Quick Reference for Residents:

Endocrine Hypertension

Soe Naing, MD, MRCP(UK), FACE

Endocrinologist
Associate Clinical Professor of Medicine
Director of Division of Endocrinology
Medical Director of Community Diabetes Care Center
UCSF-Fresno Medical Education Program

Version: SN/2-10-2016

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SUMMARY AND RECOMMENDATIONS:

Evaluation: From “Endocrine HTN” available at http://www.endotext.org/

Endocrine Hypertension accounts for about 3% of the secondary forms of hypertension and is a term
assigned to states in which hormonal derangements result in clinically significant hypertension. The most
common causes of endocrine hypertension are

1. primary hyperaldosteronism,
2. pheochromocytoma, and
3. Cushing’s syndrome.

Hypertension in young patients and refractory hypertension should alert the physician to screen for
secondary causes. The first step when evaluating a patient with suspected endocrine-related hypertension
is to exclude other causes of secondary hypertension.

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 1. Primary Hyperaldosteronism
• Primary aldosteronism (hyperaldosteronism) causes hypertension by an inappropriately high
aldosterone secretion that does not suppress adequately with sodium loading. Primary
aldosteronism is believed to account for 8% of all cases of hypertension and 20% of cases of
resistant hypertension. It should also be suspected with early-onset hypertension or stroke before
age 50 years (or both). It may be difficult to distinguish primary aldosteronism from cases of low
renin essential hypertension, with which it may overlap. Patients of all ages may be affected, but
the peak incidence is between 30 years and 60 years. Excessive aldosterone production increases
sodium retention and suppresses plasma renin. It increases renal potassium excretion, which can
lead to hypokalemia. Cardiovascular events are more prevalent in patients with aldosteronism
(35%) than in those with essential hypertension (11%). Primary aldosteronism may be caused by
an aldosterone-producing adrenal adenoma (Conn syndrome), 40% of which have been found to
have somatic mutations in a gene involved with the potassium channel. Primary aldosteronism is
also commonly caused by unilateral or bilateral adrenal hyperplasia. (from Current Medical Diagnosis &
Treatment 2016)

• This should be suspected in any patient with the triad of:

1. HTN
2. unexplained hypokalemia and
3. metabolic alkalosis.

• The most common subtypes are:

1. Aldosterone-producing adenoma (Conn’s) (APA)
2. idiopathic hyperaldosteronism (IHA)/Bilateral adrenal hyperplasia/ Bilateral micronodular
hyperplasia

• The screening test of choice is “plasma aldosterone to renin ratio or PAC/PRA ratio”.

• Protocol: (please refer to “up-to-date” under the session of "Approach to the patient with hypertension and hypokalemia" for detail)

The test is performed by measuring a morning (preferably 8 AM), ambulatory, paired,

random plasma aldosterone concentration (PAC) and plasma renin activity (PRA) or
plasma renin concentration (PRC). In general, PRA and PRC are undetectable in patients
with primary aldosteronism. In most patients with primary aldosteronism, the PAC is >15
ng/dL; the net effect is a PAC/PRA ratio greater than 20.(Some use a cutoff criteria of 30).
Most antihypertensive medications can be continued and posture stimulation is not
required.

Spironolactone and eplerenone should not be initiated until the evaluation is completed
since these can cause an elevation in PRA. The patients already receiving spironolactone,
therapy should be discontinued for at least six weeks. Other potassium-sparing diuretics,
such as amiloride and triamterene, usually do not interfere with testing unless the patient is
on high doses.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs),

and direct renin inhibitors can falsely lower PAC/PRA ratio, and therefore the test should be
repeated at least 4 weeks after stopping these medications if there is a strong clinical
suspicion of hyperaldosteronism.

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Table: Effects of Antihypertensive Drugs on the Aldosterone-Renin-Ratio (ARR)

Drug Effect on Renin Effect on Aldosterone Net Effect on ARR

β Blockers ↓ ↑ ↑
α1 Blockers → → →
α2 Sympathomimetics → → →
ACE inhibitors ↑ ↓ ↓
AT1R blockers ↑ ↓ ↓
Calcium antagonists → → →
Diuretics (↑) (↑) →/(↓)

Abbreviations: ACE, angiotensin-converting enzyme; AT1R, angiotensin II receptor type 1.

