Hypertension Rounds:

Secondary Hypertension
Oscar H. Cingolani, MD
Co-Director Hypertension Center
Assistant Professor of Medicine.
Division of Cardiology
Johns Hopkins University Hospital
ocingol1@jhmi.edu
Disclosures: None
Objectives:
Present a hypertension patient and discuss
assessment, evaluation and treatment.

Identify situations where secondary forms of
hypertension should be suspected.

Discuss appropriate tests.
Hypertension Rounds
42 year-old gentleman with recurrent nervous
heart episodes characterized by tremors,
sweating, raising HR and headaches.
Blood pressure as high as 210/140 mmHg.
Episodes last between 10 minutes and 1 hr.
Patient quite tired after these episodes.
Lost 10 Kg over the last 2 years.
Hypertension Rounds
These spells started 3 years before, and they
were getting worse and more frequent.

On one occasion, he was taken to a local ER,
propranolol was given and his BP rose from
170/100 to 220/120 mm Hg.
Case Presentation.
How many of you think this is secondary
hypertension?

How many of you think this is a
Pheochromocytoma?

How many think this is another form of secondary
hypertension?
- Onset before 20 or suddently after 50 years of age.

- Level of BP > 180/110 mmHg.

- Organ damage
Funduscopic grade 2 or higher
Serum creatinine >1.5 mg/100ml
Cardiomegaly or LVH

- Unprovoked hypokalemia
- Abdominal bruit
- Variable pressures with tachycardia, sweating, tremor.
- Poor response to therapy that is usually effective.
According to European and US guidelines, these are situations
when secondary forms of hypertension should be considered.





When to suspect secondary hypertension.
Evaluation:
Assess lifestyle and identify cardiovascular risk factors.

Assess the presence or absence of target organ
damage.

Search for identifiable causes of hypertension.

According to current guidelines, these three main aspects should be kept in
mind when evaluating a patient with hypertension. The search for an
identifiable cause of hypertension should be based on history and physical
examination first, to avoid unnecessary testing. The chances of an elderly
patient with family history of hypertension to have a secondary form of high
blood pressure is less likely than a young woman with marked elevations in
her BP, no family history and an audible abdominal bruit.


Primary Aldosterosim is now considered the most common identifiable form of
hypertension, being underdiagnosed in the general clinical practice.

Other less likely causes, such as renal vascular disease, Cushings or pheochromocytoma
should be always suspected, not because they are frequent, but because the
consequences are quite relevant.
Other identifiable causes of high blood pressure are sleep apnea
1
, ethanol
consumption
2
, and chronic use of NSAIDs
3
.

1) Konecny T, Kara T, Somers VK. Hypertension. 2014 Feb;63(2):203-9. Steinhorst AP et
al. Sleep Breath. 2013 Oct 3.
2) O'Keefe JH, Bhatti SK, Bajwa A, Dinicolantonio JJ, Lavie CJ. Mayo Clin Proc. 2014
Mar;89(3):382-393
3) Di Gennaro FP, Cingolani OH, Abbate AF, Toblli JE, Vilches A. Medicina (B Aires).
2004;64(4):301-5.

Target Organ Damage in Hypertension
Assessment of target organ damage (TOD)
should always take place in evaluating
hypertensive patients. The presence of TOD
indicates more severe and or sustained
hypertension. On contrary, in patients with
white coat hypertension, TOD is usually not
present.

Fundoscopic eye exam is key in the initial
assessment, since it gives us the opportunity
to look at the vessels directly.

LVH: ECG
ECG revealing marked LVH. When LVH is
disproportionately for the degree of hypertension,
primary ALDO or other forms of hypertension should
be suspected.
LVH: echocardiography
Tanabe A et al: Left ventricular hypertrophy is more prominent in patients with
primary aldosteronism than in patients with other types of secondary
hypertension. Hypertens Res 1997; 20:85-90.
Echocardiography (long parasternal view) image from a hypertensive patient revealing left ventricular
hypertrophy (LVH). Note the thick LV walls and dilated left atrium (LA). When LVH is out of proportion
tothe level of BP, primary aldosteronsm should be suspected, among other secondary causes of
hypertension.

Primary Aldo and renal cysts
Torres V.E., Young Jr. W.F., Offord K.P., Hattery R.R.: Association of hypokalemia,
aldosteronism, and renal cysts. N Engl J Med 1990; 322:345-351.
Primary aldosteronism might be associated with deep-seated renal cysts in 60% of cases.
A history or finding consistent with renal cysts should raise suspicious of primary also in
patients with resistant hypertension, specially if hypokalemia is present.

Primary Aldosteronism: prevalence.
It is now recognized that primary ALDo is probably the most common cause of secondary
hypertension.

Primary Aldosteronism: Pathophysiology.
Pathophysiology of primary aldosteronism, explaining symptoms.

Primary Aldosteronism
Aldosterone-producing adenoma (APA) 35% of cases.

