1. No category

Endocrine Hypertension
Ruben G. Kasala, MD.FPCP.FPSEDM
Chairman, Department of Medicine
Chief, Section of Endocrinology
The Medical City
Prevalence of Hypertension in the Philippines
National Health and Nutrition Survey (NHANESIII) US
Prevalence of Hypertension 28-30 % of adult population
90-95% Essential Hypertension
5-10 % Secondary Hypertension
Common causes of Secondary
Hypertension
Renovascular disease (3-5%)
Oral contraceptives (5%)
Primary aldosteronism (1-10%)
Pheochromocytoma (0.2%- 0.6%)
Excess mineralocorticoids other than aldosterone
( congenital adrenal Hyperplasia: 17a hydroxylase
deficiency, 11 b OH deficiency, Deoxycorticosterone
producing adenoma)
Cushing’s syndrome
Thyrotoxicosis
Hyperparathyroidism
Acromegaly
Renin producing tumors
Coarctation of the aorta
Endocrine Hypertension
More prominent presentation is uncontrolled hypertension
Primary aldosteronism (1-10%)
Pheochromocytoma (0.05%- 0.1%)
Excess mineralocorticoids other than aldosterone
( congenital adrenal Hyperplasia: 17a hydroxylase
deficiency, 11 b OHdeficiency, Deoxycorticosterone
producing adenoma)
More prominent presentation is the specific endocrine dysfunction
in addition to Hypertension:
Cushing’s syndrome
Thyrotoxicosis
Hyperparathyroidism
Acromegaly
Clinical Challenge
Who should be screened for Endocrine
Hypertension ?
What is cost effective screening
for Endocrine Hypertension?
How do we diagnose endocrine hypertension?
Case No 1:
55 y/o male hypertensive for 14 years,
On amlodepine 5 mg OD, valsartan/HCTZ 160/12.5 mg OD
Usual BP of 140-160/90
Admitted because of vertigo, vomiting and loss of consciousness
PE: BP 130/80, atrial fibrillation in MVR
Height 174 cm
Weight 85.5 kgs.
BMI 28.2 kg/m2
No neurologic deficits
Normal head CT
TSH : 0.65 uIU/ml
Creatinine: 0.87 mg/dl
Serum Na 140 mmol/L
Serum K 2.8 mmol/L
Case No 1 continued:
55 y/o male hypertensive for 14 years
Hctz was discontinued
Amlodepine 10 mg OD, Valsartan 160mg OD
Usual BP of 140-160/90-100
Repeat Serum K (mmol/L) on other occasions
2.6, 2.7, 2.8
Groups with high prevalence of Primary Aldosteronism(PA)
Patient Group
Prevalence
Moderate/Severe Hypertension
Stage 1 140-159/90-99
Stage 2 160-179/100-109
Stage 3 >180/100
Overall: 6.1%
Stage 1 (mild): 2%
Stage 2 ( moderate): 8%
Stage 3 ( severe): 13%
Resistant Hypertension: BP 140/90 while
on 3 hypertensive medications
17-23%
Hypertension with spontaneous or
diuretic induced hypokalemia
Specific prevalence not available, but
more frequently found in this group
Hypertension with adrenal incidentaloma
Media: 2% ( range 1.1-10%)
Funder, J. W., et al. Case detection, diagnosis and treatment of patients with primary aldosteronism:
An endcrine society clinical practice guidelines. 2008; 93 (9): 2366-3281.
Patients with hypertension at risk of having
Primary Hyperaldosteronism(PA)
1.  Joint National Commission(JNC)
stage 2(>160-179/100-109 mmHg),
stage 3 (>180/100 mm HG)
2.  Drug Resistant Hypertension
3.  Hypertension with spontaneous of diuretic-induced hypokalemia
4.  Hypertension with adrenal incidentaloma
5.  Hypertension with a family history of early onset hypertension
and a family history of cerebrovascular accident at
a young age ( <40 years)
6. Hypertensive first degree relative of patient with PA
Funder, J. W., et al. Case detection, diagnosis and treatment of patients with primary aldosteronism: An
endcrine society clinical practice guidelines. 2008; 93 (9): 2366-3281.
Renin Angiotensin System
Case 1 continued:
2 hours Upright Aldosterone and PRA (Plasma Renin Activity)
Results
Aldosterone (ng/ml)
97.35
PRA (ng/ml/hr)
0.34
ARR(Aldosterone renin ratio)
47.4
Patients with hypertension at risk of
Primary Aldosteronism (PA)
Plasma renin activity(PRA)
Plasma aldosterone concentration(PAC)
PRA
PAC
Investigate for Secondary
hyperaldosteronism
Renovascular Hypertension
Diuretic use
Renin secreting tumor
Malignant Hypertension
Coarctation of the aorta
PCA
PRA
PAC-PRA ratio > 20 (ng/dl; ng/ml/hr)
and
PAC > 15 ng/dl (>416pmol/L)
Investigate for
Primary aldosteronism
Adapted from:Young,WF jr, Hogan M. Renin-independent Hypermineralocorticoidism.
