Adrenocortical Functions - 2

Adrenocortical hypofunctionAdrenocortical hypofunction

Adrenocortical insufficiency may be:

A. Primary

B. Secondary

A. Primary adrenocortical A. Primary adrenocortical insufficiencyinsufficiency ( (Addison's Addison's diseasedisease))

• Autoimmune adrenalitis.

• Infective (e.g. TB, CMV, histoplasmosis,

meningococcal).

• Secondary tumor deposits.

• Infiltrative lesions (e.g. amyloidosis,

hemochromatosis).

• Congenital adrenal hyperplasia or hypoplasia.

• Drugs (e.g. etomidate).

B. Secondary to pituitary B. Secondary to pituitary diseases :diseases :

• Congenital deficiency (isolated or with GH deficiency)

• Pituitary tumors (functional or nonfunctional)

• Infections (e.g. TB, Syphilis)

• Secondary tumor deposits

• Vascular lesions (e.g. postpartum hemorrhage)

• Trauma

• Iatrogenic (e.g. surgery or radiotherapy)

• Secondary to hypothalamic disease

• Others

Clinical features of suspected Clinical features of suspected adrenocortical hypofunctionadrenocortical hypofunction

Patients with primary adrenal failure usually have

deficiencies of both glucocorticoids and

mineralocorticoids.

– In primary adrenal failure : patient present with

– Lethargy, weakness, nausea, weight loss, hypotension

and hyperpigmentation.

– Hypoglycemia, hyponatremia, hyperkalemia, s. urea

levels and acid-base disturbance.

The hypotension and electrolyte abnormalities are generally

less severe in secondary adrenal insufficiency with

preservation of aldosterone secretion

• Relatively straightforward.

• Patients should be immediately referred to hospital.

• Blood should be collected for basal measurements of plasma urea, electrolytes, glucose, serum cortisol and plasma ACTH before the patient is given cortisol.

Investigations of suspected Investigations of suspected adrenocortical hypofunctionadrenocortical hypofunction

A. Diagnosis of primary adrenal A. Diagnosis of primary adrenal hypofunctionhypofunction ((Addison's diseaseAddison's disease))

1.1. Cortisol and ACTH measurements:Cortisol and ACTH measurements:• A normal serum [cortisol] at 8 a.m. (or normal 24-hour

urinary free cortisol) does not exclude Addison's disease.

• At 8-9 a.m: – A serum [cortisol] < 50 nmol/L Addison's disease– A serum [cortisol] > 550 nmol/L exclude

hypofunction

• Simultaneous measurement of cortisol and ACTH improves diagnostic accuracy.

serum cortisol (< 200 nmol/L) and ACTH (> 200 ng/L) diagnostic of adrenal failure.

2. Short tetracosactrin2. Short tetracosactrin (Synacthen) test :(Synacthen) test :

• Stimulation of the adrenal cortex with synthetic ACTH (tetracosactrin, Synacthen) allows :

– Confirmation of the diagnosis of Addison's disease

– Assessment of adrenocortical reserve.

Short tetracosactrin (Synacthen) Short tetracosactrin (Synacthen) .. contd.. contd

Procedure:• I.M injection of 0.25 mg tetracosactrin. • Basal cortisol is measured and further

measurement is taken 30 minutes after the IM injection.

Results:• Normal response is defined as a rise in serum

[cortisol] to at least 500 nmol/L.• Addison’s disease: No response + ACTH • 2ry hypofunction: No response + ACTH

• Interpretation of results:• A normal response excludes primary

adrenocortical insufficiency.

• Failure of cortisol to respond to Synacthen, plus plasma ACTH, confirms primary adrenocortical insufficiency.

• 2ry hypofunction (hypothalamic or pituitary disease) is also extremely unlikely if the response is normal ( because adrenal cortex cells atrophied after prolonged absence of ACTH).

Short tetracosactrin (Synacthen) .. Short tetracosactrin (Synacthen) .. contdcontd

• Precautions:• Severe emotional stress.• Treatment with cortisols

within 12 hrs prior to the tetracosactrin injection.

• Taking estrogen-containing oral contraceptives.

• Patients with suspected Addison's disease

should receive steroid therapy that does not cross-react in the cortisol assay.

Short tetracosactrin (Synacthen) .. Short tetracosactrin (Synacthen) .. contdcontd

may invalidate the

test

B. Diagnosis of secondary B. Diagnosis of secondary adrenocortical insufficiency:adrenocortical insufficiency:

• Low serum cortisol + low plasma ACTH diagnosis of adrenocortical insufficiency secondary to hypothalamic or pituitary disease.

