An endocrine cause is uncommon among all hypertensive patients, so testing everyone would find few. A hormone-driven rise in pressure is a rise driven by a signal the body cannot switch off, so each excess leaves a second footprint besides the pressure: a symptom pattern and a laboratory value. Finding that footprint is the diagnosis.
Why does an endocrine cause matter if it is uncommon?
Classifying the causes shows what they are. The question now is why finding one is worth the effort.
Finding an endocrine cause changes how the patient is treated. The reason is that the treatment follows the cause: removing or blocking the excess hormone is what can bring the pressure down, while a drug aimed at the number alone does not touch the cause. An early diagnosis therefore matters because it changes management, not just the number on the cuff. Because the disease behind the pressure keeps doing damage, an early diagnosis also allows normalisation of blood pressure and prevention of the complications related to cardiovascular risk.
Early diagnosis also allows the best choice of treatment, which could be surgery or pharmacological, and it allows avoidance of inappropriate treatment, because some usual drugs are wrong for some causes. Pheochromocytoma is the worked example. Giving a beta blocker before an alpha blocker can predispose to a hypertensive crisis. Both receptor types sit in the blood vessels: alpha receptors in vascular smooth muscle constrict when catecholamines act on them, and beta-mediated vasodilation opposes that constriction. A beta blocker removes the vasodilation and leaves the alpha-mediated vasoconstriction unopposed. The tumour keeps releasing catecholamines, so the pressure can rise sharply.
If an early diagnosis pays off, which patients should make a clinician suspect one? The first group is the patients whose pressure the usual drugs fail to control.
What is resistant hypertension, and why does it point to a cause?
Resistant hypertension means blood pressure that remains above goal (>140/90 mmHg) despite the concurrent use of 3 or more antihypertensive agents of different classes. One of the agents is a diuretic, and all the agents are prescribed at optimal doses. A diuretic is part of the definition because poor control is thought to reflect salt and volume retention, which a diuretic addresses. Optimal doses are required so that the failure is a real failure of the drugs and not under-dosing.
The definition also includes patients whose blood pressure is controlled but who require 4 or more medications to reach the target values.
Resistant hypertension matters clinically because endocrine causes are more common among these patients than among hypertensive patients overall. A failed regimen is therefore a sign to look for a cause. Primary aldosteronism alone accounts for about 20% of resistant hypertension.
Resistant disease is one trigger. The others are the next question.
Who should be screened?
Testing everyone is wasteful, so a few clinical situations and clues decide who is investigated further. Suspicion of secondary hypertension should be raised by:
- hypertension in young patients, prepubertal and younger than 30 years of age;
- resistant hypertension;
- hypertension plus orthostatic hypotension associated with severe hypertension, palpitation and sweating;
- complete reversal or suppression of the circadian rhythm of blood pressure;
- hypertension plus signs and symptoms of hypercortisolism.
In a patient suspected of secondary hypertension, all renal-associated secondary causes have to be ruled out first, before reaching endocrine-associated secondary hypertension. Renal parenchymal and renovascular disease are common secondary causes, and they impair the response to drugs.
Once secondary hypertension is suspected and the renal causes are considered, the clinical picture and one specific test point toward each endocrine cause. What does each one look like?
What does each endocrine cause look like, and which test shows it?
The causes are grouped by the gland involved: adrenal, parathyroid, pituitary and thyroid. Each excess has its own footprint: the clinical clues and the test that shows the hormone, or the loss of its control.
Adrenal causes
Pheochromocytoma comes from chromaffin cells of the adrenal medulla and releases catecholamines, which act on alpha and beta receptors. Release is often in bursts, so the picture is attacks, not a steady state: headaches, palpitations, anxiety-like attacks and profuse sweating. The diagnostic tool is free plasma or fractionated urinary metanephrine. Metanephrines are breakdown products of the catecholamines and have a longer half-life, so they are easier to measure than the catecholamines themselves.
Primary aldosteronism follows from what aldosterone does in the distal nephron: it reclaims sodium and lets potassium go. An excess therefore loses potassium, and a severe hypokalemia can produce polyuria, myopathy and cardiac dysrhythmias. The tests show the same story. Aldosterone is increased and potassium is low. Plasma renin activity (PRA) is suppressed, because the excess aldosterone expands volume and raises pressure, which feeds back on renin. Autonomous aldosterone production holds renin down, so the aldosterone/renin ratio is increased, and that ratio shows a hormone that the renin system is no longer controlling.