Trend Endocrinol Metab 1994;5:97
PRA
PAC
Investigate for
Congenital adrenal hyperplasia
Exogenous mineralcorticoid
DOC producing tumor
11-b HSD deficiency
Altered aldosterone metabolism
Liddle’s syndrome
Glucocorticoid resistance
Measurement of Aldosterone-Renin ratio(ARR) approach
1. Preparation:
a. Attempt to correct hypokalemia
b. Encourage liberal sodium intake
c. Withdraw the following agents for at least 4 weeks:
spironolactone, eplerenone, amiloride, triamterene
K-wasting diuretics, products from liquorice root
d. Attempt to withdraw other medications that affect ARR for at least 2 weeks
B adrenergic blockers,
Central alpha 2 agonist (clonidine, a-methlydopa, NSAIDS)
ACE inhibitors, ARBs renin inhibitors, dihydropyridine calcium antagonists
e. Switch to hypertensive medications with less effects on ARR
Verapamil slow release, prazosin, doxazosin, terazosin
d. Discontinue Oral contraceptives and Hormonal replacement therapy
Measurement of Aldosterone-Renin ratio(ARR) approach
2. Conditions for blood collection:
a.  Mid morning, 2 hours upright (sitting, standing or walking)
seated for 5-15 minutes
a.  Avoid stasis and hemolysis
b.  Sample at room temperature
Case 1 continued:
2 hours Upright Aldosterone and PRA (Plasma Renin Activity)
Results
Aldosterone (ng/ml)
97.35
PRA (ng/ml/hr)
0.34
ARR(Aldosterone renin ratio
47.4
Funder, J. W., et al. Case detection, diagnosis and treatment of patients with primary aldosteronism: An
endcrine society clinical practice guidelines. 2008; 93 (9): 2366-3281.
Primary Aldosteronism Confirmatory Tests
Test
Procedure
Interpretation
Concerns
Oral sodium
loading test
Na intake >200mmol(6g)/
day for 3 days
KCL supplemts to
maintain normal K
24 hr urine Na
24 hour urinary
aldosterone at day 3 AM
to day 4 AM
PA unlikely: 24 hour
urinary aldosterone <
10 mcg/d
PA highly likely: 24
hour urinary
aldosterone
>12 mcg/d ( Mayo
clinic)
>14 mcg/d (cleveland)
Should not be
performed in:
Severe uncontrolled
Hypertension
Renal inssufficiency
Cardiac
insufficiency/
arrhthmia,
Sever ehypokalemia
Primary Aldosteronism Confirmatory Tests
Test
Procedure
Saline
Recumbent for 1 hour
infusion test 2 L 0.9% saline for 2 hours
starting at 8 am -930am
Pre and post infusion
Recumbent aldosterone
BP and HR monitoring
Interpretation
Concerns
PA unlikely:
aldosterone < 5 ng/dl
PA likely:
aldosterone>10 ng/dl
Indeterminate
Aldosterone 5-10 ng/dl
Should not be
performed in:
Severe uncontrolled
Hypertension
Renal insufficiency
Cardiac
insufficiency/
arrhythmia,
Severe hypokalemia
Primary Aldosteronism Confirmatory Tests
Test
Procedure
Interpretation
Fludrocorti
sone
suppression
test
>Fludrocortisone 0.1 mg
every 6 hrs for 4 days
>Slow release kcl
supplements to maintain
normal K, checking every
4x a day
>Slow release Nacl tabs
30 mmol 3x a day w meals
to maintain urinary Na
3mmol/kg BW
>Day 4 :
10 am , plasma
aldosterone/PRA seated
position and
Plasma cortisol 7 am and
10 am
PA confirmed:
aldosterone >6 ng/dl
PRA < 1ng/ml/hr
Plasma cortisol value
of 10 am less than 7
am
Concerns
Funder, J. W., et al. Case detection, diagnosis and treatment of patients with primary aldosteronism: An endcrine society clinical
practice guidelines. 2008; 93 (9): 2366-3281.
Case 1 continued…..
