SECONDARY HYPERTENSION - medkorat.in.th · MALIGNANT HT •Marked HT with retinal hemorrhages,...

SECONDARY

HYPERTENSION

Grand round for Medical student

25 October 2013

By

Rungnapa Laortanakul, MD.

OUTLINE

Primary aldosteronism

Pheochromocytoma

Cushing’s syndrome

Overview of HT

Secondary HT

Resistance HT

HYPERTENSION

Definitions by JNC 7

BP based upon the average of two or more ...

•Pre HT : SBP 120 - 139 mmHg or DBP 80 - 89 mmHg

•HT stage 1 : SBP 140 - 159 mmHg or DBP 90 - 99 mmHg

•HT stage 2 : SBP ≥160 mmHg or DBP ≥100 mmHg

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

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"

"REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY

SYNDROME"

CT - hypodensity in the posterior white matter

MRI (T2) - edema of the white matter of the parieto-occipital regions

HYPERTENSIVE URGENCY

• Severe HT : DBP > 120 mmHg with asymptom

• No acute end-organ damage

• Little short-term risk

PRIMARY (ESSENTIAL) HT

Atheroclerosis

• DM

• HT

• DLP

• Obesity

SECONDARY HTGeneral 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

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

Clinical features

suspected

Secondary HT

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

Disorder Clinical feature

Primary renal

disease• Elevated S. Cr

• Abnormal UA

Oral contraceptives • New elevation in BP temporally related to use

Sleep apnea

syndrome

• Obese who snore loudly while asleep

• Daytime somnolence, fatigue, and

morning confusion

Coarctation of the

aorta

• 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

Disorder Clinical feature

Primary aldosteronism• Unexplained hypokalemia with renal K loss

• More than one-half of Pts are normokalemia

Cushing's syndrome• Cushingoid facies, central obesity, proximal

muscle weakness, and ecchymoses

Pheochromocytoma • Paroxysmal elevations in BP

• Triad of headache

(pounding, palpitation, and sweating)

Hypothyroidism • Symptoms of hypothyroidism

Primary

hyperparathyroidism• Elevated serum calcium

Endocrine

disease

Cardiovascular

disease

Other

Reno-vascular

disease

Secondary

hypertension

Hypertension

with

hypo K

Reni

n

Aldosteron

e

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 renin-

aldosterone

Primary

hyperaldosteronism

Secondary

hyperaldosteronism

NON RENIN-ALDOSTERONE

• Cushing's syndrome

• Licorice ingestion

• Certain forms of congenital adrenal hyperplasia (CAH)

SECONDARY

HYPERALDOSTERONISM

• Renovascular disease

• Renin-secreting tumors

• Malignant HT

PRIMARY

ALDOSTERONISM

PRIMARY ALDOSTERONISM

• Disorder in which

aldosterone production

is inappropriately high

• Relatively autonomous

from the renin-

angiotensin system

• Nonsuppressible by

sodium loading

PRIMARY ALDOSTERONISM

Most common subtypes

• Aldosterone-producing adenomas

• Bilateral idiopathic hyperaldosteronism

(bilateral adrenal hyperplasia)

PRIMARY ALDOSTERONISM

Clinical features

•HT with hypoK

•Resistant HT

Laboratory

•Hypo K, metabolic alkalosis, mild hyper Na

• Muscle weakness

• Cardiovascular risk

CASE DETECTION

• HT (by JNC 7) stage 2 (160–179/100–109 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

Step of endocrine tests

• Signs and symptoms

• Labolatory tests

• Screening

• Confirmation

• Localized lesion : Imaging

Screening test

• Plasma aldosterone concentration (PAC)

• Plasma renin activity (PRA)

• Plasma aldosterone to renin ratio (ARR)

= PAC / PRA

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

ARR CUTOFF VALUES

• Recommend : plasma aldosterone to renin ratio (ARR)

to detect cases of primary aldosteronism

PAC >15 ng/dl, ARR > 30

Confirmation tests

• Oral sodium loading

• Saline infusion or Saline loading test

• Fludrocortisone suppression

• Captopril challenge

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

Step of endocrine tests

• Signs and symptoms

• Labolatory tests

• Screening

• Confirmation

• Localized lesion : Imaging

HT with hypo K

PAC, PRA

Saline loading test

CT adrenal glands

CUSHING'S SYNDROME

Normal

ACTH

NEJM 1995 Vol.332 NO 12

CUSHING'S SYNDROME

ACTH-dependent

• Cushing's disease

• Ectopic ACTH syndrome

• Ectopic CRH syndrome

ACTH-independent

•Adrenal adenoma

•Adrenal carcinoma

•Micronodular hyperplasia

•Macronodular hyperplasia

Overproduction of deoxycorticosterone,

corticosterone, and cortisol

Pituitary

Adrenal

ACTHACTHACTH

NEJM 1995 Vol.332 NO 12

NEJM 1995 Vol.332 NO 12

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):1526–1540

-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

Step of endocrine tests

• Signs and symptoms

• Labolatory tests

• Screening

• Confirmation

• Localized lesion : Imaging

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):1526–1540

Normal

ACTH ACTH

NEJM 1995 Vol.332 NO 12

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):1526–1540

J Clin Endocrinol Metab. May 2008, 93(5):1526–1540

Cushing’s syndrome suspected

Exclude exogenous

glucocorticoid exposure

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

Initial testing Subsequent testing

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 23.00

Day 2 Morning cortisol 8.00

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 1 12.00 18.00 24.00 Day2

06.00

Day 2 12.00 18.00 24.00 Day3

06.00

Morning cortisol 8.00

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

Step of endocrine tests

• Signs and symptoms

• Labolatory tests

• Screening

• Confirmation

• Localized lesion : Imaging

HT with Cushingoid

appearance

1mg DST or UFC

LDDST or UFC

ACTH level

before CT adrenal

or MRI pituitary

PHEOCHROMOCYTOMA

PHEOCHROMOCYTOMA

“Pheochromocytoma"

• Catecholamine-secreting tumors

• Arise from chromaffin cells of the

adrenal medulla and the

sympathetic ganglia

“Catecholamine-secreting

paragangliomas"

• Extra-adrenal pheochromocytomas

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.

• 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

Step of endocrine tests

• Signs and symptoms

• Labolatory tests

• Screening

• Confirmation

• Localized lesion : Imaging

DIAGNOSTIC TESTS

• Urinary and plasma fractionated

metanephrines and catecholamines

West J Med. 1992 April; 156(4): 399–407

Catecholamine biosynthesis

and metabolic degradation

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. 2011 Jun;40(2):279-94

Radiologic tests

• CT and MRI adrenal glands

• About 10 percent of the tumors are extraadrenal

Step of endocrine tests

• Signs and symptoms

• Labolatory tests

• Screening

• Confirmation

• Localized lesion : Imaging

HT with Paroxysm

Urinary fractionated

metanephrines x 2 days

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

• 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