ADRENAL DISORDERS (Including Congenital Adrenal syndrome)

ADRENAL PHYSIOLOGY cortisol is under -ve feedback controlled by ACTH released from the anterior pituitary gland, under the control of corticotrophin – releasing hormone from the hypothalamus to stimulates the corticotrophs of the antenna pituitary to secrete the peptide pro-opiomela-nocortin (POMC) the precursor of ACTH which stimulates the adrenal cortex by binding to the melanocortin – 2 receptor (MCR-2) that is the G-protein coupled.   Activation of this system result in steroid synthesis with conversion of cholesterol into one of the three principle steroids-glucocorticoid (e.g. cortisol), mineralocorticoid (e.g. aldosterone) and androgen (e.g. testosterone). The adrenal gland has two main regions; The adrenal cortex The adrenal medulla Intrauterine life, -Cortex - cortisol & dehyroepiandrosterone. Extra uterine, -cortex differentiates into three zones. outer zone- glomerulosa middle zone-fasciculata inner zone - reticularis. 2 & 3 under hypothalamic-pituiary control and produce glucocorticoids and androgens respectively.

ADRENAL PHYSIOLOGY CONT. Angiotension II improves the renal perfusion by - increasing the production of aldosterone - Directly causing vasoconstriction - stimulating the thirst   The Aldosterone produce act in the distal convoluted tubule to cause sodium and water reabsorption in exchange for potassium or hydrogen ions. The zona glomerulosa produce mineralocorticoids (aldosterone). Its production and release is under the control of renin-release from the kidney in response to reduced renal perfusion.

ASSESSMENT OF ADRENAL FUNCTION (A) Mineralocorticoid function - Reflection of blood pressure, electrolytes and plasma renin activity e.g. Deficiency – low blood pressure, low sodium and high rennin and potassium. - Excess – elevated blood pressure and low rennin and potassium.   (B) Glucocorticoid function - Measurement of fasting 8am and sleeping midnight cortisol sample - There is loss of diurnal rhythm in excess cortisol - The consecutive 24 hours urine collection - Low dose dexamethasone suppression test - Serum ACTH level high when cortisol deficiency is due to a primary defect and low when secondary or tertiary insufficiency   (C) Androgen status Standard synacthen Test – measure basal ACTH, and steroid precursors 17, hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulphate (DHAS) and androstenedione before and 60 minutes after stimulation Other Assessment Adrenal imaging – ultrasound, CT, MRI e.g. tumour

CLASSIFICATION OF ADRENAL DISORDERS (A)Glucocorticoid (i) Excess Cushing syndrome -Primary: * Adrenal tumor * Primary micronodular Hyperplasia * Mccune – Albright syndrome -Secondary: * Pituitary Cushing disease * Iatrogenic steroid administration e.g. oral, skin preparation, intranasal Steroids, inhaled steroids * Ectopic ACTH Syndrome (A) Glucocorticoid (ii) Insufficiency -Primary: * Congenital * Congenital adrenal hyperplasia (CAH) * Adrenal hypoplasia congenital (AHC) * Familial glucocorticoid deficiency Acquired (Addison disease) * Autoimmune * Tuberculosis * Adrenoleucodystrophy * Surgery, drugs (e.g. cyproterone)  

CLASSIFICATION OF ADRENAL DISORDERS CONT (B)Mineralocorticoid (i) Excess * 10 & 20 hyperaldosteronism * Fludrocortisone overdosage * Liquorice excess * CAH CIIF and 17 hydroxylase deficiency * 11 - Hydroxy steroid dehydrogenaise (apparent excess) * Glucocorticoid suppressible hyperaldosteronism * Activating defect of epithelhal sodium channel Liddle syndrome (ii) Insufficiency -Aldosterone deficiency Congenital * AHC * CAH (21-hydroxylase, 3B hydroxyl steroid dehydrogenase and STAR protein deficiency * Aldosterone synthetase deficiency Acquired * Addison disease * aldosterone resistance (Pseudohypoaldosteronism) inactivating defect of epithehal sodium channel either recessive or severe, dominant/sporadic defect  

CLASSIFICATION OF ADRENAL DISORDERS CONT (C) Androgen (i)Excess - Exaggerated adrenarche - Virilizing Causes - adrenal tumour – cortical adenoma - - Carcinoma - CAH (21 and 11- hydroxylase deficiency) ii) Insufficient AHC 17 hydroxylase deficiency Other enzymes defect - 17, 20 desmolase - 17 Hydroxy steroid dehydrogenase  

CONGENITAL ADRENAL HYPERPLASIA

CONGENITAL ADRENAL HYPERPLASIA Introduction. This is the name given to a group of five enzyme defect causing impaired cortisol synthesis with consequent increase in ACTH secretion and adrenal enlargement -commonest - 21 hydroxylase deficiency (95% ) in which progesterone and 17OH progresterone fail to be converted to deoxycorticosterone and deoxycortisol respectively resulting in failure of production of aldosterone and cortisol with excessive androgen production. The reduction cortisol production results increase ACTH secretions which cause adrenal hyperplasia and excess precursor production as well as testosterone hyper production. 2nd commonest enzyme deficiency is that of 11.β-hydroxylase deficiency which prevents deoxycorticosterone and deoxycortisol from been converted to aldosterone and cortisol respectively  

