Disorders of the Adrenal CortexCushing’s Syndrome and Primary Aldosteronism

Department of Endocrinology and Metabolism

Zhongshan Hospital

Fudan University

凌 雁 Yan Ling

Cushing’s Syndrome

Definition of Cushing’s Syndrome

• Cushing's syndrome comprises the symptoms and signs associated with prolonged exposure to inappropriately elevated levels of free plasma glucocorticoids.

• The use of the term glucocorticoid in the definition covers both endogenous (cortisol) and exogenous (e.g., prednisolone, dexamethasone) excess.

Cortex of the Adrenal Gland Secretes Cortisol

Zona Glomerulosa

Zona Fasciculata

Zona Reticularis

Medulla

Regulation of Cortisol Secretion: Feedback Loops

• Hypothalamic

• Anterior Pituitary

• Adrenal cortex

CRH: corticotropin-releasing

hormone

ACTH: Adrenocorticotropic

hormone

Causes of Cushing’s Syndrome

• ACTH-dependent

• Cushing's disease (ACTH-producing pituitary adenoma) (60-70%)

• Ectopic ACTH syndrome (15-20%)

• Ectopic CRH syndrome

• Macronodular adrenal hyperplasia

• Iatrogenic (treatment with ACTH 1-24)

• ACTH-independent

• Adrenal adenoma (10-20%) and carcinoma (<5%)

• Primary pigmented nodular adrenal hyperplasia and Carney's syndrome

• McCune-Albright syndrome

• Aberrant receptor expression (gastric inhibitory polypeptide, interleukin-1β) (ACTH-independent macronodular hyperplasia )

• Iatrogenic (e.g., pharmacologic doses of prednisolone, dexamethasone)

Effects of Glucocorticoids

glucose

lipid

protein

Clinical Features of Cushing’s Syndrome

(%Patients) (%Patients)

(%Patients)

Clinical Features of Cushing’s Syndrome

• Obesity

• Truncal obesity

• Moon face

• Fat deposits in supraclavicular fossa and posterior neck- buffalo hump

Truncal Obesity

Weight gain and obesity are the most common sign, and this is

invariably centripetal in nature.

Characteristic deposition of adipose tissue

Moon face and plethora

Enlarged supraclavicular fat pads

buffalo hump

Clinical Features of Cushing’s Syndrome

• Skin

• Thin skin

• Plethora

• Easy bruising

• Broad purplish cutaneous striae

• Pigmentation

Broad purplish cutaneous striae

The typical red-purple livid striae greater than 1 cm in

diameter are most frequently found on the abdomen but may

also be present on the upper thighs, breasts, and arms.

Clinical Features of Cushing’s Syndrome

• Reproductive

• Female: menstrual irregularity (oligomenorrhea/amenorrhea) , hirsutism, acne

• Male: loss of libido

Clinical Features of Cushing’s Syndrome

• Psychiatric

• Irritability

• Depression

• Lethargy

• Paranoia

• Overt psychosis

Clinical Features of Cushing’s Syndrome

• Bone

• Osteoporosis

• Vertebral collapse

• Pathologic fractures

• Osteonecrosis of the femoral and humeral heads

• Muscle

• Proximal myopathy (lower limb and shoulder girdle )

Clinical Features of Cushing’s Syndrome

• Cardiovascular

• Hypertension

• Cardiovascular events and thromboembolic events

Clinical Features of Cushing’s Syndrome

• Infections

• Tuberculosis

• Fungal infections of the skin and nails

• Wound infections and poor wound healing

Clinical Features of Cushing’s Syndrome

• Metabolic and Endocrine

• Glucose intolerance and overt diabetes

• Elevated cholesterol and triglycerides

• Hypokalemic alkalosis

Clinical Features of Cushing’s Syndrome

• Eye

• Raised intraocular pressure and exophthalmos

• Cataracts

• Chemosis

Diagnosis of Cushing’s Syndrome

• Functional diagnosis

• Does the patient have Cushing's syndrome?

• Etiological diagnosis

• What is the cause of the Cushing's syndrome?

Diagnosis of Cushing’s Syndrome

• Diagnostic criteria

• Increased cortisol production

• Failure to suppress cortisol secretion normally when dexamethasone is administered

Functional diagnosis

• Circadian rhythm of plasma cortisol

• A sensitive screening test

• False positive (stress of venepuncture, intercurrent illness, and admission to hospital, CBG levels)

Functional diagnosis

• Circadian rhythm of plasma cortisol in normal subjects

• Highest in the morning

• Lowest around midnight (<50 nmol/L [<2 mg/dL] in a nonstressed subject).

