What clinician needs to know about

secondary arterial hypertension?

Rene Magritte

Asoc. prof. Ilze Konrade

Riga East Clinical Hospital
Riga Stradins university
 Suspition of secondary hypertension
• Age: young or elderly (new onset)
• Treatment resistant: 3+ medication
• Adrenal incidentaloma

Consider differential diagnoses:

Endocrine:
Primary aldosteronism
Hyperthyroidism/hypothyroidism
hypercalcemia
Pheochromocytoma
Cushing syndrome (GC excess)
Vascular: coarctation of aorta,
renovascular disease
Other: Obstructive sleep apnea,
Obesity, alcoholism
Laboratory tests:
Complete metabolic panel
TSH
Plasma aldosteron-to-renin ratio
Plasma/urine metanephrines
24 h urine cortisol
CT- renal arteries
ECG, overnight oximetry
 Adrenal Incidentaloma
• A 42-year-old woman has been in a motor vehicle accident in which her
seat belt tightened. She has upper abdominal pain and is evaluated with
CT.
• This imaging shows no evidence of intraabdominal trauma but reveals a
well circumscribed and homogeneous left adrenal mass that is 3.2 cm in
diameter. The mass has an attenuation value of 7 HU on unenhanced CT.
• The patient’s history is remarkable for obesity and newly diagnosed mild
hypertension.
• On physical examination, the BP is 142/90 mm Hg. There is sternal and
upper abdominal bruising but no striae, moon facies, or fat
accumulation over the dorsocervical spine (“buffalo hump”).
• How should this patient be further evaluated and treated?
 Adrenal incidentaloma
• adrenal incidentaloma is defined as a clinically unapparent adrenal
lesion (≥1 cm in diameter) that is detected on imaging performed for
indications other than evaluation for adrenal disease.
• the prevalence of adrenal incidentaloma has been reported to be 1 to
6%:
• 75% are nonfunctioning cortical adenomas.
• ~14% of adrenal incidentalomas are functional tumors that secrete excess
cortisol, aldosterone, or (rarely) both.
• approximately 7% - pheochromocytomas
• primary adrenal cancers or metastases to the adrenal glands - approximately
4%

Cabebew E., N Engl J Med 2021;384:1542-51.

 Adrenal incidentaloma
The key clinical questions are:
• Is it functioning?
• Is it malignant?
On CT:
Tumor <4 cm in diameter
≤10 HU on CT native scans
CT contrast washout ≥40–60%
Signal loss on MRI chemical-shift
analysis
Benign apperance !
Hormonal evaluation:
Overnight 1-mg dexamethasone
suppression test;
If hypertension or K↓ present, -
plasma aldosterone-to- renin ratio
On CT:
Tumor ≥4 cm in diameter
>10 HU on CT native scans
CT contrast washout < 40–60%
On MRI, hyperintense on T2 imaging
or no signal loss on chemical-shift
analysis
Suspicious appearance !:
Additional imaging (enhanced CT,
MRI, 18F-FDG PET-CT, MIBG
scintigraphy) in some patients
Hormonal evaluation: plasma-free
metanephrine level or fractionated
metanephrine level in 24-hr urinary
specimen
 Low renin Hypertension

High (sometimes relative) aldosterone Low-normal aldosterone Low aldosterone

Low-normal potassium High potassium Low-normal potassium

Consider primary
aldosteronism and perform
confirmatory tests

Athimulam S et al., Endocrinol Metab Clin N Am 48 (2019) 701-715

Primary
Hyperaldosteronism
(Conn's Syndrome)
• PA is defined as inappropriately
elevated aldosterone production in
the setting of low plasma renin.
• Most common cause of secondary
hypertension with a prevalence of
20% among patients with resistant
hypertension.
• Only a small fraction of the patients
with PA are diagnosed and treated
Actions of aldosterone on the
ascending loop of Henle, distal
convoluted tubule and cortical
collecting ducts of the kidney

Aldosterone regulates the final stages

of Na reabsorbtion in the distal renal
tubule and collecting duct. Although
aldosterone regulates absorbtion of
just 1-5% of filtred Na, the kidney
filters the entire circulating plasma
volume 2 an hour, totaling ~180 L
plasma a day

Reduced need for aldosterone production in societies

consuming a high-Na diet;

Byrd J. B., Turcu A.F., Auchus R.J., Circulation 2018; 138: 823-835
The Emerging Clinical Implications of the Role of
Aldosterone

