Adrenocortical Functions - 2

Adrenocortical hypofunction Adrenocortical insufficiency may be: A.Primary B.Secondary

A. Primary adrenocortical insufficiency (Addison's disease) 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 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 adrenocortical 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 adrenocortical hypofunction

A. Diagnosis of primary adrenal hypofunction (Addison's disease) 1.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 ng/L)  diagnostic of adrenal failure.

2. Short tetracosactrin (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).. 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).. contd

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).. contd may invalidat e the test

B. Diagnosis of secondary 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 hours after IM injection of 1 mg depot Synacthen / day for 3 successive days. Diagnosis of secondary adrenocortical insufficiency …….. 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.

Hyperaldosteronism A)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 A II but adenoma retains diurnal rhythm and responds to changes in ACTH. 2. Idiopathic aldosteronism ( %) - Bilateral nodular adrenal hyperplasia - Aldosterone secretion by these nodules are sensitive to A II 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 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  A II (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 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