SECONDARY HYPERTENSION

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1 SECONDARY HYPERTENSION Grand round for Medical student 25 October 2013 By Rungnapa Laortanakul, MD.

2 OUTLINE Overview of HT Secondary HT Resistance HT Primary aldosteronism Pheochromocytoma Cushing s syndrome

3 HYPERTENSION Definitions by JNC 7 BP based upon the average of two or more... Pre HT : SBP mmhg or DBP mmhg HT stage 1 : SBP mmhg or DBP mmhg HT stage 2 : SBP 160 mmhg or DBP 100 mmhg

4 MALIGNANT HT Marked HT with retinal hemorrhages, exudates, or papilledema May also renal involvement "nephrosclerosis" Kidney injury, hematuria, and proteinuria Neurologic symptoms : ICH, SAH, or hypertensive encephalopathy Usually associated with DBP > 120 mmhg

5 HYPERTENSIVE ENCEPHALOPATHY Presence of signs of cerebral edema Caused by breakthrough hyperperfusion from severe and sudden rises in BP Insidious onset of headache, nausea, vomiting, followed by nonlocalizing symptoms such as restlessness, confusion, seizure, and coma. "Reversible posterior leukoencephalopathy syndrome"

6 "REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME" CT - hypodensity in the posterior white matter MRI (T2) - edema of the white matter of the parieto-occipital regions

7 HYPERTENSIVE URGENCY Severe HT : DBP > 120 mmhg with asymptom No acute end-organ damage Little short-term risk

8 PRIMARY (ESSENTIAL) HT Atheroclerosis DM HT DLP Obesity

9 SECONDARY HT General clinical clues Severe or resistant hypertension An acute rise in BP developing in a patient with previously stable values Age <30 years in non-obese, negative family history of and no other risk factors (eg, obesity) for HT Malignant or accelerated hypertension Proven age of onset before puberty

10 RESISTANT HT BP that remains above goal in spite of concurrent use of 3 antihypertensive agents of different classes One of three agents should be diuretic, and all agents should be prescribed at optimal doses (50% or more of maximum dose) Goal BP < 140/90 mmhg The 2008 American Heart Association scientific statement

11 Clinical features suspected Secondary HT

12 Disorder Clinical feature General Severe or resistant HT Acute rise BP with previously stable value Age < 30 years in non-obese with negative family history and no other risk factor for HT Renovascular disease Acute elevation in S. Cr 30% after add ACE-I or ARB Mod to severe HT in Pt with diffuse atherosclerosis, unilateral small kidney, or asymmetry in renal size of > 1.5 cm that cannot explained by another reason Mod to severe HT in Pt with recurrent episodes of flash pulmonary edema Onset of stage 2 HT after age 55 years Abdominal bruit

13 Disorder Clinical feature Primary renal disease Elevated S. Cr Abnormal UA Oral contraceptives New elevation in BP temporally related to use Sleep apnea syndrome Coarctation of the aorta Obese who snore loudly while asleep Daytime somnolence, fatigue, and morning confusion HT in the arms with diminished or delayed femoral pulses and low or unobtainable BP in the legs Left brachial pulse is diminished and equal to the femoral pulse if origin of the left subclavian artery is distal to the coarct

14 Disorder Clinical feature Primary aldosteronism Unexplained hypokalemia with renal K loss More than one-half of Pts are normokalemia Cushing's syndrome Pheochromocytoma Hypothyroidism Primary hyperparathyroidism Cushingoid facies, central obesity, proximal muscle weakness, and ecchymoses Paroxysmal elevations in BP Triad of headache (pounding, palpitation, and sweating) Symptoms of hypothyroidism Elevated serum calcium

15 Cardiovascular disease Endocrine disease Secondary hypertension Reno-vascular disease Other

16 Reni n Hypertension with Aldosteron e hypo K

17 HYPERTENSION WITH HYPO K Hypo K with renal K loss 24-hours urine potassium Spot urine potassium concentration Urine potassium to creatinine ration Transtubular potassium gradient (TTKG) Non reninaldosterone Primary hyperaldosteronism Secondary hyperaldosteronism

18 NON RENIN-ALDOSTERONE Cushing's syndrome Licorice ingestion Certain forms of congenital adrenal hyperplasia (CAH)

19 SECONDARY HYPERALDOSTERONISM Renovascular disease Renin-secreting tumors Malignant HT

20 PRIMARY ALDOSTERONISM

21 PRIMARY ALDOSTERONISM Disorder in which aldosterone production is inappropriately high Relatively autonomous from the reninangiotensin system Nonsuppressible by sodium loading