Epstein M, Am J Med, 2006; 119:912

The Emerging Clinical Implications of the Role of Aldosterone

DOCA – Low NaCl BP identical !!! DOCA – high NaCl

• Concentric left ventricular hypertrophy and poorer diastolic function;

• Diffuse noninfarct pattern of late gadolinium enhancement on cardiac
MRI;
• Myocardial fibrosis contributes to arrhythmias ans sudden death;
Q. Wang et al, JASN 2002
 Q
• A 35-year-old man presented to his primary care physician with an
elevated blood pressure of 160/100 mmHg despite being on
antihypertensive medication (HCT and amlodipine). He had a strong
family history of elevated blood pressure and haemorrhagic strokes.
His initial blood test results showed hypokalaemia (K 3,2 mmol/l).
The diagnosis of secondary hypertension due to primary
hyperaldosteronism (PA) is considered.
Which one of the following is a recomended criterion to screen for
primary hyperaldosteronism?
• A) Adrenal incidentaloma (in a normotensive patient)
• B) Diuretic-induced hypokalaemia
• C) family history or cerebrovascular disease
• D) Hypertension in pregnancy
• E) Hypertension not controlled by one antihypertensive
 Answer B
• The recommended criteria for screening for PA in patients with
hypertension include:
Young age (<30 y)
Diuretic-induced or spontaneous hypokalaemia
Resistant hypertension (to ≥3 anti-hypertensive medications at optimal
doses)
Sustained hypertension (systolic >160 mmHg, distolic>100 mmHg)
Adrenal incidentaloma (1% of patients may have PA)
A strong family history of early onset hypertension or haemorrhagic
strokes at a young age (<40 years)
All hypertensive first – degree relatives of patient with primary
aldosteronism
Sleep apnea
Funder J, Fardella C et al., An Endocrine Society Clinical Practice
guideline. J Clin Endocrinol Metab, 101(5): 1889-1916. 2016
 PA has the following seven subtypes:
Subtype frequency
Bilateral idiopathic hyperaldosteronism 60 - 65%
(IHA) (mikronodular hyperplasia)
Aldosterone- producing adenoma 30 - 35%
Unilateral adrenal hyperplasia 3 - 2%
(makronodular)
Aldosterone producing adrenal <1%
carcinoma
Glucocorticoid remediable <1%
hyperaldosteronism
Familiar hyperaldosteronism 3-5%
Ectopic aldosterone producing carcinoma <0,1%
(ovaries and kidneys) Int J Mol Sci. 2017 Apr; 18(4): 848.
ARR cutoff values, depending on Assay

ϻU/ml

pg/ml
 Q
• A 44-year-old man presented with resistant and uncontrolled
hypertension despite being on three different antihypertensive
agents. He had a strong family history of stroke and ischaemic
heart disease. A diagnosis of PA is considered and a plasma
Aldosterone-to renin ratio (ARR) was arranged as an initial
screening test.
Which one of the following medications is associated with a false
positive plasma aldosterone-serum renin activity test results?
A) Amlodipine
B) β-blockers
C) Doxazosin
D) Hydralazine
E) Lisinopril
Answer B
False positive False negative No impact on results
Β- blokers ACE inhibitors Doxazosin
Clonidine Angiotensin receptor Verapamil (non-
blockers dihydropyridine)
Hormone replacement Calcium channel blockers Terazosin
therapy
Methyldopa Eplerenone (4 weeks) Hydralazine
NSAIDs Spironolactone (4 weeks) Prazosin
Oral contraceptive pills Hypokalemia

Factor Effect on Aldosterone Effect on renin Effect on ARR

Β- blokers ↓ ↓↓
ACE –I/ ARBs ↓ ↑↑
Ca blockers (DHP) ↔↓ ↑

Funder J, Fardella C et al., An Endocrine Society Clinical Practice guideline. J Clin

