Clinical Case PresentationA Case Of Dehydration Capt Arabinda Mohan Bhattarai Guide: Lt Col Mithu Banerjee
Case History• 29 days male child• Product of a nonconsanguineous marriage• Brought to a tertiary centre with complaints of: Increased crying spells Lip smacking Passage of urine more than 40 times a day Increase tan of the skin
Case history..• The mother, gave history that the baby was always hungry and thirsty.• On 18th day of birth the child developed severe vomiting treated with antiemetics.• The baby became lethargic and severely dehydrated hence referred
Diagnosis• Based on these facts high index of suspicion of salt losing type of congenital Adrenal Hyperplasia was made.• 17 OH progesterone was 240ng/mL [ 0.10-9.4 ng/mL for age group 3 days- 2 months]• This test confirmed the diagnosis of Congenital Adrenal Hyperplasia
Adrenal glands..• Each adrenal gland has two distinct structures Outer cortex Inner medulla• Cortex consists of : Glomerulosa( 10-15% of cortex) Fasciculata( 75% of cortex) Reticularis( 5-10% of cortex)
Adrenal cortex Mineralcorticoids Glucocorticoids Androgens Adrenal MedullaEpinephrine and norepinephrine
Biosynthesis of Adrenocortical Hormones• Cholesterol ester-----esterase-->free cholesterol + FFA• sTAR ( steroidogenic acute regulatory protein)- --> transports cholesterol to mitochondria (rate limiting step).• In the mitochondria cholesterol is converted to Pregnenolone by 20 α hydroxylase
Adreno-cortical Hormones in Circulation• Steroid hormones are 90-95% bound to specific carrier protein or albumin.• Steroid sulfated / glucuronidated circulate unbound in plasma• 80-90% of cortisol is carried by Corticosteroid Binding Globulin( CBG)
Metabolism of Adrenal Steroids• Major site of steroid metabolism is P450 system in the liver.• Clearance of steroid hormones involve: HydroxylationDehydrogenationReduction of double bondsConjugation to sulfates and glucuronides
Urinary metabolites• Urinary excretion of these metabolites are helpful in the estimation of adrenal disease Hydroxylation• 17 OH progesterone- pregnanetriol.• 24- hr urine estimation was done for estimation of pregnantriol before the advent of immunoassay for diagnosis of CAH
Urinary metabolites…• Urinary metabolites of 11-deoxycortisol and cortisol (17 hydroxycorticosteroids )have been used to differentiate between 21 or 11 hydroxylase deficiency.• Both are decreased in 21 α hydroxylase deficiency, whereas deoxycortisol increased in 11 β- hydroxylase deficiency
Introduction• Congenital Adrenal Hyperplasia ( CAH) is the most common cause of adrenocortical insufficiency in newborns.• It presents with a mixed picture of cortisol deficiency and adrenal androgen overproduction.
Cause• CAH results from loss of function mutations in specific adrenocortical enzymes responsible for the synthesis of cortisol.• Inherited as autosomal recessive trait• 21-Hydroxylase deficiency which is one of the most common defects of adrenal steroidogenesis.
Cause..• Insufficient cortisol production increase in ACTH concentration- stimulate the adrenal hyperplasia in utero .• Incidence of 21 alpha hydroxylase CAH in western societies varies from 1 in 5000 to 15,000 live births
Cause..• 95% of CAH result from 21 alpha hydroxylase and remaining 11 beta hydroxylase deficiency.• Screening for these enzyme deficient newborn measure 17-alpha- hydroxyprogesterone (17-OHP)
Cause..• The metabolic block in cortisol biosynthesis leads to an accumulation of precursors of adrenal androgens.• Measurement of precursor steroid is helpful in identifying the specific enzyme defect.
Cause..• A partial block in enzyme activity may cause marked or subtle clinical manifestation, whereas complete enzyme block is incompatible with life• The closer the block to the final cortisol production, less life threatening are the symptoms
Cause..• There are two 21-hydroxylase genes in man, A and B.• Only the 21-hydroxylase B gene is thought to be active
Cortisol Deficiency• Malaise• Failure to thrive• Hypoglycemia• Vascular instability• Approx 75% of classic 21-hydroxylase deficiency have severe aldosterone deficiency and are prone for hyperkalemia especially in infancy
Investigations• Patients with salt- wasting form are identified through the measurement of serum electrolytes, aldosterone, plasma renin and potassium levels.
Diagnosis• Females of congenital adrenal hyperplasia due to 21-hydroxylase deficiency are easy to diagnose in the new born period due to ambiguous genitalia.• Males are diagnosed either a few weeks later due to a salt losing crisis resulting in dehydration, vomiting, hyponatremia and hyperkalemia
Diagnosis..• Basal 17- hydroxyprogesterone values measured by RIA exceeds 10,000 ng/dL in affected infants, [N 100ng/dL]
Diagnosis..• Fetal DNA testing helps in the prenatal diagnosis of CAH.• Maternal treatment with high dose of dexamethasone can supress excess fetal androgen production which prevents ambiguous genitalia .
11- Beta Hydroxylase Deficiency• Due to mutations of 11- Beta Hydroxylase• Mineralocorticoid deficiency doesn’t occur• Females present with ambiguous genitalia• Boys present with precocious pseudopuberty
17-alpha hydroxylase• 17 alpha hydroxylase deficiency is a rare cause of CAH.• In the absence of 17-alpha hydroxylase activity, there exists an obstruction to cortisol and sex hormones biosynthesis
3-β OHSD• This is a non P450 enzyme that converts delta(5) to delta(4) steroids.• Gonads share this pathways with the adrenal glands.• Male fetuses are undervirilised as a result of deficient testosterone production.
Treatment• Patients with 21- alpha hydroxylase deficiency CAH, aldosterone is replaced with oral fludrocortisone.• Adequacy is assessed by patients BP and renin estimation• Effectiveness of treatment is judged on the basis of the presence or absence of normal linear growth and suppression of 17-OHP and androgens