Bilateral idiopathic hyperplasia (IHA) 60% of cases.

Primary (unilateral) adrenal hyperplasia 2% of cases.
Aldosterone-producing adrenocortical carcinoma<1% of cases.
Familial hyperaldosteronism (FH)
Glucocorticoid-remediable aldosteronism (FH type I) <1% of
cases
FH type II (APA or IHA) <2% of cases
Ectopic aldosterone-producing adenoma or carcinoma<0.1% of
cases
Primary Aldosteronism
In the first 262 cases of primary aldosteronism diagnosed at
the Mayo Clinic (1957-1986), the highest blood pressure (BP)
was 260/155 mm Hg; mean (SD) was 184/112 28/16 mm
Hg. Patients with APA tend to have higher BPs than those with
IHA.

Hypokalemia leads to muscle weakness and cramping,
headaches, palpitations, polydipsia, polyuria, nocturia.

Periodic paralysis is a very rare presentation in whites, but it is
not an infrequent in patients of Asian descent.

Another rare presentation can be tetany associated with a
decrease in ionized calcium and marked hypokalemic alkalosis.

Young Jr. W.F., Klee G.G.: Primary aldosteronism. Diagnostic evaluation. Endocrinol Metab Clin North
Am 1988; 17:367-395.
Propossed algorithm to evaluate for primary Aldo.

Primary Aldosteronism: diagnosis
Saline suppression test.
Captopril suppression.
Response to spironolactone.
Adrenal venous sampling.
Imaging.
Suggested methods to confirm diagnosis of primary aldosteronism.

Spironolactone seems to drop BP substantially in patients with resistant
hypertension, when added as a 4th agent.

Could we be missing undiagnosed primary Aldo in these patients?

Renovascular HTN
Incidence 1-30%
Etiology
Atherosclerosis 75-90%
Fibromuscular dysplasia 10-25%
Other
Aortic/renal dissection
Takayasus arteritis
Thrombotic/cholesterol emboli.
Post transplantation stenosis.
Post radiation.
Different etiologies of renal artery stenosis. It is quite important to suspect fibromuscular
dysplasia in young women with elevated BP, since early diagnosis and treatment can
dramatically change the course of this disease.

RAS screening/diagnostics
Sens Spec Cost Limitation/Etc
Duplex U/S
90-
95%
60-
90%
$200
Operator dependent.
Captopril
Renography
83-
91%
87-
93%
$1000
Meds, accuracy reduced in pt
with renal insufficiency, lacks
anatomical info; good
predictor of BP response
MRA
88-
95%
95% $500
False positive artifact resp,
peristalsis, tortuous vessels;
cost
Bruit
39-
65%
90-
99%
-
Insensitive, severe stenosis
may be silent
Angiography
Gold
std
Gold
std
?
Invasive, nephrotoxicity, little
value in predicting BP
response
Captopril Renography
Captopril renography is currently no longer used in many centers. It has the
advantage that provides prognosis, but its accuracy is reduced in patients
with renal insufficiency.

MRA
MRA unilateral and bilateral RAS. Currently, MRA and Duplex are the non-invasive
tests more commonly used in many centers.

Fibromuscular Dysplasia, before
and after PTRA
Atherosclerotic RAS before and after stent
Safian & Textor. NEJM. 2001 Feb 8;344(6):431-42.


Angiography is still considered the gold standard,
although its major disadvantages are invasiveness
and contrast nephrotoxicity.

Stenting and medical therapy for atherosclerotic renal-artery
stenosis.
Cooper CJ et al. N Engl J Med 2014;370:13-22.
CORAL study. KaplanMeier Curves for the Primary Outcome. Survival curves are truncated
at 5 years owing to instability of the curves because few participants remained in the study after
5 years.

Indications for Revascularization
Resistant hypertension.

Deteriorating renal function.

Critical stenosis (or stenosis with worsening function
of a solitary kidney).

Fibromuscular dysplasia

Associated heart failure ("flash" pulmonary edema)
Cushings syndrome/ hypercortisolism
Rare cause of secondary HTN (0.1- 0.6%)
Etiology: pituitary microadenoma, iatrogenic (steroid
use), ectopic ACTH, adrenal adenoma
Clinical
Sudden weight gain,truncal obesity, moon facies,
abdominal striae, DM/glucose intolerance, HTN,
prox muscle weakness, skin atrophy,
hirsutism/acne
Cushings syndrome
Coarctation of Aorta
Brickner, et al. NEJM 2000;342:256-263
Coarctation of the aorta should always be suspected in young adults with hypertension (upper
extremities), specially if it is associated with proggresive weakness of lower extremities. Typical findings
include the presence of a bruit (mid scapular or subclavicular), pulsatile intercostal arteries (with notching
of the inferior aspect of the ribs in the chest X-ray, together with a 3 sign).