Endocrinol Metab, 101 (5): 1889-1916. 2016
Screening for Primary Aldosteronism
• Discontinuation of antihypertensive medications to facilitate testing
for PA has some risks.
• Recommendations for a screening patients in the office without discontinuing
medications;
• Although mild cases might be missed when screening is performed during
medication treatment, most patients with significant PA who will benefit from
further evaluation will still have suppressed renin;
• Only when renin is nor suppressed but the ARR are high, interfering
medications should be reduced or discontinued.
Q
• A 36-year-old man presented to the medical assesment unit with a
gradual onset headache and high blood pressure. He had no previous
history of any significant medical disease. His blood pressure was
190/110 mmHg; Investigations:
Na 145 mmol/l (135-145 mml/l)
K 4,6 mmol/l (3,5-5,5 mmol/l)
Aldosterone 1645 pmol/l (100-850 pmol/l)
PAR 0,1 pmol/ml/h (0,5-3,5 pmol/ml/h)
CT abdomen 1,5 cm left adrenal mass
Which one of the following is the most appropriate next step in his
further management?
A) Adrenal venous sampling
B) Dexamethasone supression test
C) Laparascopic left adrenalectomy
D) Start Spironolactone
E) Ultrasound-guided biopsy
Answer A
• Adrenal CT has several limitations including inability to detect
small aldosterone producing adenomas (APAs) or these lesions
getting incorrectly labelled as bilateral idiopathic
hyperaldosteronism (IHA).
• The apparent adrenal nodules on CT may actually represent an
area of hyperplasia. Incidentally-detected adrenal lesions are
also indistinguishable from APAs on CT.
• In view of the above mentioned limitations of radiological
imaging studies, it is recomended that adrenal venous sampling
should be arranged for patients with a possible APA, if surgery is
deemed practical
↓K, renin↓↓↓
PAC>20 ng/dl

No need for
confirmatory
testing
(2/+ooo)
 Adrenal venous sampling
•Interventional radiologists
V.Cava catheterize the adrenal veins;
superior •Blood from both adrenal veins
V.suprarenalis dx and a peripheral vein is taken
The right adrenal and assayed for aldosterone
vein may be and cortisol concentrations to
especially difficult confirm successful
to catheterize catheterization.
because it is short
and enters the
inferior v. cava at V.suprarenalis sin
an acute angle

V.renalis dx V. renalis sin

V.Cava
inferior

The adrenal /peripheral vein

cortisol ratio is typically more
than 2:1 without cosyntropin use
 Adrenal vein sampling
Cut-off ratio from high-side to low side >4:1

vein Aldosterone Cortisol mcg/dl A/C ratio Aldosterone

ng/dl ratio
RT Adrenal 782 1105 0,7
vein
LT Adrenal vein 8504 700 12.1 17.3 : 1

Inferior vena 87 31 2,8

cava
Younger patients (age<35) with spontaneous hypokalemia,
marked aldosterone excess, and unilateral adrenal lesions with
radiological features consistent with a cortical adenoma on
adrenal CT scan may not need AVS before proceeding to
unilateral adrenalectomy

Funder J, Fardella C et al., An Endocrine Society Clinical Practice guideline. J Clin

Endocrinol Metab, 101 (5): 1889-1916. 2016
In patients with PA due to bilateral adrenal disease (includes
Idiopathic adrenal hyperplasia), we recommend medical
treatment with an MR anatagonist;
We suggest spironolactone as the primary agent, with
eplerenone as an alternative
 Mineralocorticoid receptor antagonists
MR antagonists appear to be effective at controlling BP and protecting
target organs independent of effects on BP.
Eplerenone: a selective MR antagonist, Spironolactone: non-selective MR
no binding to the progesterone and antagonist whose structural
androgen receptors - better tolerability charachteristics resemble those of
profile; progesterone.
Shorter half-life (4-6 h) - should be given For this reason, spironolactone is
twice daily for optimal effect. associated with progestogenic and anti-
Food intake does not affect eplerenone androgenic effects, such as loss of
absorbtion; in vivo-~60% the potency of libido, gynaecomastia and menstrual
spironolactone irregularities

Eplerenon Spironolacton
12,5 -25 mg once
daily, increased by
25 to 50 mg every 4
weeks)
P.M.Seferovic et al.,
Int J of Cardiology
2015
 „The hardest thing of all is to
find a black cat in a dark
room, especially if there is no
cat.»
Confucius
 Low renin Hypertension

High (sometimes relative) Low-normal aldosterone Low aldosterone

aldosterone High potassium Low-normal potassium
Low-normal potassium

Consider primary
Gordon syndrome
aldosteronism and perform
(pseudohypoaldosteronism type 2)
confirmatory tests

