SECONDARY HYPERTENSION

Pathophysiology & Therapeutics, I (MSPR 521) Lecture No. 14

Donna Hanes, M.D.

dhanes@medicine.umaryland.edu

November 29, 2011 (11:00 - 11:50 am)

LEARNING OBJECTIVES: After having completed this section, the student should be able to: 1. Describe the clinical and pathophysiologic aspects of important forms of secondary hypertension. 2. List the most common causes of secondary hypertension. 3. Describe the clinical features, the hypertensive mechanisms, the diagnostic approach and the mode of treatment of secondary forms of hypertension involving the renin-angiotensin-aldosterone system and catecholamine secretion.
READING ASSIGNMENT: Robbins and Cotran: Pathologic Basis of Disease, 7 Ed., 525530. Cecil Textbook of Medicine, 6th Ed.
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Supplemental Reading:

OUTLINE I. Prevalence & Etiology of Hypertension A) Prevalence: 15-20% of population worldwide, and ~60 million people in the US have hypertension Greater prevalence in Blacks and elderly B) Etiology: Primary HTN (unknown etiology) = 90% *Secondary HTN (underlying problem) = 10% o *Chronic kidney disease (CKD) = 5% ( of all secondary HTN cases!) o Renovascular disease = 4% o Adrenal disease = 0.5% o Pheochromocytoma = 0.2% o Genetics causes o Obstructive sleep apnea (OSA) *Consider secondary causes of HTN if a patient presents with HTN of less than 1 year in duration (vs. primary HTN occurs much more gradually)

This lecture deals with the classical secondary endocrine forms of hypertension related to abnormal function of the renin-angiotensin aldosterone system, (renal artery stenosis and mineralocorticoid excess) and to excess catecholamine production (pheochromocytoma).

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II.

Chronic kidney disease (CKD): scarring of the renal parenchyma # of functional nephrons *#1 cause of secondary HTN makes up 50% of all cases Pathophysiology: # of functional nephrons poor control of H2O and Na+ balance HTN! o May be a result of other diseases such as SLE or diabetes o Clear relationship between high BP and development of ESRD **BP goals: o Patients w/ CKD: <130 / 85 mmHg o Patients w/ CKD + proteinuria: < 125 / 75 mmHg **Treatment: ACE inhibitors & ARBs must be used (especially in pts. with proteinuria) to control BP and slow progression of renal failure not doing so can be grounds for malpractice! Renal artery stenosis a.ka. renovascular hypertension (RVH): HTN resulting from abnormal function of the RAAS Classical example of renin-mediated, angiotensin-II dependent 2 hypertension with secondary hyperaldosteronism Narrowing of the renal artery renal perfusion (under-perfused kidney) GFR *inappropriate activation of RAAS*: renin angiotensin-II aldosterone result: systemic BP o Angiotensin-II released will constrict the efferent arteriole maintains GFR & renal perfusion o *Removal of A-II (ex: ACE inhibitor) no efferent arteriole constriction GFR deterioration of renal function ACE inhibitors are absolutely contraindicated in pts. with renal artery stenosis!**

III.

*Key features: o ** [renin] due to compromised renal perfusion via the renal artery & inappropriate activation of RAAS, not seen in primary HTN! o ** [Angiotensin-II] Administration of captopril (ACE inhibitor): blocks A-II production o Renal (abdominal) bruit o Hypokalemia = plasma [K+] < 3.5 o Smokers (more common) *2 types of renal artery stenosis both characterized by high [renin] and often renal bruits: o Atheroma: RVH due to atherosclerosis (plaques) Older adults (>50 y/o) o Fibromuscular dysplasia (FMD): RVH due to fibromuscular displasia Young females *Abdominal bruits: suggestive of renal artery stenosis, but not purely diagnostic (can occur in normal patients and not always present) Reduce blood flow to kidney reflex RAAS BP *ACE Inhibitors contraindicated (GFR) Diagnosis: o **Captopril renal scan: measurement of plasma [renin] both at before and following an oral dose of captopril (ACE inhibitor) Primary (essential) HTN: administration of captopril is followed by no significant change in plasma [renin] indicates non-RAASmediated HTN! vs. *Renal artery stenosis: administration of captopril is followed by a marked plasma [renin] and BP indicates that the HTN is mediated by RAAS (renal artery stenosis)! Unilateral stenosis: radiotracer activity in the stenotic kidney

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will rise slower and peak later in comparison to the unaffected kidney!

