Endocrine hypertension

A short discussion on Endocrine Causes of hypertension, clinical evaluation and few case example of endocrine hypertension.

1. Dr. Lala Shourav das DEM Student Department of Endocrinology, BIRDEM

2. Definition of Hypertension:

3. Pheochromocytoma Primary hyperaldosteronism Hyperdeoxycorticosteronism Congenital adrenal hyperplasia 11β- Hydroxylase deficiency 17α- Hydroxylase deficiency DOC-producing tumor Primary cortisol resistance Cushing Syndrome Hypothyroidism Hyperthyroidism Acromegaly Cushing Disease Due to 11β- HSD Deficiency Genetic Type 1 AME Type 2 AME Acquired Licorice or carbenoxolone ingestion (type 1 AME) Cushing syndrome (type 2 AME)

4. Clues to identify patient’s of endocrine HTN Hypertension in a young patient without positive family history of HTN. (<30 years). Hypertension and hypokalemia (even in concomitant use of diuretics). Severe Hypertension ( ≥ 160mmHg, ≥ 100mmHg). Resistant Hypertension (Uncontrolled or poorly controlled despite taking 3 antihypertensive drugs.) Fluctuating Hypertension and association with anxiety, sweating, tremor, palpitation, signs of virilization. Hypertension in adrenal Incidentaloma. Positive family history of endocrine disorder, eg: MEN, Pheochromocytoma, Thyroid diseases etc.

5. Approach to a patient with suspected Endocrine HTN Proper History Taking: Duration of HTN, aggravating factors. Transient or stable hypertension. Association with palpitation, anxiety, sweating, headache, generalized weakness or any relevant symptoms. Past medical history, including h/o renal or cardiac diseases. Family history of HTN, cardiac and endocrine disorders. Drug history, eg: antihypertensive drugs, anti thyroid drugs, steroids etc. Personal history, including smoking, recreational drug abuse, life style and stressful events.

6. Approach to a patient with suspected Endocrine HTN (cont.) Clinical Examination: Identifying HTN by measuring BP : In proper setting, relax position > 5min with empty bladder. The patient should avoid caffeine, exercise, and smoking for at least 30 min before measurement. Remove all clothing covering the location of cuff placement. Neither the patient nor the observer should talk during the rest period or during the measurement. Documentation of least 2 reading of HTN in different occasion, with proper BP measuring calf's (particularly in case of children and plotting it against age related BP chart, >95 th Percentile) before declaring patient it hypertensive. Other relevant examinations: General: Pulse, Skin condition, Pigmentation, features of Cushing syndrome, acromegaly, Thyroid gland and status etc. Systemic Examination: Cardiovascular system to exclude Cardiovascular cause of HTN and find out any target organ damage. Renal system : Relevant examinations, including renal bruits. Abdominal Examinations : Special care if Pheochromocytoma is suspected as deep palpation may aggravate a hypertensive crisis. Neurological: Features of myopathy.

7. Features that warrants investigations for Pheochromocytoma Spell Related Symptoms: Anxiety and fear of impending death Diaphoresis Dyspnea Epigastric and chest pain Headache Hypertension Nausea and vomiting Pallor Palpitation (forceful heartbeat) Tremor Chronic Signs and Symptoms Fatigue General increase in sweating Hypertensive retinopathy Hyperglycemia Resistant Hypertension Orthostatic hypotension Congestive heart failure Painless hematuria Weight loss Not Typical of Pheochromocytoma Flushing A familial syndrome that predisposes to catecholamine secreting tumors (e.g., MEN2, NF1, VHL, Carney triad)

8. Suspected Pheochromocytoma case Source: William’s Endocrinology, 13 th Edition Foods: Banana, Caffeine, pineapple, walnut, chocolates etc.

9. Calcium Channel Blockers : Nicardipine, Target BP : 130/80mmHg Arrhythmia managed by Lidocaine, Esmolol . The treatment of choice for Pheochromocytoma is complete surgical resection. It often may provide a cure for endocrine Hypertension. Treatment of Pheochromocytoma

10. Features that warrants investigations for Primary hyperaldosteronism: Hypertension and hypokalemia Resistant hypertension Adrenal Incidentaloma and hypertension Onset of hypertension at a young age (<20 y) Severe hypertension (> 160/100 mm Hg) Hypokalemia is frequently absent (Only present in up to 33% cases) and may evident only with the addition of a potassium-wasting diuretic. Primary Hyperaldosteronism has significantly higher rate of cardiovascular events (e.g ., stroke, atrial fibrillation, myocardial infarction) than the patients with essential hypertension. Whenever considering secondary hypertension Periodic paralysis (more common in Asian population). Tetany associated with the decrease in ionized calcium with marked hypokalemic alkalosis. (Rare)

11. 3 steps of evaluation in primary Hyperaldosteronism Intravenous Saline Infusion Test: The test is done after an overnight fast. Two liters of 0.9% sodium chloride solution is infused intravenously with an infusion pump over 4 hours with the patient recumbent . At the completion of the infusion, blood is drawn for measurement of PAC. 10 ng/dl = Primary hyperaldosteronism Confirmed. 5-10 ng/dl = ? IHA < 5ng/dl = Normal In our settings, we interpret high value of reference range comparing to baseline PAC as positive result. Salt Loading Test.

