Evaluation of the Endocrine Causes of Hypertension

Hypertension, or high blood pressure, has been established as a major modifiable risk factor for several diseases such as ischemic heart disease, heart failure, chronic kidney disease, and cerebrovascular accidents. It is the leading determinant of cardiovascular morbidity and mortality and was estimated to affect over 30% of the global adult population in 2019.¹ Characterized by chronic elevated systemic arterial blood pressure, a consensus definition of hypertension is blood pressure values of ≥140/90 mmHg.²

The American College of Cardiology/American Heart Association guidelines categorize hypertension as elevated, defined as a systolic pressure of 120 to 129 mmHg with a diastolic pressure of <80 mmHg; stage 1, defined as 130 to 139 mmHg systolic pressure or 80 to 89 mmHg diastolic pressure; and stage 2, defined as a blood pressure reading of ≥140/90 mmHg.^2-4

Hypertension is classified as primary/essential hypertension and secondary hypertension based on etiology; the former is the most common form of the condition and occurs without a discernable cause, while secondary hypertension accounts for 10% of cases.^5-7 Endocrine pathologies, including primary hyperaldosteronism, pheochromocytoma, Cushing`s syndrome, acromegaly, primary hyperparathyroidism, and thyroid disorders, account for 10% of the underlying causes of secondary hypertension.^7,8 The evaluation and diagnosis of the secondary causes of hypertension are crucial in its treatment as they guide the selection of the most appropriate therapy that could potentially lead to the complete remission of hypertension. However, extensive testing for secondary hypertension is impractical as the list of potential etiologies is wide.⁹ Nonetheless, there are suggestive clinical findings for which screening and diagnostic testing are recommended, as will be discussed in this article, with a focus on endocrinopathies.

Resistant Hypertension

Hypertensive patients may present with a form of the condition that is difficult to control despite the use of at least three antihypertensive agents, including a diuretic, in the correct combination and at the highest tolerated doses (referred to as resistant hypertension).^2,10,11 Resistant hypertension is also defined as hypertension that requires four or more antihypertensive drugs for optimum control.^10,11 The first steps in evaluating resistant hypertension are objective determination of compliance to and adequate selection and dosing of antihypertensive medications, exclusion of secondary causes of hypertension, and ambulatory blood pressure monitoring (ABPM).^10,11 Additionally, exclusion of pseudo-resistant hypertension, defined as an apparent lack of blood pressure control despite adequate doses of at least three well-selected antihypertensive medications, including a diuretic, is necessary.² Factors that lead to the development of this entity include the white-coat effect (elevated in-office blood pressure and normal or significantly lower out-of-office values); poor adherence to pharmacological therapy; periodic dietary changes (e.g., high sodium and alcohol intake); concomitant use of medications that elevate blood pressure, e.g., sympathomimetics; and rapid weight gain.^2,11

True resistant hypertension is characterized by at-home ambulatory blood pressure values of ≥135/85 mmHg during the daytime or ≥130/80 mmHg over 24 hours.^2,10

In assessing secondary causes of resistant hypertension, primary hyperaldosteronism is typically the first endocrine pathology considered as it is among the most common causes.¹⁰ Pheochromocytomas, Cushing’s syndrome, thyroid dysfunction, and hyperparathyroidism are rarer endocrine causes of resistant hypertension.¹¹

Endocrine Causes of Hypertension

Primary Hyperaldosteronism

Primary hyperaldosteronism (PHA) is the leading endocrine cause of secondary hypertension⁵ and the most common cause of resistant hypertension.^7,9 It is characterized by excessive levels of aldosterone independent of the renin-angiotensin-aldosterone system (RAAS).⁹ Aldosterone is a hormone produced by the cortex of the adrenal glands in response to activation of the RAAS and elevated serum potassium. It plays a role in the regulation of blood pressure by stimulating renal reabsorption of sodium and water, thus controlling water retention, extracellular fluid levels, and consequently blood pressure.^12,13