Functional diagnosis

• Circadian rhythm of plasma cortisol in patients with Cushing's syndrome

• Circadian rhythm is lost

• Midnight cortisol > 200 nmol/L (>7.5 mg/dL): indicates the diagnosis

• Random morning cortisol: of little value in diagnosis

Functional diagnosis

• Urinary free cortisol excretion

• A useful screening test

• An integrated measure of plasma free cortisol

• 24-hour urinary excretion > 140nmol/d (50ug/d) indicates the diagnosis

• Urinary free cortisol may be normal in up to 8% to 15% of patients with Cushing's syndrome.

Functional diagnosis

Low-dose dexamethasone suppression test

The diagnostic test of Cushing’s syndrome

Normal Regulation of Cortisol Secretion

CRH: corticotropin-releasing

hormone

ACTH: Adrenocorticotropic

hormone

The Rationale of Low-Dose Dexamethasone

Suppression Test

• Feedback mechanism of ACTH-adrenal axis: the ACTH release mechanism is sensitive to the circulating glucocorticoid level. When blood levels of glucocorticoid are increased in normal individuals, less ACTH is released from the anterior pituitary and less steroid is produced by the adrenal gland.

• Test the integrity of this feedback mechanism by administration low but supraphysiologic doses of synthetic glucocorticoid dexamethasone.

• In normal subjects, the administration of a supraphysiologic dose of glucocorticoid results in suppression of ACTH and cortisol secretion.

• In Cushing's syndrome of whatever cause, there is a failure of

this suppression when low doses of dexamethasone are given.

Functional diagnosis

• Low-dose dexamethasone suppression test

• Overnight test:

• 1 mg at midnight.

• Normal: plasma cortisol < 140 nmol/L (<5 ug/dL) at 08.00 hours the following morning

• 48-hour low-dose dexamethasone test:

• 0.5 mg Q6 hr×48 hours.

• Urine cortisol during last 24 hours

• Plasma cortisol at 48 hours

• Normal:

• Urine cortisol < 25 nmol/24 hours ( < 10ug/24 hours)

• Plasma cortisol < 140 nmol/L (<5 ug/dL)

Causes of Cushing’s Syndrome

• ACTH-dependent

• Cushing's disease (pituitary-dependent) (70%)

• Ectopic ACTH syndrome (15%)

• Ectopic CRH syndrome

• Macronodular adrenal hyperplasia

• Iatrogenic (treatment with ACTH 1-24)

• ACTH-independent

• Adrenal adenoma (10-15%) and carcinoma (<5%)

• Primary pigmented nodular adrenal hyperplasia and Carney's syndrome

• McCune-Albright syndrome

• Aberrant receptor expression (gastric inhibitory polypeptide, interleukin-1β)

• Iatrogenic (e.g., pharmacologic doses of prednisolone, dexamethasone)

Etiological diagnosisACTH-dependent or ACTH-independent?

• Plasma ACTH

• Separating ACTH-dependent from ACTH-independent causes

• 8:00-9:00 plasma ACTH < 2 pmol/L (10 pg/mL) suggests ACTH-independent causes

Etiological diagnosisACTH-dependent or ACTH-independent?

• CT/MRI Scanning of Adrenals

• Adrenal adenoma

• Adrenal carcinoma

Etiological diagnosisCushing’s disease or ectopic ACTH syndrome?

• Differential diagnosis of ACTH-dependent Cushing’s syndrome

• Cushing’s disease

• Ectopic Cushing’s syndrome

Etiological diagnosisCushing’s disease or ectopic ACTH syndrome?

High-Dose Dexamethasone Suppression Test

A diagnostic test to distinguish patients with

Cushing’s disease from those with other

forms of Cushing's syndrome

The Rationale of High-Dose Dexamethasone Suppression Test

• In Cushing's disease, there is a relative resistance of ACTH secretion to normal glucocorticoid feedback inhibition. ACTH-secreting pituitary adenomas function at a higher than normal set-point for glucocorticoid feedback. Thus, cortisol levels do not suppress with low-dose, but do so following high-dose dexamethasone.

• The ACTH release of pituitary has been inhibited in ectopic ACTH syndrome and adrenal neoplasms and will not be effected by dexamethasone further. Thus, cortisol levels do not suppress with both low-dose and high-dose dexamethasone.

Etiological diagnosisCushing’s disease or ectopic ACTH syndrome?