Renal angiography: allows visualization of regions of renal artery stenosis and delayed uptake of contrast dye

Treatment: o **Renal balloon angioplasty: balloon used to open up the stenotic renal artery, with or without stent placement Much more successful for patient with FMD than atheromas! Results in significantly improve serum [creatinine] o *Medical therapy

IV.

Adrenocortical Diseases: all have low [Angiotensin-II] due to (-) feedback on the RAAS will show no response to ACE inhibitors (ex: captopril)! Aldosterone: autonomously produced in the adrenal cortex, acts on DCT in the

kidney to: o Na+ & H2O reabsorption BP, volume expansion, hypernatremia = plasma [Na+] o H+ & K+ secretion hypokalemia = plasma [K+] , slight alkalosis * [aldosterone] causes (-) feedback on the RAA loop: plasma [renin] [A-II] *Since aldosterone secretion from the adrenal cortex is autonomous, its secretion is independent of A-II stimulation therefore, [aldosterone] remains elevated despite [A-II]!

A) Primary (1) aldosteronism: excessive aldosterone secretion resulting from adrenocortical adenoma or adrenocortical hyperplasia **DIAGNOSTIC CLUES for primary (1) aldosteronism o HTN + low plasma [K+] o Plasma [aldosterone] / [renin] >25 Key features: classic form of low-renin HTN o * plasma [renin] o * plasma [K+] = hypokalemia (but urinary [K+] as a direct result of K+ secretion) o * plasma [aldosterone] Etiology: results from 2 types of adrenal gland abnormalities: o Adrenal adenoma: unilateral venous [aldosterone] Rx: surgery o Adrenal hyperplasia: usually bilateral venous [aldosterone] Rx: medical management

Diagnosis: o *Lasix (furosemide) stimulation test: Normal: plasma [renin] due to Na+ and H2O depletion ** 1 aldosteronism: suppression of plasma [renin] = remains unchanged b/c aldosterone suppresses renin secretion o *Saline stimulation test: Normal: plasma [aldosterone] due to high Na+ load & volume expansion ** 1 aldosteronism: no change in plasma [aldosterone] = continuous secretion of aldosterone o *Spironolactone stimulation test: spironolactone acts as a aldosterone receptor blocker (diuretic)

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Normal: no or little BP ** 1 aldosteronism: BP tells you that the HTN is a secondary result of high aldosterone levels!

B) Apparent mineralocorticoid excess syndrome: when excessive plasma [cortisol] begins to compete with aldosterone to activate the on the renal mineralocorticoid receptor tested a lot on Step 1! Normally: aldosterone (mineralocorticoid) receptor in the renal DCT responds only to aldosterone and does not bind cortisol (glucocorticoid) because the enzyme 11-HSD breaks down cortisol (active) cortisone (inactive) *Pathologic: if 11B-HSD is defective or inhibited by a genetic deficiency or *black licorice* or *chewing tobacco*, it will lead to build-up of active cortisol substrate high amounts of cortisol will be able to bind and activate the mineralocorticoid receptor result: Na+ retention & K+ excretion (just like actions of aldosterone) o *Key features: plasma [aldosterone] plasma [cortisol] o Treatment: spironolactone (mineralcorticoid receptor blocker), dexamethasone ( suppresses ACTH upregulation of cortisol)