PHA is typically idiopathic and involves both adrenal glands.^7,12 It may also arise as a result of an adrenal adenoma, less commonly, unilateral/bilateral adrenal hyperplasia and familial hyperaldosteronism syndrome, and, rarely, adrenocortical carcinoma.^7,9 The clinical presentation is variable, with most patients developing resistant hypertension and hypokalemia (low potassium levels).⁷ The clinical suspicion of PHA-associated hypertension is high in hypertensive patients with hypokalemia, patients with resistant hypertension, hypertensive patients with an incidental adrenal mass, young patients with early onset hypertension or cerebrovascular accidents, those previously evaluated for other causes of secondary hypertension, or a family history of PHA.^7,12

When PHA is suspected, the initial recommended test performed (screening) is a morning measurement of the plasma aldosterone-to-renin ratio in the upright position.^7,9,12 As this test is highly sensitive, the diagnosis can be made, when there is a high index of clinical suspicion, after at least two measurements of plasma aldosterone >20 ng/dL and renin (activity or concentration) below detection levels.⁵ Interpretation of the plasma aldosterone-to-renin ratio is made with caution as several factors can produce false negative/positive results; these include medications (e.g., many antihypertensive drugs, oral contraceptives, and selective serotonin reuptake inhibitors), renovascular hypertension, hypokalemia, and pregnancy.^7,14 Other screening tests include plasma and urinary potassium levels and plasma aldosterone. However, they are less sensitive and not used on their own as some patients may have normal levels of potassium and aldosterone.⁹ Further investigations, such as the oral sodium loading test and saline infusion test, may be necessary for a definitive diagnosis and are typically ordered by a specialist.^7,14 The oral sodium loading and saline infusion tests aim to increase plasma volume and, in the absence of PHA, will suppress renin and thus aldosterone production.¹⁵

The oral sodium loading test, which is performed in stable and potassium-replete patients, is often used and is highly sensitive and specific. A 24-hour urine aldosterone level >12 μg/24h with a concomitant 24-hour urine sodium excretion >200 mmol/d confirms the diagnosis.^7,12,14

Imaging tests are recommended following a biochemical diagnosis of PHA to determine the underlying etiology. A computed tomography (CT) scan is the first modality of choice used to differentiate unilateral adrenal adenoma from bilateral adrenal hyperplasia and to rule out other pathologies such as adrenocortical carcinoma.¹² Magnetic resonance imaging (MRI) and scintigraphy may also be used.^7,14 Imaging may be combined with other tests, most notably adrenal vein sampling (AVS).⁷ AVS is the most reliable method used to distinguish between unilateral and bilateral hyperaldosteronism and is essential in adrenal surgical planning.^7,12 This procedure involves blood sampling from left- and right-sided adrenal and peripheral veins through femoral catheterization, followed by aldosterone/cortisol measurements in each blood sample to assess whether there is unilateral dominance of aldosterone hypersecretion.¹⁵ However, some schools of thought suggest that AVS is not required in all patients,¹² such as those below the age of 40 years with marked PHA and a distinct unilateral adrenal adenoma on CT scan, with significant surgical risk, suspected of having adrenocortical carcinoma, or with proven familial hyperaldosteronism.^16,15

Pheochromocytoma

Pheochromocytomas, often grouped with catecholamine-secreting paragangliomas, are rare neuroendocrine tumors that produce excess circulating catecholamines—epinephrine, norepinephrine, and, very rarely, dopamine.^7,17,18 Catecholamines possess both neurotransmitter and hormonal activity; their functions include the “fight or flight” response, blood pressure regulation, and glucose metabolism, to mention a few.¹⁹ Pheochromocytomas arise from neural crest-derived cells of the adrenal medulla (adrenal pheochromocytoma) and sympathetic ganglia (paraganglioma or extra-adrenal pheochromocytoma), with the former representing most cases.¹⁷ The majority are benign whereas 10–15% are malignant, mainly extra‐adrenal pheochromocytomas.^17,18 Clinically, they mimic numerous conditions of catecholamine overproduction and may manifest with the classic triad of headache, sweating, and tachycardia.^7,9 Hypertension is the most common sign associated with pheochromocytomas and is present in the majority of patients.^7 (7) It presents as sustained or paroxysmal elevations in blood pressure due to constant or episodic excess catecholamine secretion, respectively.^7,9 Patients with sustained hypertension frequently develop orthostatic hypotension, thought to result from hypovolemia as a result of persistent vasoconstriction and diminished sympathetic reflex.^7,18 Paroxysmal attacks of hypertension may be spontaneous or triggered by anesthesia, tumor manipulation, pain, trauma, postural changes, exercise, or medications such as anti-depressants, β-blockers, and opioid analgesics.^17,18 If the diagnosis or treatment is delayed, these tumors can result in severe clinical sequelae. Such complications include secondary erythrocytosis, new-onset diabetes mellitus, congestive heart failure, isolated dilated cardiomyopathy, cardiac arrhythmias, and hypertensive crisis.^7,17,18

