Cushing

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Cushings syndrome

• Dr. Atallah Al-Ruhaily
• Consultant Endocrinologist

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Cushings syndrome

• Dr. Atallah Al-Ruhaily
• Consultant Endocrinologist

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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.

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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.

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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

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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.

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Pathology of Cushings Syndrome 1/3

• Anterior Pituitary Gland
• Pituitary adenoma (gt 90 of Cushings disease)
• Microadenoma (lt 10 mm in diameter) 80-90.
• Macroadenoma (gt 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.

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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
• 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
• Primary Pigmented Nodular Adrenocortical Disease,
  PPNAD)
• Massive Macronodular Adrenal Hyperplasia).

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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.

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CLINICAL SYMPTOMS AND SIGNS OF CUSHINGS SYNDROME

• General
• Central obesity
• Proximal muscle weakness
• Hypertension
• Headaches
• Psychiatric disorders
• Skin
• Wide(gt1cm), 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

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Clinical features of Cushings 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

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Clinical features of Cushings 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)

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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.

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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.

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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.

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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.

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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.

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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.

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Features suggesting specific causes

1. 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.

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Features suggesting specific causes

1. 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.

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Features suggesting specific causes

1. Adrenal Adenomas

• Usually the clinical picture of glucocorticoid
  excess alone.
• Androgenic effects usually absent.
• Gradual onset.
• Mild to moderate hypercortisolism.

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Features suggesting specific causes

1. 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.

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Diagnosis of Cushings Syndrome
Stages of Evaluation

• Clinical suspicion.
• Biochemical diagnosis of hypercortisolism status.
• Differential diagnosis for etiology of
  hypercortisolism (Biochemical Imaging Tests).

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Diagnosis of Cushings 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

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Diagnosis of Cushings syndrome
Cushings syndrome suspected
Overnight 1mg Dexamethasone suppression test
High AM cortisol (? 3µg/dL)
Low AM cortisol (lt 3µg/dL)

• Normal

24-hour urine free cortisol
Normal
Elevated

• Repeat screening tests if highly suspected

• Hypercortisolism is confirmed
• Needs differential diagnosis

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Cushings syndrome established
ACTH (by IRMA)
gt10 pg/mL
lt5 pg/mL
CT adrenals
MRI pituitary
IPSS
Unilateral Mass
Bilateral Enlargement
Abnormal
Normal
CRH test
IPS/Pgt2.0
IPS/Plt1.8
Peak ACTH gt20 pg/mL
Peak ACTH lt10 pg/mL
Adrenal Surgery
Pituitary Surgery
Ectopic ACTH
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Problems in Diagnosis of Cushings Syndrome
pseudo-Cushings syndromes

• Conditions
• Depression
• Alcoholism withdrawal from alcohol intoxication
• Eating disorders (anorexia nervosa bulimia)

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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

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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 lt 15
  mL/min)
• Hypometabolism of dexamethasone (e.g., liver
  failure)

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Problems in Diagnosis of Cushings Syndrome
pseudo-Cushings syndromes

• Similarities in biochemical features of
  Cushings 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

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Problems in Diagnosis of Cushings Syndrome
pseudo-Cushings syndromes

• Distinguishing Tools
• History physical examination
• Repeating screening tests
• Dexamethasone suppression test followed by CRH
  stimulation measurement of plasma cortisol.

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Treatment of Cushings Syndrome
Cushings 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)

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Treatment of Cushings Syndrome
Other types of Cushings syndromes

1. Ectopic ACTH syndromes
2. Adrenal Adenomas
3. Adrenal Carcinomas
4. Nodular Adrenal Hyperplasia

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Prognosis of Cushings Syndrome

1. Cushings Disease
2. Ectopic ACTH syndromes
3. Adrenal Adenomas
4. Adrenal Carcinomas
5. Nodular Adrenal Hyperplasia

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Other Adrenal Disorders

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