CONGENITAL ADRENAL HYPERPLASIA

CONGENITAL ADRENAL HYPERPLASIA CLINICAL FEATURES The clinical presentation of this condition is usually in the neonatal period with Genital hypertrophy in the male and in the female with hypertrophy of the clitoris and labia, and labial fusion which may present. In more severe case with ambiguous genitalia. The genitalia may display pigmentation after several weeks because of increased ACTH secretion. Salt – losing crisis presentation is about 70% of the 21 hydroxylase deficiency variety. Episode of this crisis may be from 3-4 day of life to about three week of life with hypotension, features of dehydration, shock and collapse. There is high serum potassium and low sodium. CLINICAL FEATURES CONT. The 11β-hydroxylase deficiency present less commonly with salt- losing crisis and hypotension. -Hypertension is a more common presentation. Since the build-up of 11 deoxycorticosterone appears to protect against hypotension as well as causing hypokalaemia. This has some mineralocorticoid activity. Partial defects exists where there may be no symptoms until puberty. -delayed clinical presentation, also includes excessive growth, but because of premature epiphyseal closure the final height is lower than expected.

CONGENITAL ADRENAL HYPERPLASIA MANAGEMENT Investigation. -Urine Chromatography for raised urinary 17 ketosteroid (Androgen Metabolites) and decrease 17 hydroxycorticosteroids (cortisol metabolites) -serum-elevated 17 OH progesterone level in 21 OH deficiency and 11 deoxycortisol in 11 β hydroxylase deficiency.   Biochemical abnormalities will depend on the enzyme defect e.g- 21 OH deficiency with salt losing low sodium, low glucose, high potassium, metabolic acidosis and high urea and haematocrit. -11β hydroxylases deficiency. Hypokalaemic. Exclude other causes of ambiguous genitalia.

CONGENITAL ADRENAL HYPERPLASIA TREATMENT Resuscitation with I.V fluid such as normal saline, glucose and intravenous hydrocortisone. Long term treatment involve the use of hydrocortisone and a salt- retaining minerialocorticoid such as fludrocortisone in order to prevent continued ACTH induced hyperplasia whilst also allowing adequate replacement. -monitor treatment with serum or salivary 17 OH progesterone levels. -sex assigned and possible early in girls for surgical correction.

CUSHING SYNDRONE

CUSHING SYNDRONE CONT. CAUSES An ACTH secreting tumour of the pituitary Cushing disease. Adrenal adenona/ carcinoma secreting cortisol ↓ ACTH. Ectopic ACTH production e.g Wilim’s tumour. Hyperplasia of the zona reticularis and fasciculata (mainly reticularis) Exogenous steroid (the commonest cause)

CUSHING SYNDRONE CONT. CLINICAL FEATURES Skin –Thinning of the skin with striae, easy bruising, pigmentation; if ACTH is excess Truncker or centripetal obesity with moon face, buffalo hump, protuberant abdomen. Limb muscle wasting (leading to proximal myopathy) Hypertension- 20 Na retention cortisol has some mineralocorticoid activity with hyokalaemia and metabolic acidosis CLINICAL FEATURES CONT. Osteoporosis Peptic ulcer Glucose intolerance with diabetic mellitus. Androgen may lead to hirsutism and acne Psychiatric disturbance.  

CUSHING SYNDRONE CONT. INVESTIGATION Usually cortisol is highest at 8a.m and lowest at midnight. There is lost diurnal rhythm 24 hours urinary cortisol levels are high. Dexamethasone suppression test. INVESTIGATION CONT. Biochemical, sodium is high, potassium is low and plasma glucose may be high Insulin stress test. TREATMENT Depend on the cause and tumours may require surgery.

ADRENAL INSUFFICIENCY

ADRENAL INSUFFICIENCY Not common in childhood. May be acute or chronic.

ADRENAL INSUFFICIENCY ACUTE FORMS -20severe hypotension, trauma, sepsis, or chronic steroid use with sudden withdrawal (or failure to increase dosage with period of stress such as trauma or surgery). -Waterhouse–friederichsen syndrome (bilateral adrenal haemorrhage secondary to septicaemia most commonly resulting from meningococcemia). CHRONIC FORMS -Addison disease, tuberculosis (may be noticed as adrenal calcification on x-ray). -20 adrenal insufficiency can result from surgery, trauma, irradiation or tumour of pituitary and hypothalamus because of lack of ACTH.

ADRENAL INSUFFICIENCY CLINICAL FEATURES ACUTE Look for precipitating cause. -Hypotension -Salt loss and vascular collapse -Hypoglycaemia with metabolic acidosis. -Hyponatraemia and raised potassium.   CLINICAL FEATURES CONT. CHRONIC -Slow onset of generalized fatigue and weakness, anorexia, nausea, vomiting, abnormal pain, diarrhoea, postural hypotension and pigmentation of palmar crease and buccal mucosa, if the ACTH is high.  

ADRENAL INSUFFICIENCY INVESTIGATION ­Biochemistry –low sodium and high potassium and low blood glucose. -Normocytic- normochronic Anaemia -Serum ACTH-high in primary, low in secondary. -Synacthen test. Short –adrenal insufficiency. Long – differentiates primary (adrenal) from secondary causes (hypothalamic/pituitary cause) TREATMENT Replacement therapy with cortisol