose DXM suppression test

- 2 mg DXM every 6 hours for 48 hours
- Measure plasma or urinary free cortisol at 0 and

+48 hours

- Supression > 50% from basal value

Cushings disease

4. CRH test
- CRH 1g/kg or 100g I.V.
- Can be performed after DXM test

- Cortisol and ACTH measurements before and every 15 minutes after, for 2 hours - Normal response ACTH and cortisol rise of 15-20% - ACTH rise > 50 % and cortisol rise > 20 % Cushings disease

5. Inferior petrosal sinus sampling

100 g CRH I.V. - Measurement of peripheral and petrosal ACTH level at 2, 5 and 15 minutes after.
- Ratio petrosal sinus/periphery prior CRH > 2:1 pituitary source of ACTH oversecretion - Ratio petrosal sinus/periphery after CRH > 3:1 pituitary source of ACTH oversecretion - Ratio petrosal sinus/periphery < 1.4:1 ectopic ACTH secretion

6. CT/MRI pituitary
- Only after dynamic tests!

ACTH secreting pituitary microadenomas

6. CT/MRI - adrenal
Massive macronodular hyperplasia. Adrenal glands are replaced by multiple nodules (arrows)

Typical solitary left adrenal adenoma causing Cushings syndrome

Cushings syndrome etiology

Hypoadrenalism suspected
Basal cortisol > 14.5 g/dl (400 nmol/L) intact HPA axis
1.Routine biochemical profile 2.Mineralocorticoid status 3.Hypothalamic-pituitary-adrenal axis function evaluation 4.Other tests

1. Routine biochemical profile

- Hyponatremia - Hyperkalemia

- Hypercalcemia
- Azotemia - Anemia - Eosinophilia

2. Mineralocorticoid status
Primary hypoadrenalism PRA, aldosterone

Secondary hypoadrenalism intact RAA axis

3. Assessing adequacy of function of the HPA axis

1. ACTH stimulation test
2. ACTH depot stimulation test 3. CRH test 4. Insulin tolerance test

3.1 ACTH stimulation test

- Cortrosyn 250/5/1g I.V. or I.M.
- Cortisol measurement at 0-30-60 minutes

- Normal response cortisol over 18-20g/dl

3.2 ACTH depot stimulation test

Cortrosyn depot 1 mg I.M.
Cortisol measurement at baseline and after 24 hours

Normal response doubling of the cortisol level

Primary hypoadrenalism no response Secondary hypoadrenalism late response

3.3 CRH test

- CRH 1g/kg or 100g I.V.
- Cortisol and ACTH measurements before and every 15 minutes after, for 2 hours

- Primary hypoadrenalism Exaggerated elevation of ACTH at 45 minutes - Secondary response hypoadrenalism no ACTH

3.4 Insulin tolerance test

Insulin 0.05-0.15 UI/kg I.V.
Serum glucose, cortisol - every 30 minutes for 2 hours

Valid if serum glucose decreases 40mg/dl

Normal response cortisol rise above 18-20 g/dl

4. Other tests
- Imaging testing adrenal CT - Serum antibodies against 21-hydroxylase
Bilateral metastases

Bilateral hemorrhage