• High-Dose Dexamethasone Suppression Test

• 2 mg Q6 hr×48 hours

• Urine cortisol (basal and last 24 hours)

• Plasma cortisol (basal and at 48 hours)

• Suppression rate

• (90%) Cushing’s disease > 50%

• (90%) ectopic ACTH syndrome < 50 %

Etiological diagnosisCushing’s disease or ectopic ACTH syndrome?

• Corticotropin-Releasing Hormone Test

• CRH 1mg/Kg or 100mg iv.

• ACTH and cortisol Q15min×2h

Diagnostic Tests to Determine the Cause of Cushing’s Syndrome

Etiological diagnosisCushing’s disease or ectopic ACTH syndrome?

• MRI Scanning of Pituitary-pituitary microadenoma

Tumors Associated with the Ectopic ACTH Syndrome

Tumor Type Approximate

Incidence (%)

Small cell lung carcinoma 50

Non–small cell lung carcinoma 5

Pancreatic tumors (including carcinoids) 10

Thymic tumors (including carcinoids) 5

Lung carcinoids 10

Other carcinoids 2

Medullary carcinoma of thyroid 5

Pheochromocytoma and related tumors 3

Rare carcinomas of prostate, breast, ovary,

gallbladder, colon

10

Etiological diagnosis

• Inferior Petrosal Sinus Sampling/Selective Venous Catheterization

• ACTH Ratio=ACTH (the

inferior petrosal sinus) / ACTH

(peripheral venous)

• Cushing’s disease >2

(baseline) or >3 (post-CRH)

• Ectopic ACTH syndrome <1.4

Differential Diagnosis

• Exogenous obesity

• Chronic alcoholism

• Depression

• Acute illness

• Iatrogenic Cushing’s syndrome

Treatment of Cushing's Syndrome

• Adrenal adenomas

• Unilateral adrenalectomy

• 100% cure rate

• Replacement therapy with glucocorticoid after operation

Treatment of Cushing's Syndrome

• Adrenal carcinomas

• Surgery

• Adrenolytic agent: o,p′-DDD (Mitotane)

• Radiotherapy

• Very poor prognosis: dead within 2 years

Treatment of Cushing's Syndrome

• Cushing's disease

• Transsphenoidal surgery

• Replacement therapy with glucocorticoid after operation

Treatment of Cushing's Syndrome

• Ectopic ACTH syndrome

• Surgery

• Treatment dependent on the cause

Case 1: A patient with cortisol-produing adrenal adenoma

• History:

• Female

• 53-year old

• 3-year history of hypertension

• Three antihypertensive medications administered

• Blood pressure level: 140/95mmHg

• Symptoms and signs:

• Heat intolerance, sweating, weight gain

• Plethora, BMI 26Kg/m2, waist circumference: 88cm

Case 1: A patient with cortisol-produing adrenal adenoma

皮质醇昼夜节律消失

ACTH降低

地塞米松抑制试验

•Circadian rhythm of cortisol disappeared

•ACTH suppressed

•Dexamethasone suppression test

•Functional diagnosis:

Cushing’s syndrome

•Localization: cortisol-

producing adenoma of the

left adrenal

Case 1: A patient with cortisol-produing adrenal adenoma

Unilateral adrenalectomy by

laparoscopy

Pathologic diagnosis: cortisol-

producing adenoma

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Case 1: Follow-up of the patient

Case 2: A patient with pituitary ACTH-producing adenoma

• History:

• Female

• 35-year old

• 9-month history of amenorrhea

• Symptoms and signs:

• Weight gain

• Plethora, round face

Case 2: A patient with pituitary ACTH-producing adenoma

• ACTH and cortisol rhythm

8:00 16:00 0:00

ACTH(pg/ml) 64.7 76.4 79.8

Cortisol(nmol/l) 398.4 520.7 424.3

• ACTH and cortisol level after low-dose and high-dose dexamethasone suppression test

Low-dose(8:00) High-dose(8:00)

ACTH(pg/ml) 100.4 85.7

Cortisol(nmol/l) 409.8 412.6

• Urinary free cortisol: 598.6 ug/24h

• Pituitary MRI: pituitary microadenoma

Case 2: A patient with pituitary ACTH-producing adenoma

Position of sampling ACTH (pg/ml)

Postcava 67.8

Precava 84.1

Right internal jugular vein 76.3

Left internal jugular vein 75.0

Right inferior petrosal sinus 82.2

Left inferior petrosal sinus 139.9

Right sigmoid sinus 78.4

Left sigmoid sinus 71.0

• Inferior petrosal sinus sampling:

Case 2: Follow-up of the patient ( 2 months after surgery)

• ACTH and cortisol rhythm

• Regular menses

8:00 16:00 0:00

ACTH(pg/ml) 24.5 10.0 7.9

Cortisol(nmol/l) 82.2 11.1 6.6

• Cortisone 20mg/d

Questions for Review

• What is the definition of Cushing’s syndrome? What are the clinical manifestations of Cushing’s syndrome?