22 PRIMARY ALDOSTERONISM Most common subtypes Aldosterone-producing adenomas Bilateral idiopathic hyperaldosteronism (bilateral adrenal hyperplasia)

23 PRIMARY ALDOSTERONISM Clinical features HT with hypok Resistant HT Muscle weakness Cardiovascular risk Laboratory Hypo K, metabolic alkalosis, mild hyper Na

24 CASE DETECTION HT (by JNC 7) stage 2 ( / mmhg), stage 3 ( >180/110 mm Hg) Drug-resistant HT HT spontaneous or diuretic-induced hypokalemia HT with adrenal incidentaloma HT and a family history of early-onset HT or CVA at a young age < 40 yr

25 Step of endocrine tests Signs and symptoms Labolatory tests Screening Confirmation Localized lesion : Imaging

26 Screening test Plasma aldosterone concentration (PAC) Plasma renin activity (PRA) Plasma aldosterone to renin ratio (ARR) = PAC / PRA

27 MEASUREMENT OF THE ARR Correct hypo K Withdraw agents that markedly affect to ARR If necessary to HT control --> verapamil slow-release, hydralazine, prazocin, doxazosin Collect blood mid-morning, after Pt has been up (sitting, standing, or walking) for at least 2 hr. Maintain sample at room temperature

29 ARR CUTOFF VALUES Recommend : plasma aldosterone to renin ratio (ARR) to detect cases of primary aldosteronism PAC >15 ng/dl, ARR > 30

30 Confirmation tests Oral sodium loading Saline infusion or Saline loading test Fludrocortisone suppression Captopril challenge

31 Saline loading test Infusion of 2 liters of 0.9% saline iv over 4 h Post-infusion PAC < 5 ng/dl PA unlikely PAC >10 ng/dl Very probable sign of PA

32 Step of endocrine tests Signs and symptoms HT with hypo K Labolatory tests Screening Confirmation PAC, PRA Saline loading test Localized lesion : Imaging CT adrenal glands

33 CUSHING'S SYNDROME

34 Normal ACTH NEJM 1995 Vol.332 NO 12

35 CUSHING'S SYNDROME Overproduction of deoxycorticosterone, corticosterone, and cortisol ACTH-dependent ACTH-independent Cushing's disease Ectopic ACTH syndrome Adrenal adenoma Adrenal carcinoma Adrenal Ectopic CRH syndrome Pituitary Micronodular hyperplasia Macronodular hyperplasia

36 ACTH ACTH ACTH NEJM 1995 Vol.332 NO 12

37 NEJM 1995 Vol.332 NO 12

weakness) Striae (especially if reddish purple and > 1 cm wide) In children,

38 Features that best discriminate Cushing s syndrome; most do not have a high sensitivity Easy bruising Facial plethora Proximal myopathy (or proximal muscle weakness) Striae (especially if reddish purple and > 1 cm wide) In children, weight gain with decreasing growth velocity J Clin Endocrinol Metab. May 2008, 93(5):

39 -11 beta-hydroxysteroid dehydrogenase (11 beta-hsd) is a key enzyme in cortisol metabolism -11 beta-hsd type 1 : oxidize reaction, inactivate cortisol to cortisone -11 beta-hsd type 2 : reverse (reductase) reaction, conversion of cortisone to cortisol

40 Step of endocrine tests Signs and symptoms Labolatory tests Screening Confirmation Localized lesion : Imaging

41 Initial testing for Cushing s syndrome One of the following tests : 1. Urine free cortisol (UFC; at least two measurements) 2. Late-night salivary cortisol (two measurements) 3. 1-mg overnight dexamethasone suppression test (DST) 4. Longer low-dose DST (2 mg/d for 48 h) J Clin Endocrinol Metab. May 2008, 93(5):

42 Normal ACTH ACTH NEJM 1995 Vol.332 NO 12

43 Subsequent evaluation for Cushing s syndrome For the subsequent evaluation of abnormal initial test results, recommend performing another recommended test Suggest the additional use of the dexamethasone- CRH test or the midnight serum cortisol test in specific situations J Clin Endocrinol Metab. May 2008, 93(5):