From Harrison's Principles of Internal Medicine, 19e

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 Treatment
Conn syndrome (unilateral aldosterone-secreting adrenal adenoma) is usually treated by laparoscopic
adrenalectomy, although long-term medical therapy is an option. Bilateral adrenal hyperplasia is best
treated with medical therapy. Medical treatment must include a potassium-sparing diuretic,
particularly spironolactone, eplerenone, or amiloride. Spironolactone also has antiandrogen activity and
men frequently experience breast tenderness, gynecomastia, or reduced libido; it is given at initial doses
of 12.5–25 mg orally once daily; the dose may be titrated upward to 200 mg daily. Spironolactone is
contraindicated in pregnancy and reproductive-age women are cautioned to use contraception during
therapy. Eplerenone is becoming favored for men, since it does not have antiandrogen effects; however, it
has a short half-life and must be taken orally twice daily in doses of 25–50 mg. Another option is amiloride,
which is effective in doses of 10–20 mg/day and is the preferred medication for hyperaldosteronism during
pregnancy. Blood pressure must be monitored daily when beginning these anti-mineralocorticoid
medications; significant drops in blood pressure have occurred when these drugs are added to other
antihypertensives. Other antihypertensive drugs may be required, particularly amlodipine, and ACE
inhibitors or ARBs. (from Current Medical Diagnosis & Treatment 2016)

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Overview of management of patients with suspected mineralocorticoid excess.

From Harrison's Principles of Internal Medicine, 19e

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 2. Pheochromocytoma

Pheochromocytomas and paragangliomas are catecholamine-producing tumors derived from the

sympathetic or parasympathetic nervous system. These tumors may arise sporadically or be inherited
as features of multiple endocrine neoplasia type 2, von Hippel–Lindau disease, or several other
pheochromocytoma-associated syndromes. The diagnosis of pheochromocytomas identifies a
potentially correctable cause of hypertension, and their removal can prevent hypertensive crises that
can be lethal. The clinical presentation is variable, ranging from an adrenal incidentaloma to a
hypertensive crisis with associated cerebrovascular or cardiac complications.

Pheochromocytoma is estimated to occur in 2–8 of 1 million persons per year, and ∼0.1% of
hypertensive patients harbor a pheochromocytoma. The mean age at diagnosis is ∼40 years, although
the tumors can occur from early childhood until late in life. The classic “rule of tens” for
pheochromocytomas states that ∼10% are bilateral, 10% are extra-adrenal, and 10% are malignant.

Its clinical presentation is so variable that pheochromocytoma has been termed “the great
masquerader”.

Table: Clinical Features Associated with Pheochromocytoma,

Listed by Frequency of Occurrence

1. Headaches 10. Weight loss

2. Profuse sweating 11. Paradoxical response to antihypertensive drugs
3. Palpitations and tachycardia 12. Polyuria and polydipsia
4. Hypertension, sustained or paroxysmal 13. Constipation
5. Anxiety and panic attacks 14. Orthostatic hypotension
6. Pallor 15. Dilated cardiomyopathy
7. Nausea 16. Erythrocytosis
8. Abdominal pain 17. Elevated blood sugar
9. Weakness 18. Hypercalcemia
From Harrison's Principles of Internal Medicine, 19e

 This should be suspected in any patient with the triad of:

1. headache,
2. sweating and
3. tachycardia

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 Diagnosis of Pheochromocytoma and Paraganglioma

 The screening test of choice is “24-hour urine fractionated catecholamines and metanephrines
and/or plasma fractionated metanephrines”.

Table: Biochemical and Imaging Methods Used for Diagnosis of Pheochromocytoma and Paraganglioma

Diagnostic Method Sensitivity Specificity

24-h urinary tests
Catecholamines +++ +++
Fractionated metanephrines ++++ ++
Total metanephrines +++ ++++
Plasma tests
Catecholamines +++ ++
Free metanephrines ++++ +++
Imaging
CT ++++ +++
MRI ++++ +++
MIBG scintigraphy +++ ++++
Somatostatin receptor scintigraphya ++ ++
Fluoro-DOPA PET/CT
18
+++ ++++

aValues are particularly high in head and neck paragangliomas.

Abbreviations:
MIBG, metaiodobenzylguanidine; PET/CT, positron emission tomography plus CT. For the biochemical tests, the
ratings correspond globally to sensitivity and specificity rates as follows: ++, <85%; +++, 85–
95%; and ++++, >95%.

From Harrison's Principles of Internal Medicine, 19e: Pheochromocytoma

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 PHEOCHROMOCYTOMA-ASSOCIATED SYNDROMES
From Harrison's Principles of Internal Medicine, 19e: Pheochromocytoma

About 25–33% of patients with a pheochromocytoma or paraganglioma have an inherited syndrome. At

diagnosis, patients with inherited syndromes are a mean of ∼15 years younger than patients with sporadic
tumors.