Coarctation of Aorta
Congenital defect, male > female
Clinical
Differential systolic BP arms vs legs.
May have differential BP in arms if defect is prox to L
subclavian artery.
Diminished/absent femoral arterial pulses.
Often asymptomatic
Associated with Turners, bicuspid AV.
If uncorrected 67% will develop LV failure by age 40 and 75%
will die by age 50.
Surgical Rx, long term survival better if corrected early.
Obstructive Sleep Apnea
Is OSA being underdiagnosed as the main secondary form of hypertension?

The Relationship between Obstructive Sleep
Apnea and Hypertension
The odds of having
hypertension is 37% greater
in persons with obstructive
sleep apnea.
The odds of having
hypertension is 46% greater
in those who spend greater
percentage of sleep time
below 90% oxygen
saturation.
Nieto, F. J. et al. JAMA 2000;283:1829-1836
Norman, D. et al. Hypertension 2006;47:840-845
Change in 24-hour ABPM after 2 weeks of therapy
with CPAP
Norman et al, as well as many others have shown that OSA patients BP responds to CPAP.

Pheochromocytoma
Uncommon tumors composed of chromaffin cells
which synthesize and release catecholamines.

Surgically correctable forms of hypertension.

0.1% to 0.3% of hypertensive patients have an
underlying pheochromocytoma.
Clinical Features
Hypertension: often severe, occasionally malignant,
and may be resistant to treatment with standard
antihypertensive drugs.

Paroxysms or Crisis: frequent or sporadic, occurring
at intervals as long as weeks or months. With time,
the paroxysms usually increase in frequency,
duration, and severity.
Other Distinctive Clinical Features
Increased metabolic rate, such as profuse sweating
and mild to moderate weight loss.

Sinus tachycardia, sinus bradycardia,
supraventricular arrhythmias, and ventricular
premature contractions have all been noted.

Angina and acute myocardial infarction.
Diagnosis
The diagnosis is established by the demonstration of
increased production of catecholamines or
catecholamine metabolites.

The diagnosis can usually be made by the analysis of
a single 24-h urine sample, provided the patient is
hypertensive or symptomatic at the time of
collection.
Pheochromocytoma
Pheochromocytomas are usually seen on imaging studies when they are symptomatic.

Back to our patient: outside studies.
ECG: Normal sinus rythm/sinus tachycardia.
Labs: All in the normal range.
Stress echo, abdominal and thoracic CT
(contrast), and full body MRI were normal.
Thyroid hormones, plasma epinephrine and
norepinephrine, serum Aldo and plasma Renin
all normal.
Renal Duplex unremarkable.
Back to our patient: physical exam
HR= 64/min, BP (4 limbs) = 126/72. No ortho.
Normal physical exam (fundoscopic evaluation)
Uppon abdominal exam, he became tachycardic,
diaphoretic and BP rose to 190/102 mmHg.
HR and BP returned to normal after 15 min.
Plasma metanephrine levels were slightly
elevated at 80 pg/mL (normal < 57 pg/mL) with
normal normetanephrine values and
chromogranin-A.
24 hs Holter and BP monitor
A
B
C
D
BP = 122/74 mmHg
HR= 75/min
Pulse Ox= 97%
BP = 150/92 mmHg
HR= 107/min
Pulse Ox= 97%
BP = 196/104 mmHg
HR= 142/min
Pulse Ox= 97%
BP = 138/82mmHg
HR= 99/min
Pulse Ox= 97%
23: 21 PM
23: 23 PM
23: 55 PM
23: 57 PM
Cingolani OH et al. Circulation. 2014. In press.
Holter and BP monitoring revealed transient elevations in HR and BP at night. Sinus tachycardia
and hypertension returned to normal values in 30 min.

Hypertension Rounds
How many of you think this is secondary
hypertension?

How many of you think this is a Pheo?

How many think this is another form of
secondary hypertension?
Abdomen CT and MIBG scan
Cingolani OH et al. Circulation. 2014. Mar 4;129(9).
Although CT scan revealed normal adrenal glands, a Iodine-131-metaiodobenzylguanidine
(MIBG) radioisotope scan was strikingly positive for isotope uptake from the left adrenal
gland, therefore the gland was succesfully removed laparoscopically after alpha and beta
blocking treatment was instituted.

Adrenal Medullary Hyperplasia
Cingolani OH et al. Circulation. 2014. Mar 4;129(9)
Normal adrenal gland Primary adrenal medullary hyperplasia
Adrenal Medullary Hyperplasia
Uncommon condition that can clinically mimic
pheochromocytoma.
Most commonly, the condition is associated with
multiple endocrine neoplasia (MEN) syndromes.
It might antecede the formation of Pheo.
It might recur in the contralateral gland.
Responds to alpha and beta blockade.
Kurihara K, Mizuseki K, Kondo T, Ohoka H, Mannami M, Kawai K. Adrenal medullary
hyperplasia. Hyperplasia-pheochromocytoma sequence. Acta Pathol Jpn. 1990;40:683-686
Thank You!
Oscar H. Cingolani, MD

ocingol1@jhmi.edu