2 hours Upright Aldosterone and PRA (Plasma Renin Activity)
Results
Aldosterone (ng/dl)
47.4
PRA (ng/ml/hr)
0.49
ARR(Aldosterone renin ratio
96.7
Saline Infusion Suppression test
Plasma aldosterone concentra3on (ng/dl) Pre -­‐ Saline Suppression 30.44 Post -­‐ Saline Suppression 31.34 (unsuppressed, > 10 ng/dl) Five major types of Primary Aldosteronism
• Unilateral Aldosterone Producing Adenoma (APA)
ACTH responsive form
Renin-responsive form
• Idiopathic Hyperaldosteronism (IHA) due to bilateral
zona glomerulosa hyperplasia
• Unilateral Primary Adrenal Hyperplasia(PAH)
• Glucocorticoid Remediable (suppressible) Aldosteronism(GRA)
• Aldosterone-producing adrenocortical Carcinoma (CA)
Prevalence:1% to 10% of hypertensive population
25% APA
70% IHA
05% PAH GRA CA
Funder, J. W., et al. Case detection, diagnosis and treatment of patients with primary aldosteronism: An
endcrine society clinical practice guidelines. 2008; 93 (9): 2366-3281.
CT Adrenal grand
•  A 1.1 x 1.1 x 0.9 cm isodense nodule is
seen in the lateral limb of the left adrenal
gland. The right adrenal gland is
unremarkable.
•  Impression:
–  Adrenal gland nodule, Left.
–  Bilateral hypodense renal cortical nodules,
likely cysts. A contrast enhanced study or
UTZ exam may be done for further
verification.
Sensitivity & Specificity
Test
Adrenal CT
scan
AVS using
Sensitivity
Specificity
78 %
75 %
95 %
100 %
Aldosterone ratio ≥ 4:1
Funder, J. W., et al. Case detection, diagnosis and treatment of patients with primary aldosteronism: An endcrine society clinical practice guidelines.
2008; 93 (9): 2366-3281.
Features Prevalence Bilateral IHA / BAH more common APA / Unilat. AH less common Age at diagnosis older Younger (< 40 y.o) Clinical Features less severe HTN, less frequent hypokalemia CT scan features can be a normal looking adrenal, micronodularity, bilateral nodules or atypical unilateral mass (ex. > 2 cm.) 1-­‐2 cm hypodense unilateral, solitary nodule w/ a normal contralateral adrenal < 25 ng/dl > 25 ng/dl Slight decrease in aldosterone Aldosterone remains high Effect of Adrenalectomy unilateral or bilateral adrenalectomy seldom corrects HTN corrects hypokalemia in all paNents, normalizes BP in at least 1/3 of pxs, improves HTN in nearly all pxs Treatment of Choice MineralocorNcoid receptor antagonist unilateral adrenalectomy Plasma aldosterone level Captopril Challenge more severe HTN, more frequent severe hypokalemia Funder, J. W., et al. Case detection, diagnosis and treatment of patients with primary aldosteronism: An
endcrine society clinical practice guidelines. 2008; 93 (9): 2366-3281.
Adrenal vein sampling
Adrenal Vein Sampling Uns3mulated Results Renin (ng/ml/hr) ARR Right adrenal 175.96 22.8 7.72 LeZ adrenal 237.74 18.5 12.85 IVC Antecubital 0.34 0.49 120.18 96.7 40.86 47.4 19.8 22 2.06 2.17 Site Aldosterone Cor3sol Cor3sol-­‐Corrected Aldosterone (ng/dl) (mcg/dl) Aldosterone Ra3o 1.66 : 1 Adrenal Vein Sampling S3mulated Results Site Aldosterone Cor3sol Cor3sol-­‐Corrected Aldosterone (ng/dl) (mcg/dl) Aldosterone R Ra3o Right adrenal 398.3 245.2 1.62 LeZ adrenal 938.25 373.3 2.51 IVC 109.2 26.9 4.05 Antecubital 79.88 23.4 3.41 1.55 : 1 Criteria for lateralization:(cortisol corrected aldosterone ratio high side to low side
4:1 indicative 3:1 suggestive 95% sensitivity 100% specificity
Funder, J. W., et al. Case detection, diagnosis and treatment of patients with primary
aldosteronism: An endcrine society clinical practice guidelines. 2008; 93 (9): 2366-3281.
Case no 2:
49 y/o female
3 years ago( 2012):
acute abdomen secondary to appendicitis associated with hypertension
CT scan confirmed acute appendicitis and an adrenal incidentaloma, 2cm
developed hypertensive crisis intra operatively
Lost to follow up
Interim period:
persistent hypertension despite 3 antihypertensives
consulted a psychiatrist because of anxiety and palpitation
Case No. 2 continued….
