1. Consultant Endocrinologist
Cushing’s syndrome
Dr. Atallah Al-Ruhaily
Consultant Endocrinologist

2. Consultant Endocrinologist
Cushing’s syndrome
Dr. Atallah Al-Ruhaily
Consultant Endocrinologist

3. Cushing’s Syndrome Definitions
Cushing’ Syndrome:
A state of chronic glucocorticoid excess leading to constellation of symptoms and signs of hypercortisolism regardless of the cause.
Cushing’s Disease:
The specific type of Cushing’s syndrome due to excessive ACTH secretion from a pituitary tumor.
Ectopic ACTH syndrome:
type of Cushing’s syndrome due to ACTH secretion by nonpituitary tumor.

4. Cushing’s Syndrome
The most common cause is iatrogenic due to chronic use of glucocorticoid.
Regardless of etiology, all cases of endogenous or spontaneous Cushing’s syndrome are due to overproduction of cortisol by the adrenal glands.
Most endogenous types are due to Bilateral Adrenal Hyperplasia due to ACTH secretion by pituitary adenoma.
Incidence of pituitary-dependent adrenal hyperplasia in women is 3 times that in men.
The most frequent age of onset is 3rd to 4th decade.

5. Cushing’s syndrome: Differential Diagnosis
ACTH-dependent
pituitary adenoma (Cushing’s disease)
non-pituitary neoplasm (ectopic ACTH)
ACTH-independent
Iatrogenic (glucocorticoid, megestrol acetate)
Adrenal neoplasm (adenoma, carcinoma)
Nodular adrenal hyperplasia
primary pigmented nodular adrenal disease.
massive macronodular adrenonodular hyperplasia
food-dependent (GIP-mediated)
Factitious

6. Tumors causing ectopic ACTH syndome
small cell carcinoma of the lung (50% of ectopic ACTH cases).
pancreatic islet cell tumors.
carcinoid tumors (lung, thymus, gut, pancreas, ovary).
medullary carcinoma of the thyroid.
pheochromocytoma and related tumors.

7. Pathology of Cushing’s Syndrome 1/3
Anterior Pituitary Gland
Pituitary adenoma (> 90% of Cushing’s disease):
Microadenoma (< 10 mm in diameter) 80-90%.
Macroadenoma (> 10 mm in diameter) & could be invasive.
Mostly benign adenoma; rarely malignant.
Pituitary Hyperplasia:
Diffuse hyperplasia of corticotrophs cells are rare.
Due to excessive stimulation of pituitary by CRH.

8. Pathology of Cushing’s Syndrome 2/3
Adrenocortical Hyperplasia
Bilateral hyperplasia of adrenal cortex.
Results from chronic ACTH hypersecretion.
There are 3 types of adrenocortical hyperplasia:
Simple Adrenocortical Hyperplasia (Cushing’s disease)
Ectopic ACTH syndrome
Bilateral Nodular Hyperplasia
Nodular enlargement of adrenal glands resulting from long-standing ACTH hypersecretion (pituitary or nonpituitary).
There are 2 types of Bilateral Nodular Hyperplasia:
Primary Pigmented Nodular Adrenocortical Disease, PPNAD)
Massive Macronodular Adrenal Hyperplasia).

9. Pathology of Cushing’s Syndrome 3/3
Adrenal Tumors
Adrenal Adenomas:
Glucocorticoids-secreting adenomas.
Encapsulated;
weigh 10 – 70 gr.
Size: 1- 6 cm.
Adrenal Carcinomas:
Usually weigh over 100 gr.; commonly palpable mass.
Encapsulated.
May invade local structures.

10. CLINICAL SYMPTOMS AND SIGNS OF CUSHING’S SYNDROME
General:
Central obesity
Proximal muscle weakness
Hypertension
Headaches
Psychiatric disorders
Skin:
Wide(>1cm), purple striae
Spontaneous echymoses
Facial plethora
Hyperpigmentation
Acne
Hirsutism
Fungal skin infections
Endocrine and Metabolic Derangements:
Hypokalemic alkalosis
Osteopenia
Delayed bone age in children
Menstrual disorders, decreased libido, impotence
Glucose intolerance, diabetes mellitus
Kidney stones
Polyurea