The diagnosis of pheochromocytoma requires a high index of clinical suspicion. The clinical findings that are suggestive of pheochromocytoma include resistant hypertension; unexplained orthostatic hypotension in untreated hypertensive patients; headaches, palpitations, and sweating in a hypertensive patient; paradoxical blood pressure increases while taking β-blockers; paroxysmal attacks of hypertension triggered by anesthesia, tumor manipulation, pain, etc.; incidental finding of an adrenal tumor (adrenal incidentaloma); syndromic features suggesting hereditary pheochromocytoma; and a family history of pheochromocytoma in hypertensive patients.^7,18 The standard diagnostic procedure for pheochromocytoma is the measurement of plasma free metanephrines or 24-hour urinary metanephrines in the supine position.^7,9,18 A plasma free metanephrine test is used when the clinical index of suspicion is significant as this test provides greater sensitivity than specificity. In contrast, a 24-hour urinary metanephrine test is preferred when the clinical suspicion is lower as this test has greater specificity.^7,20  A four-fold increase in plasma free metanephrines above the upper cutoff value is highly diagnostic of pheochromocytomas.^17,18 Plasma 3-methoxytyramine (dopamine metabolite) may be performed along with free plasma metanephrines when metastatic disease is suspected, which is important for the diagnosis of malignant pheochromocytomas.^17,18 Imaging studies are recommended after biochemical confirmation of a pheochromocytoma. CT and MRI are the main imaging modalities used to identify these tumors and are useful for surgical treatment planning.^7,18   

Cushing’s Syndrome

Cushing’s syndrome is a rare and potentially life-threatening endocrine disorder caused by longstanding exposure to excess endogenous or exogenous glucocorticoids.²¹ Endogenous glucocorticoids, i.e., cortisol and corticosterone, are steroid hormones produced by the adrenal cortex in response to stimulation by the pituitary hormone, adrenocorticotropic hormone (ACTH).²² Cortisol is the main biologically active glucocorticoid in humans and exhibits anti-inflammatory and immunosuppressive properties.²² Cushing’s syndrome infrequently results from the endogenous overproduction of cortisol.²³  The majority of cases are iatrogenic, resulting from prolonged administration of exogenous glucocorticoids (i.e., systemic corticosteroids).^9,23 Endogenous Cushing’s syndrome is typically ACTH-dependent, arising from ACTH-producing pituitary (most prevalent) or ectopic tumors. Less commonly, it is ACTH-independent, in which case there is autonomous glucocorticoid overproduction by the adrenal gland.²¹ Chronic excessive cortisol levels are associated with several conditions, including but not limited to obesity, insulin resistance, impaired glucose tolerance, hypertension, cardiovascular diseases, and infections.^15,23

Hypertension is present in 80% of patients with endogenous Cushing’s syndrome,⁹  although it represents an infrequent cause of hypertension in the general population.⁸

The mechanisms by which cortisol raises blood pressure are postulated to involve an interplay between various pathophysiological pathways, including increased mineralocorticoid activity, activation of the RAAS, enhanced reactivity to vasoconstrictors, and increased sympathetic activity, among others.^23-25

An increase in mineralocorticoid activity is thought to be the major contributing factor.²⁵ Cortisol binds to the mineralocorticoid receptor with equal affinity as aldosterone; this action is normally enzymatically inhibited.