44 Cushing s syndrome suspected Exclude exogenous glucocorticoid exposure Initial testing Subsequent testing 1. Urine free cortisol 2. Late-night salivary cortisol 3. 1-mg overnight DST 4. Low-dose DST (2 mg/d for 48 h) 1. Urine free cortisol 2. Late-night salivary cortisol 3. 1-mg overnight DST 4. Low-dose DST (2 mg/d for 48 h) 5. dexamethasone-crh test 6. midnight serum cortisol J Clin Endocrinol Metab. May 2008, 93(5):

45 1 mg dexamethasone suppression test 1 mg dexamethasone is usually given between 2300, and cortisol is measured between 0800 the following morning Normal person : Post-dexamethasone serum cortisol <1.8 µg/dl Sensitivity rates >95%, Specificity rates 80% Day 1 Dexamethasone (0.5) 2 tab oral at Day 2 Morning cortisol 8.00

46 Low dose dexamethasone suppression test (LDDST) Dexamethasone (0.5 mg) 1 tab oral q 6 h (8 dose) Serum cortisol within 6 h after the last dose of dexamethasone Normal person : Post-dexamethasone serum cortisol <1.8 µg/dl Day Day Day Day Morning cortisol 8.00

47 ACTH level ACTH level < 5 pg/ml ACTH-independent CS >>> CT adrenal glands ACTH level > 20 pg/ml ACTH dependent CS >>> Pituitary or Ectopic ACTH

48 Step of endocrine tests Signs and symptoms HT with Cushingoid appearance Labolatory tests Screening Confirmation 1mg DST or UFC LDDST or UFC Localized lesion : Imaging ACTH level before CT adrenal or MRI pituitary

49 PHEOCHROMOCYTOMA

50 PHEOCHROMOCYTOMA Pheochromocytoma" Catecholamine-secreting tumors Arise from chromaffin cells of the adrenal medulla and the sympathetic ganglia Catecholamine-secreting paragangliomas" Extra-adrenal pheochromocytomas

51 CLINICAL PRESENTATION Symptoms o Classic triad : Paroxysm Episodic headache, sweating, and tachycardia Discovery of an incidental adrenal mass Familial pheochromocytoma VHL syndrome, MEN2, Neurofibromatosis type1, Familial paraganglioma

Neurofibromatosis type1 A syndrome caused by neurogenic tumors arising from neural sheath cells located along peripheral and cranial nerves.

52 Neurofibromatosis type1 A syndrome caused by neurogenic tumors arising from neural sheath cells located along peripheral and cranial nerves. Autosomal dominant Lisch nodules of the iris, schwannomas, café au lait macules, axillary freckling, optic-nerve gliomas, astrocytomas, multiple neurofibromas, and plexiform neurofibromas. N Engl J Med 2011; 365:2020

53 Step of endocrine tests Signs and symptoms Labolatory tests Screening Confirmation Localized lesion : Imaging

54 DIAGNOSTIC TESTS Urinary and plasma fractionated metanephrines and catecholamines

55 Catecholamine biosynthesis and metabolic degradation West J Med April; 156(4):

56 Catecholamine metabolites Vanillymandelic acid (VMA) has been shown to have poor diagnostic sensitivity Fractionated catecholamine metabolites-metanephrine and normetanephrine in the plasma or urine- are the preferred screening tests for pheochromocytoma Endocrinol Metab Clin North Am Jun;40(2):279-94

57 Radiologic tests CT and MRI adrenal glands About 10 percent of the tumors are extraadrenal

58 Step of endocrine tests Signs and symptoms HT with Paroxysm Labolatory tests Screening Urinary fractionated metanephrines x 2 days Confirmation Localized lesion : Imaging CT or MRI adrenal

Summary Secondary HT should be suspected : Severe or resistant HT, Acute rise BP with previously stable value, Age < 30 years in non-obese with negative family history and no other risk factor for HT

59 Summary Secondary HT should be suspected : Severe or resistant HT, Acute rise BP with previously stable value, Age < 30 years in non-obese with negative family history and no other risk factor for HT Approach : Cardiovascular, Renovascular, Renal parenchyma, Endocrine disease, other Endocrine disease : Primary aldosteronism, Cushing s syndrome, and Pheochromocytoma Step of endocrine tests : signs&symptoms, screening test, confirmation test, and imaging

How to Recognize Adrenal Disease

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