11. Clinical features of Cushing’s syndrome 1/2
General :
-Obesity 90%
-Hypertension 85%
Skin:
-plethora (70%)
-hirsutism (75%)
-striae (50%)
-acne (35%)
-bruising (35%)
Musculoskeletal:
-osteopenia (80%)
-weakness (65%)
Neuropsychiatric (85%):
-emotional lability
-euphoria
-depression
-psychosis

12. Clinical features of Cushing’s syndrome 2/2
Metabolic:
-glucose intolerance(75%)
-diabetes (20%)
-hyperlipidemia (70%)
-polyuria (30%)
-kidney stones (15%)
Gonadal dysfunction:
-menstrual disorders (70%)
-impotence, decreased libido(85%)

13. Cushing’ Disease
The most common type of endogenous Cushing’s syndrome (70%).
Female : Male Ratio about 8 : 1
Incidence age ranges from childhood to 70 years.

14. Ectopic ACTH Hypersecretion
15-20% of ACTH-dependent Cushing’ syndrome.
Very high ACTH may result in severe hypercortisolism with lack of classical features of Cushing’s syndrome.
More common in men.
Age incidence: years.

15. Primary Adrenal Tumors
10% of cases of Cushing’s syndrome.
Most are benign adrenocortical adenomas.
Adrenocortical carcinomas are uncommon.
Both adenomas & carcinomas are more common in women.

16. Childhood Cushing’s Syndrome
Adrenal carcinoma is the commonest (51%) & Adrenal adenoma (14%).
More common in girls than in boys.
Most in age 1 – 8 years.
Cushing’s disease more common in adolescents (35%); most at age over 10 years.

17. Routine Laboratory Findings
High normal Hb, Htc & RBC.
WBC usually normal but lymphoctytes may be subnormal.
Eosinophils may be reduced.
Electrolytes:
Hypokalemia & alkalosis in marked steroid hypersecretion (ectopic ACTH).
Impaired glucose tolerance or hyperglycemia
Serum Calcium normal but hypercalciuria in 40%.

18. Features suggesting specific causes
Cushing’s Disease
Typifies classic clinical picture:
Female predominance
Onset age: 20 – 40 years.
Slow progression over several years.
Hyperpigmentation & hypokalemic alkalosis are rare.
Androgenic manifestations are limited to acne & hirsutism.
Moderately increased cortisol & adrenal androgens.

19. Features suggesting specific causes
Ectopic ACTH Syndrome (Carcinoma)
Predominantly in males.
Highest incidence at age 40 – 60 years.
Clinical manifestations are frequently limited to: weakness, hyperpigmentation & glucose intolerance.
Primary tumor is usually apparent.
Hyperpigmentation, hypokalemia & alkalosis are common.
Weight loss & anemia are common.
Hypercortisolism is of rapid onset.
Steroid hypersecretion is frequently severe with equally elevated levels of glucocorticoids, androgens & DOC.

20. Features suggesting specific causes
Ectopic ACTH Syndrome (Benign Tumor)
Slowly progressive course with typical features of Cushing’s syndrome.
Presentation may be identical to pituitary-dependent Cushing’s disease & the responsible tumor may not be apparent.
Hyperpigmentation, hypokalemic alkalosis & anemia are variably present.

21. Features suggesting specific causes
Adrenal Adenomas
Usually the clinical picture of glucocorticoid excess alone.
Androgenic effects usually absent.
Gradual onset.
Mild to moderate hypercortisolism.

22. Features suggesting specific causes
Adrenal Carcinomas
Rapid onset & rapid progression.
Clinical picture of excessive glucocorticoids, androgens & mineralocorticoids secretion.
Marked elevation of cortisol & androgens.
Abdominal pain, palpable masses & metasteses in liver & lungs.
Hypokalemia is common.

23. Diagnosis of Cushing’s Syndrome
Stages of Evaluation
Clinical suspicion.
Biochemical diagnosis of hypercortisolism status.
Differential diagnosis for etiology of hypercortisolism (Biochemical & Imaging Tests).