• What is the difference between Cushing’s syndrome and Cushing’s disease? What are the main types of Cushing’s syndrome?

• What is the purpose of performing a low-dose dexamethasone suppression test and what’s the rationale of this test?

Primary Aldosteronism

Definition of Primary Aldosteronism

• A syndrome associated with hypersecretion of the mineralocorticoid aldosterone by abnormal zona glomerulosa tissue of the adrenal gland.

• Hypertension, suppressed plasma renin activity (PRA), and increased aldosterone excretion characterize the syndrome of primary aldosteronism.

Cortex of the Adrenal Gland Secretes Aldosterone

Zona Glomerulosa

Zona Fasciculata

Zona Reticularis

Medulla

Causes of Primary aldosteronism

• Aldosterone-producing adenoma (APA) (35%)

• Bilateral idiopathic hyperplasia (IHA) (60%)

• Primary (unilateral) adrenal hyperplasia (PAH) (2%)

• Aldosterone-producing adrenocortical carcinoma (<1%)

• Familial Hyperaldosteronism (FH)

• Glucocorticoid-remediable aldosteronism (FH type I) (<1%)

• FH type II (APA or IHA) (<2%)

• Ectopic aldosterone-producing adenoma or carcinoma

(<0.1%)

Effects of Aldosterone

• Effects on epithelia (the classic functions)

• Sodium-retaining effect

• Water-retaining effect

• Potassium-losing effect

• Escape phenomenon

• Escape by the renal tubules from the sodium-retaining action of aldosterone

• No escape from the potassium-losing effect of aldosterone

Effects of Aldosterone on epithelia of distal tubule

Effects of Aldosterone

• Effect on nonepithelial cells

• Mineralocorticoid receptor identified in a number of nonepithelial cells (e.g., neurons, myocytes, endothelial cells, vascular smooth-muscle cells)

• Mediating the expression of several collagen genes; genes controlling tissue growth factors (e.g., TGF-β, and PAI-1); or genes mediating inflammation.

• Leading to microangiopathy, necrosis (acutely), and fibrosis in various tissues such as the heart, the vasculature, and the kidney

Effects of Aldosterone

• Excess aldosterone secretion

• Causeing hypertension through two main mechanisms:

• Mineralocorticoid-induced expansion of plasma and extracellular fluid volume.

• Increasing in total peripheral vascular resistance.

• Causing hypokalemia

• Target organ damage (heart and kidney)

Regulation of Aldosterone Secretion

• Factors regulating aldosterone secretion

• Renin-angiotensin system

• Potassium ion

• ACTH

Renin-Angiotensin-Aldosterone System

Macula densa

Regulation of Aldosterone Secretion

The interrelationship of the volume and potassium feedback loops on aldosterone secretion

Clinical Features of Primary Aldosteronism

• Hypertension and excess aldosterone

• Left ventricular hypertrophy

• Damage of cerebral circulation

• Impairment of retinal vasculature

• Damage of kidney

Clinical Features of Primary Aldosteronism

• Potassium depletion and hypokalemia

• Weakness and fatigue

• Polyuria and polydipsia

• Metabolic alkalosis

• Palpitations

• ECG:

• prominent U waves

• cardiac arrhythmias

Diagnosis of Primary Aldosteronism

• Diagnostic criteria

• Hypertension

• Hyposecretion of renin (low plasma renin activity) that fails to increase appropriately during volume depletion

• Hypersecretion of aldosterone that does not suppress appropriately in response to volume expansion

Diagnosis of Primary Aldosteronism

• Functional diagnosis

• Screening tests

• Confirmatory tests

• Etiological diagnosis

• Subtype evaluation tests

Functional Diagnosis - Screening tests

Functional Diagnosis - Confirmatory tests

• To determine if aldosterone is secreted autonomously by examining

• if secretion of aldosterone can be suppressed appropriately in response to volume expansion.