In Cushing’s syndrome, the levels of cortisol are overwhelmingly elevated, and thus, cortisol freely binds to and activates the mineralocorticoid receptor, leading to increased aldosterone-like activity and consequently hypertension.^24,25 Evidence suggests that Cushing’s syndrome can also result in hypertension through increased expression of angiotensin hormone receptors, thus implicating the RAAS system.²⁴ Additionally, it has been demonstrated that cortisol raises the levels of angiotensinogen, the angiotensin precursor.²⁵ Cushing’s syndrome is also associated with a marked increase in endothelin-1, a very potent vasoconstrictor. Furthermore, there is reduced activity of the nitric oxide vasodilatory system. Thus, hypertension may also develop due to significant vasoconstriction.^24,25

The diagnosis of Cushing’s syndrome may present challenges as patients often have nonspecific and variable clinical features like weight gain, excessive abdominal adiposity, thin skin, purple striae, increased irritability, acne, hirsutism, and menstrual irregularity.^21,23 (21) Thus, screening for hypercortisolism-induced hypertension is recommended in select clinical situations: resistant hypertension; the presence of an adrenal incidentaloma; cushingoid-like features unusual for the patient’s age, such as hypertension, uncontrolled diabetes, or female balding; the presence of multiple suggestive signs and symptoms; and weight gain with a decrease in height percentile and delayed puberty in children.^9,21,23 At least two measurements of 24-hour urinary free cortisol, a low-dose (1mg) dexamethasone suppression test, or at least two late-night salivary cortisol measurements can be performed as the initial screening procedure for Cushing’s syndrome.^9,21,23 The choice of test is individualized based on patient characteristics to circumvent false positive and false negative results, and findings are interpreted with caution based on specific limitations for each test.^7,23 The diagnosis of endogenous Cushing’s syndrome is confirmed when at least two of the initial screening tests are overtly abnormal, after excluding prolonged exogenous glucocorticoid use.²³ 24-hour urinary free cortisol values that are four-fold over the upper limit have high diagnostic accuracy.²¹ The dexamethasone suppression test involves oral intake of two 0.5 mg dexamethasone tablets at bedtime (11:00 PM) and early morning (08:00 AM) cortisol measurement the following day.¹⁵ Normal findings are a fall in cortisol levels below 50 nmol/L, whereas higher values indicate a lack of negative feedback mechanism associated with Cushing’s syndrome.^15,21 A late-night salivary cortisol test will demonstrate high cortisol levels in patients with Cushing’s syndrome due to loss of diurnal variation.²¹ Some specialists may perform further diagnostic tests such as the 48-hour 2 mg daily dexamethasone suppression test or intravenous 4 mg dexamethasone suppression test.¹⁵ After biochemical confirmation of Cushing’s syndrome, additional evaluation of patients involves investigation of the cause of cortisol hypersecretion, whether ACTH-dependent or ACTH-independent.¹⁵

Other Endocrine Causes of Hypertension

Thyroid Disease

Thyroid hormones, i.e., thyroxine (T4) and triiodothyronine (T3), are secreted by the thyroid gland in response to stimulation by the thyroid-stimulating hormone (TSH) from the pituitary gland.²⁶ They play a role in the regulation of heart rate, blood pressure, body temperature, and basal metabolic rate. Both thyroid hormone excess and deficiency have been associated with hypertension.²⁶ Hypothyroidism can cause an elevation in diastolic blood pressure, whereas hyperthyroidism can elevate systolic blood pressure.^9,26 The indications for screening are the same in hypertensive and non-hypertensive populations.^5 (5) Screening is done in individuals presenting with common clinical features of thyroid dysfunction, risk factors of thyroid disease, or a history of thyroid disease or treatment.²⁷ Plasma measurement of TSH is the first test of choice for the evaluation of thyroid disorders.²⁸ Plasma T4 measurement is necessary in acutely ill patients.²⁹ Free T4 levels are a better indicator of thyroid secretory function compared to total T4.^27,29

Primary Hyperparathyroidism

Primary hyperparathyroidism results from excessive secretion of parathyroid hormone (PTH) from one or more of the parathyroid glands. It is characterized by unexplained hypercalcemia and can affect vascular reactivity, renal function, and circadian blood pressure rhythm.⁹ The levels of PTH may be elevated, as expected, or inappropriately normal.³⁰ Primary hyperparathyroidism is most often caused by a single parathyroid adenoma. It can also arise due to hyperplasia of all four parathyroid glands and less commonly multiple adenomas and parathyroid cancer.³⁰ The diagnosis is confirmed with an elevated albumin-adjusted calcium level (hypercalcemia) along with an elevated or unexpectedly normal PTH level after excluding secondary hyperparathyroidism.³⁰

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