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