Athimulam S et al., Endocrinol Metab Clin N Am 48 (2019) 701-715

 Gordona sindroms
• Occurs secondary to mutations in WNK1, WNK4, CUL3, or
KLHL3 genes, and can be inherited in either an autosomal
dominant or recessive form.
• The WNK (With No Lysine) kinases, encoded by WNK1 and
WNK4 genes, regulate the expression of the Na/Cl
cotransporter in the distal nephron, while the scaffold protein
Cullin 3 and the adaptor protein Kelch 3 (encoded by the
CUL3 and KLHL3 genes, respectively) are involved in the
ubiquitination and proteasomal degradation of the WNK
kinases.
• The effects of these complex interactions are upregulation of
the Na/Cl cotransporter at the plasma membrane resulting in
increased Na reabsorption, reduced expression of renal outer
medullar K channel, and subsequent hyperkalemia.
• Patients diagnosed with Gordon syndrome may be treated
with thiazide diuretics that act by inhibiting the Na/Cl
cotransporter Athimulam S et al., Endocrinol Metab Clin N Am 48 (2019) 701-715
 Low renin Hypertension

High (sometimes relative) Low-normal aldosterone Low aldosterone

aldosterone High potassium Low-normal potassium
Low-normal potassium

Consider primary Gordon syndrome Genetic: Acquired:

aldosteronism and perform (pseudohypoaldosteronism Liddle syndrome Deoxycorticosterone
confirmatory tests type 2) Apparent secreting tumors
Mineralcorticoid Hypercortisolism
excess Licorice ingestion
CYP17 deficiency Grapefruit ingestions
Glucocorticoid Low renin eesential
resistance hypertension
Mineralocorticoid High salt diet
receptor activating
mutation
Athimulam S et al., Endocrinol Metab Clin N Am 48 (2019) 701-715
 Minerālkortikoīdu Sites of pathologic relevance within the principal cells
of the collecting tubules and collecting ducts of the
kidney.
ekscess 1) Glucocorticoid remediable aldosteronism (GRA)
is caused by a chimeric gene formation that
produces aldosterone under the stimulation of
ACTH.
2) Apparent mineralocorticoid Excess (AME) occurs
due to a mutation in the gene encoding 11βHSD2
that results in reduced oxidation of cortisol,
thereby permitting cortisol activation of the MR.
3) Geller syndrome is caused by a missense, gain-of-
function mutation on the MR that permits
binding of progesterone. During pregnancy,
progesterone levels are elevated, leading to
excess activation of the MR pathway.
4) Liddle’s syndrome is the result of mutation of
either beta or gamma subunits of ENaC that
prevents Nedd4-2 binding. As a result, ENaC
avoids ubiquitination and degradation; The result
of the inhibited breakdown of ENaC leads to
increased ENaC expression on the apical
Peter E. Levanovich et al., Current Hypertension Reviews, membrane which causes increased Na+
2020, 16, 91-107 reabsorption
Pheochromocytoma and Paraganglioma
 Q
• A 42-year-old woman presented to the accident and emergency
department with sudden onset anxiety, palpitations, and headache.
On examination, she had blood pressure of 200/120 mmHg;
• Investigations: urinary noradrenaline 12,8 mkmol/24h (<4,0)
Urinary adrenaline 16,0 mkmol/24h (<2,0)
• On the basis of her clinical presentation and biochemestry results a
diagnosis of Pheo was considered.
Which one of the following investigation is most appropriate for initial
localization of the tumour?
• A) CT abdomen
• B) MIBG scan
• C) Octreotide scan
• D) PET scanning
• E) Technetium scan
 Answer A
• CT of the abdomen remains the initial modality of choice to localize
the tumor if biochemestry results are suggestive of the diagnosis of
PH or extra-adrenal PGLs (which are mostly intra-abdominal).
• MIBG scanning should be considered for patients suspected with PH
or PGL, if the initial CT fails to localize the tumour or to assess for any
possible metastasis (e.g. in patients with Von Hippel-Lindau syndrome
or SDHB mutation). MIBG is usualy required for most of the extra-
adrenal PGL and intra-adrenal PH tumours>5 cm to confirm the
tumour.
 Which patient has the pheo?
1) Hypertension 1) Normal BP;
2) Plasma normetanephrine increased 2) Normal plasma fractionated
40% above ULN metanephrines;
3) CT phenotype: Precontrast HU<10 3) CT phenotype: dense and vascular,
and > 50% contrast washout at 10 inhomogeneus with cystic degenerative
min areas. Precontrast HU >20 and <50%
contrast washout at 10 min