12. Principles of treatment in primary Hyperaldosteronism Normalization of blood pressure should not be the only goal . The treatment goal is to prevent the morbidity and fatality associated with hypertension, hypokalemia, and cardiovascular damage. Normalization of circulating aldosterone or mineralocorticoid receptor blockade should be part of the management plan for all patients with primary aldosteronism . Surgical Treatment of Aldosterone-Producing Adenoma and Unilateral Hyperplasia Pharmacologic Treatment for IHA and Glucocorticoid-Remediable Aldosteronism Primary Hyperaldosteronism 40% patient may have persistent HTN even after surgery Mineralocorticoid receptor antagonist: Spironolactone/ Eplerenone ACTH suppressive Steroid for GRA

13. OTHER FORMS OF MINERALOCORTICOID EXCESS OR EFFECT Congenital Adrenal Hyperplasia: Approximately 90% of CAH cases are caused by 21-hydroxylase deficiency, which does not result in hypertension . Deficiencies of 11 β- hydroxylase or 17 α- hydroxylase cause hypertension and hypokalemia because of hypersecretion of the mineralocorticoid DOC . These mutations are autosomal recessive in inheritance and typically are diagnosed in childhood . However, partial enzymatic defects have been shown to cause hypertension in adults . Confirmatory testing includes germline mutation testing. Others: Deoxycorticosterone-Producing Tumor (usually malignant) Primary Cortisol Resistance (rare)

14. Apparent Mineralocorticoid Excess Syndrome AME is the result of impaired activity of the microsomal enzyme HSD11B2, which normally inactivates cortisol in the kidney by converting it to the inactive 11-keto compound, cortisone . Cortisol can be a potent mineralocorticoid, and when HSD11B2 is genetically deficient or its activity blocked, high levels of cortisol accumulate in the kidney and stimulate mineralocorticoid receptors. C/F includes: HTN, hypokalemia, metabolic alkalosis , low renin, low aldosterone, and normal plasma cortisol levels . The diagnosis of apparent mineralocorticoid excess is confirmed by demonstration of an abnormal (high ) ratio of cortisol to cortisone in a 24-hour urine collection. Treatment: Mineralocorticoid receptor blocker or ACTH suppressive Steroid.

15. Hypertension in other endocrine disorders Cushing syndrome Mechanism of HTN in Cushing syndrome: Increased production of DOC Enhanced pressor sensitivity to endogenous vasoconstrictors (eg: Epinephrine, Angiotensin-II) Increased cardiac output. Activation of RAA system by increased production of hepatic angiotensinogen Overload of cortisol inactivation system in kidney with Mineralocorticoid receptor stimulation. Detection with appropriate protocol and subtype detection Treatment of specific Cause Surgical approach if possible. Pharmacological approach Mineralocorticoid receptor blocker Diuretics Other antihypertensive

16. Hypertension in other endocrine disorders Hyperthyroidism: E xcessive amounts of circulating thyroid hormones interact with thyroid hormone receptors on peripheral tissues, resulting in increase of both metabolic activity and sensitivity to circulating catecholamines. Thyrotoxic patients usually have tachycardia, high cardiac output, increased stroke volume , decreased peripheral vascular resistance, and increased systolic blood pressure. The initial management in patients with hypertension and hyperthyroidism includes use of a β-adrenergic blocker. The definitive treatment of hyperthyroidism is cause-specific.

17. Hypothyroidism The frequency of hypertension (usually diastolic ) is increased threefold in hypothyroid patients. The mechanisms for the elevation in blood pressure include increased systemic vascular resistance and extracellular volume expansion . Treatment of thyroid hormone deficiency decreases blood pressure in most patients with hypertension and normalizes blood pressure in one third of them. Hypertension in other endocrine disorders

18. Hypercalcemia and Primary Hyperparathyroidism: Hypercalcemia is associated with an increased frequency of hypertension. The mechanisms of hypertension are unclear because there is no direct correlation with the elevated parathyroid hormone or calcium levels . The treatment of primary hyperparathyroidism is surgical. Acromegaly: Hypertension occurs in 20% to 40% of the patients with acromegaly and is associated with sodium retention and extracellular volume expansion. If a surgical cure is not possible, the hypertension usually responds well to diuretic therapy . Other endocrine & Metabolic Disorders like DM, Obesity can also cause HTN indirectly. Hypertension in other endocrine disorders

19. Endocrine HTN in clinical scenario (case-1) Mrs. X, 26 years old female with h/o HTN for 1 years and DM for 6 months during evaluation of secondary causes of HTN found to have biochemical hypercortisolism (unsuppressed ONDST, raised 24hr urinary free cortisol) with clinical features of Cushing like generalized weakness, body ache and features of proximal myopathy. She was also found to be hypertensive, BP >160/90mmHg and poorly controlled by antihypertensive drug along with Hypokalemia. Grade –III hypertensive changes were found in retina. She was diagnosed as a case of endogenous Cushing syndrome with HTN. After biochemical confirmation, for control of Hypertension and hypokalemia Spironolactone was started, which normalized her BP and Electrolyte imbalance. Lateralization studies for Cushing disease for specific management is ongoing and patient is in regular follow up.

20. Mrs. Y, 60 years old female patient with recurrent episode of headache and palpitation for 2 months and BP fluctuation for same duration presented with and USG of W/A and CT Scan of Abdomen which was suggestive of Left adrenal mass. After proper evaluation, we diagnosed her as a case of suspected Pheochromocytoma. Proper preoperative management was done. Surgery was uneventful, and patient remained normotensive after laparoscopic adrenalactomy. Histopathology report from adrenal mass was suggestive of Pheochromocytoma. Endocrine HTN in clinical scenario (case-2)

21. Points to remember

22. References: Greenspan's Basic and Clinical Endocrinology, 10 th Edition Williams Textbook of Endocrinology, 13 th Edition AHA guideline 2017 for management of HTN, https://goo.gl/w8Zx4H