2014
Admitted due to hypertensive crisis, vomiting and
headache
BP 240/100 HR 100/min
BMI: 25
Anxious cold extremities
Referred to endocrine service:
49 y/o female, severe uncontrolled hypertension,
adrenal incidentaloma
Date: June 15,2012
2.1x 1.7 x 2.7 well defined solid nodule,
Right adrenal gland
attenuation of 40 HU
unremarkablel Left adrenal gland
Date: Nov 3, 2014
Interval increase in size of R
Adrenal mass 3.5 x3.1x 3.3
Unremarkable L adrenal gland
Clinical Setting for Testing for PPGL
Signs and symptoms of PPGL, triad of Headaches, sweating and
tachycardia, in particular if paroxysmal
PPGL symptoms provoked by use of medications associated with
adverse effects
Adrenal incidentaloma, with or without hypertension
Hereditary predisposition or syndromic features suggesting
hereditary PPGL
Lenders et al, Pheochromocytoma and Paraganglioma:
Previous history of PPGL
An Endocrine Society Clinical Practice Guidelines.
J Clin Endocrinol Metab, June 2014, 99(6):1915–1942
Lenders et al, Pheochromocytoma and Paraganglioma:
An Endocrine Society Clinical Practice Guidelines.
J Clin Endocrinol Metab, June 2014, 99(6):1915–1942
Test
Result
Normal Value
Plasma Free Metanephrine
512.26 pg/ml
<90 pg/ml
24 hour urinary
Metanephrine
10.0 mg/24 hours
< 1 mg/d24 hours
Pheochromocytoma
Age: 30-50 years
0.2 – 0.6% of hypertensives
10% extra adrenal
10% bilateral
10 % occur in children
10% malignant
10% familial (MEN 2A, MEN 2B)
10% incidentally discovered (adrenal incidentaloma)
MEN Syndrome
MEN 1 Pituitary adenoma Parathyroid Adenoma MEN 2 A MEN 2 B Medullary Thyroid Medullary Thyroid CA CA Pheochromocytoma Pheochromocytoma Parathyroid Adenoma Duodeno-­‐pancreaNc endocrine tumor Cushing's Syndrome MulNple Mucosal Neuromas Lap adrenalectomy was done but because of technical
difficulty precedure was converted to open adrenalectomy
3 weeks post operatively on follow up:
BP ranges from 100/80 to 120/80 HR 85/min without any
hypertensive meds
Pending repeat plasma and urine metanephrines
Plasma and urine biochemical tests
sensitivity
Plasma tests
hereditary
specificity
sporadic
hereditary
sporadic
Free
metanephrines
97%
98%
89%
89%
Cathecolamines
66%
93%
91%
69%
Fract
metanephrines
97%
97%
69%
69%
Total
metanephrines
60%
89%
98%
87%
Cathecolamines
75%
93%
96%
70%
VMA
43%
83%
99%
84%
Urinary tests
Pheochromocytoma Metastatic Potential
PASS score < 4 reliably predicts benign lesion
PASS score > 6 are most often malignant tumors
There are reports however of lact of reproducibility or reliability
Clinical suspicion of Pheochromocytoma
Plasma free Metanephrine*
>3x elevation (98 % sensitive)
(89 % specific)
24 hour urinary fractionated metanephrine*
>3x elevation (97% sensitivity
(89% specific)
localize
Adrenal CT scan : sensitivity 95%
no adrenal mass or
Metastatic or increased risk
for metastatic disease
+ adrenal mass
Lap adrenalectomy (<6 cm )
Open adrenalectomy (>6 cm)
I-131 MIBG scan
( if I-131 MIBG tx is contemplated)
MRI
Genetic testing
Summarized from: Lenders et al, Pheochromocytoma and
• 
• 
liquid chromatography
with mass spectrometric or electrochemical detection methods
Paraganglioma:An Endocrine Society Clinical Practice Guidelines.
J Clin Endocrinol Metab, June 2014, 99(6):1915–1942
Summary for the Internist/GPs
Suspect Primary Hyperaldosteronism ( PA)
1.  Joint National Commission(JNC)
stage 2(>160-179/100-109 mmHg),
stage 3 (>180/100 mm HG)
2.  Drug Resistant Hypertension
3.  Hypertension with spontaneous of diuretic-induced hypokalemia
4.  Hypertension with adrenal incidentaloma
5.  Hypertension with a family history of early onset hypertension
and a family history of cerebrovascular accident at
a young age ( <40 years)
6. Hypertensive first degree relative of patient with PA
Screening : 2 hours Upright Aldosterone/ PRA ratio(ARR)
ARR > 20 investigate for PA
Refer to Endocrinologist
Summary for the Internist/GPs
Suspect Pheochromocytoma
1.Signs and symptoms of PPGL, triad of Headaches, sweating and tachycardia,
in particular if paroxysmal
2.PPGL symptoms provoked by use of medications associated with
adverse effects
3.Adrenal incidentaloma, with or without hypertension
4.Hereditary predisposition or syndromic features suggesting
hereditary PPGL
5.Previous history of PPGL
Screening : Plasma Free metanephrine
24 hour urinary fractionated Metanephrines
> 3x elevated (97% sensitive 89% specific)
Refer to Endocrinologist
Thank you for your attention