C) Other monogenic determinants of hypertension NOT ON EXAM! Congenital adrenal hyperplasia (CAH) Liddles syndrome V. Pheochromocytoma: catecholamine-secreting tumor of the adrenal medulla Etiology: produces surges of NE/Epi (catecholamines) activates -receptors and -receptors widespread VASOCONSTRICTION BP (malignant HTN) Key features: very rapid & dramatic onset of high BP, headache, HR (tachycardia), pallor, anxiety, sweating, abnormal chest pain o Usually only goes on for up to a few weeks before it comes to medical attention o Can be FATAL due to end-organ damage due to malignant HTN! Diagnosis: o ** plasma [metanephrines] specifically plasma [VMA] o MRI scan: pheochromocytomas will light up (white)

Treatment: surgical tumor removal after careful premedication medical management (ABCs of pheochromocytoma treatment) o BP (hypertension): - blockers (A) o Tachyarrhythmias: -blockers (B) after - blockers o catecholamines production: catecholamine synthesis inhibitor (C): methyl P-tyrosine Complications: o Hypertensive crisis Rx: IV -blocker (phentolamine) o Hypotension (post-op?) Rx: IV norepinephrine

VI.

Obstructive Sleep Apnea (OSA): intermittent periods of asphyxia during sleep, with marked BP elevation *Key features: o Intermittent asphyxia (over 100 episomes/night) o Sleep fragmentation o Daytime hypersomnolence o **Marked BP (50% of cases) predisposition to CV morbidity! Etiology: airway can close off at night (due to anatomic abnormalities or excess fat), PCO2 = hypercapnea (pt. stops breathing on avg for 6-10 sec each time, at least 100x/night) metabolic alkalosis patient awakes with a surge of sympathetic activation BP o **If you fix the sleep apnea, the HTN goes away! Treatment: o Weight loss = major improvement in symptoms! o Positive pressure breathing devices (CPAP)

VII.

*CLUES TO A DIAGNOSIS OF SECONDARY HYPERTENSION* Age of onset: Before age 30, after age 50 (atypical for essential hypertension) Sudden deterioration in apparently stable essential hypertension Level of BP: Stage III hypertension = BP >180/110mmHg Presence of target organ damage: Optic fundal hemorrhages and exudates (Grade III) Serum [creatinine] > 1.5mg/dl

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Left ventricular hypertrophy Episodes of paroxysmal nocturnal dyspnea Special clinical features: Hypokalemia Abdominal bruit Variable or paroxysmal BP Associated headache, tachycardia, sweating Strong family history Heavy smoker Poor or inappropriate response of BP or serum [creatinine] with routine antihypertensive therapy

Screening for 2 hypertension involving the RAAS

Baseline Plasma Aldosterone/Renin

high aldo high renin

high aldo low renin Adrena -Adenoma - Hyperplasia -Carcinoma Familial (GRA)

low aldo low renin Apparent Mineralocorticoid Excess Syndrome Cushings Syndrome

-Renovascular -Hypovolemia LVF

Renin secreting tumor

Questions from Dr. Plotnick 1. 2. 3. 4. 5.

Liddles syndrome -CAH: 11 and 17 hydroxylase

What is the most common cause of secondary hypertension? What are the other causes? What are the factors involved in the control of blood pressure? Explain the 2-kidney, one clip Goldblatt model. How do the clinical characteristics of renovascular hypertension secondary to atherosclerosis, renovascular hypertension secondary to fibromuscular dysplasia and primary hypertension differ? 6. What tests can differentiate renal hypertension from other forms of hypertension? 7. When should one suspect primary aldosteronism and what tests are used to make the diagnosis? 8. What are the various forms of aldosteronism and how do they differ? 9. What are the effects of licorice ingestion? 10. What are the clinical clues to pheochromocytoma and what tests are used to make the diagnosis? 11. How are patients with pheochromocytoma treated? 12. What is obstructive sleep apnea?

13. List the clinical clues to the diagnosis of secondary hypertension. 14. Describe the screening tests used in patients suspected of having secondary hypertension.