Neurofibromatosis type 1 (NF1) was the first described pheochromocytoma-associated syndrome.

The NF1 gene functions as a tumor suppressor by regulating the Ras signaling cascade. Classic features
of neurofibromatosis include multiple neurofibromas, café au lait spots, axillary freckling of the skin, and
Lisch nodules of the iris. Pheochromocytomas occur in only ∼1% of these patients and are located
predominantly in the adrenals. Malignant pheochromocytoma is not uncommon.

Neurofibromatosis. A. MRI of bilateral adrenal pheochromocytoma. B. Cutaneous neurofibromas. C. Lisch

nodules of the iris. D. Axillary freckling.

The best-known pheochromocytoma-associated syndrome is the autosomal dominant disorder multiple

endocrine neoplasia type 2 (MEN2) . Both types of MEN2 (2A and 2B) are caused by mutations
in RET (rearranged during transfection), which encodes a tyrosine kinase. The locations of RET mutations
correlate with the severity of disease and the type of MEN2. MEN2A is characterized by medullary thyroid
carcinoma (MTC), pheochromocytoma, and hyperparathyroidism; MEN2B also includes MTC and
pheochromocytoma as well as multiple mucosal neuromas, marfanoid habitus, and other developmental
disorders, though it typically lacks hyperparathyroidism. MTC is found in virtually all patients with MEN2,
but pheochromocytoma occurs in only ∼50% of these patients. Nearly all pheochromocytomas in MEN2
are benign and located in the adrenals, often bilaterally. Pheochromocytoma may be symptomatic before
MTC. Prophylactic thyroidectomy is being performed in many carriers of RET mutations;
pheochromocytomas should be excluded before any surgery in these patients.

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Von Hippel–Lindau syndrome (VHL) is an autosomal dominant disorder that predisposes to retinal and
cerebellar hemangioblastomas, which also occur in the brainstem and spinal cord. Other important
features of VHL are clear cell renal carcinomas, pancreatic neuroendocrine tumors, endolymphatic sac
tumors of the inner ear, cystadenomas of the epididymis and broad ligament, and multiple pancreatic or
renal cysts.
Other syndromes are the paraganglioma syndromes (PGLs) and familial pheochromocytoma (FP).

Von Hippel–Lindau disease. A. Retinal angioma. All subsequent panels show findings on MRI: B–
D. Hemangioblastomas of the cerebellum (B) in brainstem (C) and spinal cord (D). E. Bilateral
pheochromocytomas and bilateral renal clear cell carcinomas F. Multiple pancreatic cysts.

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 3. Cushing’s syndrome
From up-to-date and Harrison's Principles of Internal Medicine, 19e

Cushing’s syndrome reflects a constellation of clinical features that result from chronic exposure to
excess glucocorticoids of any etiology. The disorder can be ACTH-dependent (e.g., pituitary
corticotrope adenoma) or ACTH-independent (e.g., adrenocortical adenoma), as well as iatrogenic
(e.g., administration of exogenous glucocorticoids). The term Cushing’s disease refers specifically
to Cushing’s syndrome caused by a pituitary corticotrope adenoma.

Cushing’s syndrome is generally considered a rare disease. It occurs with an incidence of 1–2 per
100,000 population per year. In the overwhelming majority of patients, Cushing’s syndrome is
caused by an ACTH-producing corticotrope adenoma of the pituitary.

 This should be suspected in any patient with

1. supraclavicular fat pads,
2. easy bruising/ skin atrophy,
3. wide purplish abdominal striae, and
4. proximal muscle weakness.

 The 3 screening tests to establish the diagnosis of Cushing's syndrome or hypercortisolism:

1. 24-hour urinary cortisol,
2. late night salivary cortisol, and
3. low-dose dexamethasone suppression tests.

 The tests to establish the cause of Cushing's syndrome:

1. Plasma ACTH concentrations
2. High-dose dexamethasone suppression tests
3. CRH (corticotropin-releasing hormone) stimulation test
4. Petrosal venous sinus catheterization.

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Typical findings in Cushing syndrome. (from Current Medical Diagnosis & Treatment 2016)

Clinical features of Cushing’s syndrome. (From Harrison's Principles of Internal Medicine, 19e)
A. Note central obesity and broad, purple stretch marks (B. close-up). C. Note thin and brittle skin in an elderly patient with
Cushing’s syndrome. D. Hyperpigmentation of the knuckles in a patient with ectopic adrenocorticotropic hormone (ACTH) excess.

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 >1.8 mcg/dL

>1.8 mcg/dL

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