24. Diagnosis of Cushing’s Syndrome
Biochemical diagnosis of hypercortisolism status
Dexamethasone suppression test
24 h Urine free cortisol
Diurnal rhythm of cortisol secretion
Differential diagnosis of etiology of hypercortisolism (Biochemical & Imaging Tests).
Plasma ACTH
Pituitary MRI
High-dose Dexamethasone suppression test
Inferior Petrosal Sinus Sampling with CRH stimulation
Localizing occult ectopic ACTH
Adrenal localizing procedures

25. Diagnosis of Cushing’s syndrome
Cushing’s syndrome suspected
Overnight 1mg Dexamethasone suppression test
High AM cortisol ( 3µg/dL)
Low AM cortisol (< 3µg/dL)
Normal
24-hour urine free cortisol
Normal
Elevated
Repeat screening tests if highly suspected
Hypercortisolism is confirmed
Needs differential diagnosis

26. Cushing’s syndrome established
ACTH (by IRMA)
<5 pg/mL
>10 pg/mL
CT adrenals
MRI pituitary
IPSS
Unilateral Mass
Bilateral Enlargement
Normal
Abnormal
CRH test
IPS/P<1.8
IPS/P>2.0
Peak ACTH <10 pg/mL
Peak ACTH >20 pg/mL
Adrenal Surgery
Ectopic ACTH
Pituitary Surgery

27. Problems in Diagnosis of Cushing’s Syndrome
pseudo-Cushing’s syndromes
Conditions:
Depression
Alcoholism & withdrawal from alcohol intoxication
Eating disorders (anorexia nervosa & bulimia)

28. NON-CUSHING CAUSES OF HYPERCORTISOLEMIA
Physical stress
Operations, trauma
Chronic exercise
Malnutrition
Mental stress and psychiatric disorders
Hospitalization
Drug and alcohol abuse and withdrawal
Chronic depression (unipolar, bipolar)
Panic disorder
Anorexia nervosa
Metabolic abnormalities
Hypothalamic amenorrhea
Elevated cortisol-binding globulin (estrogen therapy, pregnancy, hyperthyroidism)
Glucocorticoid resistance
Complicated diabetes mellitus

29. PITFALLS IN THE INTERPRETATION OF THE 1-MG OVERNIGHT DEXAMETHASONE SUPPRESSION TEST
False-positive tests (I.e., lack of suppression)
Non-Cushing hypercortisolemia
Obesity
Stress
Alcoholism
Psychiatric illness (anorexia nervosa, depression, mania)
Elevated cortisol binding globulin (estrogen, pregnancy, hyperthyroidism)
Glucocorticoid resistance
Test-related artifacts
Laboratory error, assay interference
insufficient dexamethasone delivery into the circulation
Noncompliance
Decreased absorption
Increased metabolism (drugs)
False-negative tests
chronic renal failure (creatinine clearance < 15 mL/min)
Hypometabolism of dexamethasone (e.g., liver failure)

30. Problems in Diagnosis of Cushing’s Syndrome
pseudo-Cushing’s syndromes
Similarities in biochemical features of Cushing’s syndrome:
Elevation of urine free cortisol
Disruption of the normal diurnal pattern of cortisol secretion
Lack of suppression of cortisol after overnight 1 mg dexamethasone suppression test

31. Problems in Diagnosis of Cushing’s Syndrome
pseudo-Cushing’s syndromes
Distinguishing Tools:
History & physical examination
Repeating screening tests
Dexamethasone suppression test followed by CRH stimulation & measurement of plasma cortisol.

32. Treatment of Cushing’s Syndrome
Cushing’s syndromes
Pituitary microsurgery
Transphenoidal hypophysectomy
Transfrontal hypophysectomy
Radiotherapy
Conventional irradiation (not recommended)
Heavy particles irradiation
Gamma-knife radiosurgery
Implantation of radioactive seeds (gold & ytrium)
Medical Therapy
Ketoconanzole
Aminoglutethimide
Mitotane (adrenolytic drug)

33. Treatment of Cushing’s Syndrome
Other types of Cushing’s syndromes
Ectopic ACTH syndromes
Adrenal Adenomas
Adrenal Carcinomas
Nodular Adrenal Hyperplasia

34. Prognosis of Cushing’s Syndrome
Cushing’s Disease
Ectopic ACTH syndromes
Adrenal Adenomas
Adrenal Carcinomas
Nodular Adrenal Hyperplasia

35. Other Adrenal Disorders
Not covered in this lecture and need to be studied:
Pheochromocytoma
Hyperaldoteronism
Syndomes of congenital adrenal hyperplasia (CAH).
Hirsutism
Virilization