Imaging phenotype «trumps» biochemical testing any day;

Imaging phenotype will guide your management: pre-biochemical phase;
The tumor can always be found in the pt with pheo- the avg diameter is 4,5 cm.
If you are having trouble localizing a pheo, it is usually because your patient
does not have a pheo and you have ignored some of the biochemical dx tips
Medications that may elevated measured levels of
catecholamines
• Tricyclic antidepressants
• Levodopa
• Drugs containing adrenergic receptor agonists (e.g.,
decongestants)
• Amphetamines
• Buspirone and most psychoactive agents (exept not-
selective serotonin reuptake inhibitors (SSRIs)
• Withdrawal from clonidine and other drugs (e.g., illicit
drugs)
• Ethanol
Cushing’s syndrome

Henry VIII of England;

National Maritime Museum, London
Q
• A 48-year old woman presented to her GP with symptoms of
progressive weight gain, fatigue, and menstrual irregularity. On
examination, she had facial pletora, central obesity, increased facial
and body hair, proximal myopathy. Based on her signs and symptoms,
a clinical suspicion of Cushing’s syndrome was raised and a 24-h
urinary free cortisol measurement is arranged.
• Which one of the following clinical features is relatively
discriminatory for the diagnosis of Cushing’s syndrome?
A Facial pletora
B Hirsutism
C Strech marks
D Weight gain
E Worsening glycaemic control
Answer A
• Cushing’s syndrome can present with a wide spectrum of clinical
manifestations, which may be seen in conditions leading to
hypercortisolism, such as depression, alcoholism, obesity, and poorly-
controlled diabetes. The following clinical features are considered to
be more discriminatory for Cushing’s syndrome (although not highly
sensitive):
• Easy bruisability
• Facial pletora
• Proximal myopathy
• Reddish-purple striae
• Retardation of growth velocity and weight gain in children
 Endogenous Cushing Syndrome
Incidence: 0,2-5,0 patients/miljonu iedzīvotāju;
Prevalence: 39-79 patients/miljonu iedzīvotāju;
Vidējais diagnozes noteikšanas vecums 41,4 gadi
female-to-male incidence ratio 3:1
 Screening Tests for Cushing's Syndrome

1mg dexamethasone Late-night salivary

Urinary free cortisol (UFC)
suppression test cortisol (LNSC)
(2X)
(≤1,8µg/dL)
Q
• A 50-year-old man presented to the clinic with progressive wieght gain
and easy bruisability. He had a backgraund medical hystory of epilepsy
and type 2 diabetes, and he was taking Phenytoin and metformin
tablets. On examination, he had central obesity, facial fullness, and thin
skin, although there was no evidence of proximal myopathy or facial
pletora.
• Which one of the following test is most appropriate for initial
screening of Cushing’s syndrome in his clinical scenario?
A 24-h urinary free cortisol
B Insulin tolerance test
C Overnight dexamethasone supression test
D Plasma ACTH levels
 Answer A
• The dexamethasone suppression test should not be used in patients
with epilepsy who are taking medications that increase
dexamethasone clearence.
• Measurement of urinary or salivary cortisol in this scenario provides
relatively more accurate results.
Medications that may interfere with diagnostic tests for Cushing’s syndrome:
Inducers of hepatic Impaired Increased CBG (false Increase urinary free
enzymes (increased dexamethasone positive cortisol results) cortisol
dexamethasone clearence) clearence
Carbamazepine Diltiazem Oral contraceptive pills Liquorice
Fhenytoin Fluoxetine Mitotane Fenofibrate
Phenobarbiturates Itraconazole Carbenoxolone
Pioglitasonum Ritonavir
Rifampicin

Gilbert R and Lim E. The diagnosis of Cushing’s syndrome. Clinical Biochemist Reviews, 2008; 29 (3):103-106
Non of the tests are «Golden Standard»
Cyclic Cushing's syndrome- UFC for a cyclic
Cushings syndrome
 Classification and etiology of Cushing’s syndrome
First- hypercortisolaemia,
For an etiologic group: ACTH

ACTH-dependent Cushing syndrome ACTH-independent Cushing

syndrome

Pituitary dependent Ectopic Cushing’s adrenal-dependent Bilateral adrenal

Cushing’s syndrome syndrome Cushing’s syndrome hyperplasia
MRI findings