11β-hydroxylase deficiency is a block in the cortisol pathway. Low cortisol drives ACTH up, and the pathway backs up behind the block into androgens, so androgen production is increased. The deoxycorticosterone (DOC) that piles up has mineralocorticoid activity, so it raises blood pressure. The androgens explain the sex-development findings: prenatal virilization in females, and pseudoprecocious puberty in males. The raised substances are the products that accumulate before the block and the androgens made from them: 17-OH progesterone, DOC, 11-deoxycortisol, androstenedione, testosterone and dehydroepiandrosterone sulfate (DHEA-S). Germline mutation testing confirms the inherited enzyme defect.
17α-hydroxylase deficiency involves an enzyme that is needed for both cortisol and the sex hormones. Without it the sex steroids are lost, so XY males show pseudohermaphroditism, and females show sexual infantilism and primary amenorrhea. Androstenedione, testosterone, DHEA-S, 17-hydroxyprogesterone, aldosterone and cortisol are low or low-normal, because the sex steroids and cortisol are made beyond the block. Germline mutation testing again confirms the defect.
Hypercortisolism is the other adrenal cause. Cortisol acts on many organs, so the signs are spread across systems: weight gain, insomnia, depression, easy bruising, fatigue, acne, hirsutism and hyperglycemia. Three tests are used. The 24-h urinary free cortisol excretion measures how much unbound cortisol the body makes over a day. The ACTH is suppressed, which shows that the adrenal makes cortisol on its own, because cortisol feeds back to switch off the pituitary. The 1 mg overnight dexamethasone suppression test checks whether cortisol can be suppressed: a normal axis is suppressed, and autonomous cortisol is not.
| Adrenal cause | Clinical clues | Tests |
|---|---|---|
| Pheochromocytoma | Headaches, palpitations, anxiety-like attacks, profuse sweating | Free plasma or fractionated urinary metanephrine |
| Primary aldosteronism | Polyuria, myopathy, cardiac dysrhythmias in severe hypokalemia | Increased aldosterone/renin ratio, suppressed PRA, increased aldosterone, low potassium |
| 11β-hydroxylase deficiency | Increased androgen production; prenatal virilization in females; pseudoprecocious puberty in males | Increased 17-OH progesterone, DOC, 11-deoxycortisol, androstenedione, testosterone, DHEA-S; germline mutation testing |
| 17α-hydroxylase deficiency | Pseudohermaphroditism in XY males; sexual infantilism and primary amenorrhea in females | Low or low-normal androstenedione, testosterone, DHEA-S, 17-hydroxyprogesterone, aldosterone and cortisol; germline mutation testing |
| Hypercortisolism | Weight gain, insomnia, depression, easy bruising, fatigue, acne, hirsutism, hyperglycemia | 24-h urinary free cortisol excretion, suppressed ACTH, 1 mg overnight dexamethasone suppression test |
Parathyroid cause
Hyperparathyroidism: PTH raises calcium by acting on bone, kidney and gut. The clues are therefore the effects of high calcium on the kidney (hypercalcemia with hypercalciuria and nephrocalcinosis), on bone (cortical bone loss) and on muscle and mood (proximal myopathy, weakness, depression). The tests show the hormone and its effect: intact PTH and an increased serum calcium concentration.
Pituitary causes
Acromegaly brings enlargement of the lower lip and nose, prognathism, mild hirsutism, sweating, oily skin and diabetes mellitus. The test is insulin-like growth factor 1 (IGF-1).
Cushing disease is the pituitary form of hypercortisolism, so the clues are the same cortisol excess: weight gain, insomnia, depression, easy bruising, fatigue, acne, hirsutism and hyperglycemia. The tests are the 24-h urinary free cortisol and the dexamethasone suppression test. The ACTH is high or increased, because the pituitary adenoma makes it. Compare adrenal hypercortisolism, where ACTH is suppressed: that difference separates the pituitary from the adrenal source. A pituitary MRI then looks for the source in the pituitary after the biochemical diagnosis.
Thyroid causes
Hypothyroidism gives fatigue, weight gain, bradycardia and loss of appetite. TSH is increased, and free triiodothyronine (FT3) and free thyroxine (FT4) are low.
Hyperthyroidism gives nervousness, anxiety, palpitations, hyperactivity, weight loss and tachycardia. TSH is low, and FT3 and FT4 are increased.
Knowing the clue and the test does not yet say how common each cause is, who is at risk, or how each hormone raises the blood pressure. How often do primary aldosteronism, pheochromocytoma and hypercortisolism turn up, and how does each excess push the pressure up?