Cushings syndrome

Dr. Atallah Al-Ruhaily

Consultant Endocrinologist

Cushings syndrome

Dr. Atallah Al-Ruhaily

Consultant Endocrinologist

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

Cushings Syndrome

The most common cause is iatrogenic due to chronic

use of glucocorticoid.
Regardless of etiology, all cases of endogenous or
spontaneous Cushings 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.

Cushings syndrome: Differential Diagnosis

ACTH-dependent

pituitary adenoma (Cushings 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

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.

Pathology of Cushings Syndrome 1/3

Anterior Pituitary Gland
Pituitary adenoma (> 90% of Cushings 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.

Pathology of Cushings Syndrome 2/3

Adrenocortical Hyperplasia

Bilateral hyperplasia of adrenal cortex.

Results from chronic ACTH hypersecretion.
There are 3 types of adrenocortical hyperplasia:
1.
2.
3.

Simple Adrenocortical Hyperplasia (Cushings 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:
A. Primary Pigmented Nodular Adrenocortical Disease, PPNAD)
B. Massive Macronodular Adrenal Hyperplasia).

Pathology of Cushings 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.

CLINICAL SYMPTOMS AND SIGNS

OF CUSHINGS 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

Clinical features of Cushings syndrome

1/2
General :

Musculoskeletal:

-Obesity 90%

-osteopenia (80%)

-Hypertension 85%

-weakness (65%)

Skin:

Neuropsychiatric (85%):

-plethora (70%)

-emotional lability

-hirsutism (75%)

-euphoria

-striae (50%)

-depression

-acne (35%)

-psychosis

-bruising (35%)

Clinical features of Cushings syndrome

2/2
Gonadal dysfunction:
-menstrual disorders
(70%)
-impotence, decreased
libido(85%)

Metabolic:
-glucose intolerance(75%)
-diabetes (20%)
-hyperlipidemia (70%)
-polyuria (30%)
-kidney stones (15%)

Cushing Disease
The most common type of endogenous

Cushings syndrome (70%).

Female : Male Ratio

about 8 : 1

Incidence age ranges from childhood to 70

years.

Ectopic ACTH Hypersecretion

15-20% of ACTH-dependent Cushing syndrome.

Very high ACTH may result in severe hypercortisolism

with lack of classical features of Cushings syndrome.

More common in men.

Age incidence: 40-60 years.

Primary Adrenal Tumors

10% of cases of Cushings syndrome.
Most are benign adrenocortical adenomas.
Adrenocortical carcinomas are uncommon.
Both adenomas & carcinomas are more

common in women.

Childhood Cushings Syndrome

Adrenal carcinoma is the commonest (51%) &

Adrenal adenoma (14%).

More common in girls than in boys.

Most in age 1 8 years.
Cushings disease more common in

adolescents (35%); most at age over 10 years.

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%.

Features suggesting specific causes

1. Cushings 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.

Features suggesting specific causes

2. 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.

Features suggesting specific causes

3. Ectopic ACTH Syndrome (Benign Tumor)

Slowly progressive course with typical features of

Cushings syndrome.

Presentation may be identical to pituitary-dependent

Cushings disease & the responsible tumor may not be
apparent.

Hyperpigmentation, hypokalemic alkalosis & anemia are

variably present.

Features suggesting specific causes

4. Adrenal Adenomas

Usually the clinical picture of glucocorticoid excess alone.

Androgenic effects usually absent.

Gradual onset.

Mild to moderate hypercortisolism.

Features suggesting specific causes

5. 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.

Diagnosis of Cushings Syndrome

Stages of Evaluation

Clinical suspicion.

Biochemical diagnosis of hypercortisolism status.

Differential diagnosis for etiology of hypercortisolism

(Biochemical & Imaging Tests).

Diagnosis of Cushings Syndrome

Biochemical diagnosis of hypercortisolism status

1. Dexamethasone suppression test
2. 24 h Urine free cortisol
3. Diurnal rhythm of cortisol secretion

Differential diagnosis of etiology of hypercortisolism

(Biochemical & Imaging Tests).
1. Plasma ACTH
2. Pituitary MRI
3. High-dose Dexamethasone suppression test
4. Inferior Petrosal Sinus Sampling with CRH stimulation
5. Localizing occult ectopic ACTH
6. Adrenal localizing procedures

Diagnosis of Cushings syndrome

Cushings syndrome suspected

Overnight 1mg Dexamethasone suppression test

High AM cortisol ( 3g/dL)

24-hour urine free cortisol

Normal

Repeat screening tests if

highly suspected

Low AM cortisol (< 3g/dL)

Normal

Elevated

Hypercortisolism is confirmed
Needs differential diagnosis

Cushings syndrome established

ACTH (by IRMA)
<5 pg/mL

>10 pg/mL

CT adrenals

MRI pituitary

Unilateral Mass

Bilateral Enlargement

IPSS

Normal

Abnormal

CRH test
IPS/P<1.8 IPS/P>2.0
Peak ACTH
<10 pg/mL
Adrenal Surgery

Peak ACTH
>20 pg/mL
Ectopic ACTH

Pituitary Surgery

Problems in Diagnosis of Cushings Syndrome

pseudo-Cushings syndromes

Conditions:
1. Depression
2. Alcoholism & withdrawal from alcohol intoxication
3. Eating disorders (anorexia nervosa & bulimia)

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

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)

Problems in Diagnosis of Cushings Syndrome

pseudo-Cushings syndromes

Similarities in biochemical features of Cushings syndrome:

1. Elevation of urine free cortisol
2. Disruption of the normal diurnal pattern of cortisol secretion
3. Lack of suppression of cortisol after overnight 1 mg
dexamethasone suppression test

Problems in Diagnosis of Cushings Syndrome

pseudo-Cushings syndromes

Distinguishing Tools:
1. History & physical examination
2. Repeating screening tests
3. Dexamethasone suppression test followed by CRH
stimulation & measurement of plasma cortisol.

Treatment of Cushings Syndrome

Cushings syndromes
1. Pituitary microsurgery

Transphenoidal hypophysectomy
Transfrontal hypophysectomy

2. Radiotherapy

Conventional irradiation (not recommended)

Heavy particles irradiation
Gamma-knife radiosurgery
Implantation of radioactive seeds (gold & ytrium)

3. Medical Therapy

Ketoconanzole
Aminoglutethimide
Mitotane (adrenolytic drug)

Treatment of Cushings Syndrome

Other types of Cushings syndromes

1.
2.
3.
4.

Ectopic ACTH syndromes

Adrenal Adenomas
Adrenal Carcinomas
Nodular Adrenal Hyperplasia

Prognosis of Cushings Syndrome

1.
2.
3.
4.
5.

Cushings Disease
Ectopic ACTH syndromes
Adrenal Adenomas
Adrenal Carcinomas
Nodular Adrenal Hyperplasia

Other Adrenal Disorders

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