• if aldosterone secretion is regulated by renin-angiotensin

Functional Diagnosis - Confirmatory tests

• Oral sodium loading test

• Sodium load and volume expansion

• Intravenous saline infusion test

• Sodium load and volume expansion

• Fludrocortisone suppression test

• A synthetic corticosteroid with potent mineralocorticoid effect

• Sodium retention and volume expansion

• Captopril challenge test

• An angiotensin-converting enzyme inhibitor

• Blocking the synthesis of angiotensin Ⅱ

Regulation of Aldosterone Secretion

The interrelationship of the volume and potassium feedback loops on aldosterone secretion

Functional Diagnosis - Confirmatory tests

• Intravenous saline infusion test

• Patients stay in the recumbent position for at least 1 h before and during the infusion of 2 liters of 0.9% saline iv over 4 h, starting at 08:00-09:30 h.

• Blood samples for renin, aldosterone, cortisol, and plasma potassium are drawn at time zero and after 4 h, with blood pressure and heart rate monitored throughout the test.

• Postinfusion plasma aldosterone levels < 5 ng/dl make the diagnosis of PA unlikely, and levels >10 ng/dl are a very probable sign of PA. Values between 5 and 10 ng/dl are indeterminate.

• This test should not be performed in patients with severe uncontrolled hypertension, renal insufficiency, cardiac

insufficiency, cardiac arrhythmia, or severe hypokalemia.

Etiological diagnosis - Subtype evaluation tests

• To determine the hypersecretion of aldosterone is due to

• Unilateral lesion: a unilateral adenoma (APA) or primary adrenal hyperplasia (PAH)

• Bilateral lesion: bilateral idiopathic hyperplasia (IHA)

Diagnosis of Primary AldosteronismSubtype evaluation tests

• Adrenal computed tomography / magnetic resonance imaging

• Unilateral macroadenoma (>1cm)

• Unilateral microadenoma (≤1cm)

• Adrenal thickening/nodularity (unilateral or bilateral)

• Normal-appearing adrenals

Diagnosis of Primary AldosteronismSubtype evaluation tests

• Adrenal venous sampling

• The reference standard test to differentiate unilateral from bilateral disease in patients with primary aldosteronism

• Dividing the right and left adrenal vein PACs by their respective cortisol concentrations (cortisol-corrected aldosterone)

• A cutoff of the cortisol-corrected aldosterone ratio from high side

to low side more than 4:1 indicating unilateral aldosterone excess(APA or PAH)

Diagnosis of Primary AldosteronismSubtype evaluation tests

Differential Diagnosis – Primary or Secondary Aldosteronism?

Plasma renin activity is useful to distinguish between primary or secondary aldosteronism

Treatment of Unilateral Hypersecretion of Aldosterone

• Unilateral hypersecretion of aldosterone

• Aldosterone-producing adenoma (APA)

• Primary adrenal hyperplasia (PAH)

• Unilateral adrenalectomy

• Normalization of hypokalemia in all

• Hypertension is improved in all and is cured in approximately 30% to 60% of them

Treatment of Bilateral Idiopathic Hyperplasia

• Pharmacologic treatment

• Aldosterone receptor blocker

• Spironolactone (non-selective aldosterone receptor blocker)

• Antagonist at the testosterone receptor (painful gynecomastia, erectile dysfunction, and decreased libido in men)

• Agonist at the progesterone receptor (menstrual irregularity in

women )

• Eplerenone (selective aldosterone receptor blocker)

• Other antihypertensive agents

• Adrenalectomy seldom corrects the hypertension

A patient with aldosterone-producing adenoma

• History:

• Female

• 33-year old

• 8-month history of hypertension

• Two antihypertensive medications administered

• Blood pressure level: 140/90mmHg

• Symptoms:

• fatigue, increased nocturia

• Laboratory:

• potassium 3.5 mmol/L

A patient with aldosterone-producing adenoma

•ARR 236

•Captopril challenge test

•Intravenous saline infusion test

•Functional diagnosis: primary aldosteronism

•Localization: aldosterone-producing adnoma of the right adrenal

A patient with aldosterone-producing adenoma

Unilateral adrenalectomy by laparoscopy

Pathologic diagnosis:

aldosterone-producing adenoma

CCB and ARB discontinued. Spironolactone 240mg qd

CCB

+ARB

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Follow-up of the patient

Questions for Review

• What is the definition of Cushing’s syndrome? What are the clinical manifestations of Cushing’s syndrome?

• What is the difference between Cushing’s syndrome and Cushing’s disease? What are the main types of Cushing’s syndrome?

• What is the purpose of performing a low-dose dexamethasone suppression test and what’s the rationale of this test?

Thank you!