• The atrophied adrenocortical cells that fail to respond in the short Synacthen test can respond to the depot (long) Synacthen test.

1) Depot (long) Synacthen test:Procedure:

• Serum cortisol is measured on a basal

sample, and further samples for cortisol

are taken between 5 - 8 hours after IM

injection of 1 mg depot Synacthen / day

for 3 successive days.

Diagnosis of secondary Diagnosis of secondary adrenocortical adrenocortical insufficiency …….. insufficiency …….. contd contd ::

Interpretation of results:

• In Addison's disease, the cortisol fails to rise above 600 nmol/L.

• In Secondary adrenocortical insufficiency, a stepwise increase in the cortisol response.

HyperaldosteronismA) Primary hyperaldosteronism

(Low-renin hyperaldosteronism): It is a rare cause of hypertension• Causes:

1. Conn’s syndrome ( 65 % of cases).- Unilateral aldosterone - producing adenoma- Aldosterone is autonomus and unresponsive to AII but adenoma

retains diurnal rhythm and responds to changes in ACTH.

2. Idiopathic aldosteronism (32- 45 %) - Bilateral nodular adrenal hyperplasia - Aldosterone secretion by these nodules are sensitive to AII and

such patients show an exaggerated increase in aldosteone secretion when they move from supine to erect position.

3. Glucocorticoid suppressible hyperadosteronism (GSA) (<1%) - Autosomal dominant inherited disorder produced by hybrid gene

(11 β- hydroxylase + aldosterone synthase ) which allows aldosterone to be produced by Z. Fassciculata under the control of ACTH .

B) Secondary hyperaldosteronism: ( High – renin hyperaldosteronism)

• More common.

• Sometimes associated with hypertension.

• Due to conditions that stimulate renin secretion, often as a result of reduced renal Na+ filtration (e.g. congestive heart failure, cirrhosis, Na+ deprivation).

• Diuretic therapy is the commonest cause of secondary hyperaldosteronism.

– Primary hyperaldosteronism can be distinguished from secondary hyperaldosteronism by measuring PRA .

– If PRA is high the patient has secondary hyperaldosteronism.

– If PRA is low the patient may have primary hyperaldosteronism.

2. [Aldosterone] : PRA ratio :• A high plasma [aldosterone] : PRA ratio in the

supine position after an overnight fast in primary hyperaldosteronism.

1. Plasma Renin Activity (PRA):

Investigations of primary hyperaldosteronism

3. Posture test:Day 1: • A 24-h urine collection is started (for Na+, K+) and blood

is taken in the morning at about 8.30 h after the patient has remained supine for at least 30 minutes.

• Further blood is taken at approximately 12.30 h after the patient has been in the erect position for at least 1 h.

Day 2: • The patient returns the complete 24-h urine collection

and the supine /erect sampling protocol is performed again as in day 1.

Renin activity, aldosterone, cortisol , urea & electrolytes are measured in the blood sample.

Interpretation of results:

• In normal individuals:

– standing decreases renal blood flow and renin AII (The rise of AII overcomes the effect of low ACTH ) aldosterone.

– ACTH high in morning and low in evening

Interpretation of results:

Cause Plasma [Aldosterone] ratio erect 12.30 h : supine 8.30 h

Normal > 1

Conn’s syndrome < 1

GSA < 1

Idiopathic >> 1.3

Congenital adrenal hyperplasia (CAH)

• 21-Hydroxylase deficiency • An autosomal recessive condition (about 95 %

of all cases of CAH). • Impair synthesis of cortisol and aldosterone. cortisol ACTH secretion adrenal

hyperplasia. • Severe cases mineralocorticoid deficiency,

with salt and water loss adrenal crisis.• Steroids accumulate before the enzyme block

diverted to strong androgens ( androstenedione) metabolized to testosterone virilization of the female fetus & precocious puberty in boys.

Diagnosis:

• High concentration of 17-hydroxyprogesterone in a serum sample taken at least 2 days after birth.

• Treatment :• Glucocorticoids ACTH output &

androgen production.

• Mineralocorticoids.

• 17-hydroxyprogesterone should be measured for monitoring of treatment.

11 β- hydroxylase deficiency:

• Accounts for 5 % of CAH. 11-deoxycorticosterone mineralocorticoid. androgen production verilisation.

Diagnosis:• High serum concentration of 11-deoxycortisol.

Treatment:• Cortisol alone