A Young hypertensive with an endocrine cause .pptx

Young HT

1. A Young hypertensive Philip Abraham

2. A 23-year-old man is referred for further evaluation of hypertension that was first detected during a routine medical assessment for a pilot's license. His medical history is otherwise unremarkable, and he is not taking any medications. Both his father and paternal grandfather were diagnosed with hypertension at a young age; his grandfather died suddenly at age of 42 years, and his father had a myocardial infarction at age 38 years. The patient does not smoke cigarettes, drink alcohol, or consume licorice.

3. On physical examination, his height is 182.9 cm and weight is 81.6 kg (BMI = 24.4 kg/m 2 ). His blood pressure is 185/92 mm Hg, and pulse rate 68 beats/min and regular. Physical examination findings are unremarkable

4. Laboratory test results: Serum sodium= 143 mEq /L (136-142 mEq /L) Serum potassium= 3.0 mEq /L (3.5-5.0 mEq /L) Serum bicarbonate= 31 mEq /L (21-28 mEq /L) Serum creatinine= 1.0 mg/dL (0.7-1.3 mg/ dLµmol /L]) Plasma renin activity= 0.05 ng/mL per h (0.6-4.3 ng/mL per h Plasma aldosterone concentration= <2.S ng/dL (4-21 ng/dL) Urinary free cortisol= 40 µg/24 h (4-50 µg/24 h)  

5. W hich of the following is the most likely cause of this pat i ent's presentation? A. Congenital adrena l h yp e rplasia due to 1 1 ~-hydroxylase deficiency B. Gluco cor ticoid resistance s yndrom e C. Liddle s yndrome D. Pseudohypoaldosteronism type 2 (G o r don s yn d rome) E . Syndrome of apparent minera l oc o rticoid exc ess

6. This man has hypertension with unprovoked hypokalemic alkalosis, low plasma renin, and low aldosterone. Both genetic and acquired causes are recognized: Genetic: Activating variation in the mineralocorticoid receptor gene Apparent m ineralocorticoid excess 11 beta hydroxylase deficiency 17 hydroxylase/17-20 lyase deficiency Glucocorticoid resistance Liddle syndrome

7. Acquired: Deoxycorticosterone-secreting tumor High-salt diet Licorice or grapefruit juice . Low renin hypertension Nonsteroidal anti-inflammatory drugs/ cyclooxygenase 2 inhibitor Severe hypercortisolism

8. In a young patient with a strong family history (early-onset hypertension with premature cardiovascular disease), an inherited basis should be considered once dietary and medication confounders have been excluded. In this case, an autosomal dominant mode of inheritance is suggested, which potentially points to 2 disorders: ( 1) an activating variation in the mineralocorticoid receptor gene (2) Liddle syndrome

9. Activating pathogenic variant in the mineralocorticoid receptor gene Only a single family has been reported with gain-of-function of mineralocorticoid receptor Presented with early-onset severe hypertension, suppressed renin, low aldosterone, and mild hypokalemia. Mechanism -Genetic variation induces a conformational change in receptor that stabilized complexes of the mutant mineralocorticoid receptor with aldosterone, progesterone, and spironolactone, predisposing to exacerbation of hypertension in pregnancy and during treatment with spironolactone.

10. Congenital adrenal hyperplasia Option A CYP17A1 (encoding 17 a-hydroxylase and 17,20-lyase) or CYP11B1 (encoding 11 -hydroxylase) 17-hydroxylase deficiency - impaired generation of DHEA and androstenedione 46,XY pseudohermaphroditism [with female external genitalia] 46,XX primary amenorrhea with delayed sexual development). Excess progesterone is directed towards overproduction of deoxycorticosterone and corticosterone that stimulate the mineralocorticoid receptor. Presentation is typically in childhood/ adolescence. 11 -Hydroxylase deficiency leads to impaired conversion of deoxycorticosterone and 11 - deoxycortisol to corticosterone and cortisol, respectively, with resultant hypertension and virilization and precocious puberty. Presentation is usually at a young age (infancy and early childhood).

11. A pparent mineralocorticoid excess (Answer E) is rare , severe juvenile hypertension, autosomal recessive . Impaired function of the enzyme 11 -hydroxysteroid dehydrogenase type 2 required to inactivate cortisol E xcessive stimulation of the mineralocorticoid receptor by cortisol, with accompanying low plasma renin and low plasma aldosterone. In its classic form, low birth weight, failure to thrive, onset of severe hypertension in early childhood, hypercalciuria, and nephrocalcinosis. A late-onset form has been described in adults who have a milder phenotype. Chronic excessive ingestion of licorice (containing glycyrrhetinic acid and its metabolite glycyrrhizic acid) or grapefruit juice has been reported to produce a clinical picture that mimics apparent mineralocorticoid excess by inducing an acquired deficiency of 11 -HSD2.

12. Glucocorticoid resistance syndrome (Option B) is an autosomal recessive disorder caused by defective gene, which encodes the glucocorticoid receptor. End-organ insensitivity to glucocorticoid action leads to compensatory ACTH hypersecretion with increased production of cortisol, adrenal androgens, and precursors with mineralocorticoid activity ( eg , deoxycorticosterone, deoxycortisol ). The development of low­ renin hypertension is also a likely consequence of saturation of 11 -HSD2 function. Features of glucocorticoid insufficiency are usually evident and affected c hildr en may manifest precocious puberty. Twenty-four-hour ur inary free cortisol le ve l s are elevated.

13. Pseudo hypoaldosteronism type 2 ( Gordon syndrome) (Option D) A ssociated with hyperkalemia. increased trafficking of the sodium-chloride co- tr ansporter to the apical membrane of the distal convoluted tubule, with re su ltant increased reabsorption of luminal so dium c hloride. This in turn lead s to redu ced sod ium absorption more distally with accompanying decreased potas siu m and h ydrogen ion secretion, resulting in hyperkalemia and metabolic acidosis.

14. Liddle syndrome (Answer C), a low-renin hypertension , autosomal dominant transmission, gain-of-function of the epithelial sodium channel, with over excretion of potassium .Increased sodium absorption suppresses renin , aldosterone .Patients have normal urinary cortisol and normal physical examination. More than 30 different causal variants in more than 70 families have been identified. P resents with early-onset hypertension, although milder clinical phenotypes have been reported including normokalaemic variants

15. Thank you