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Teachable Moment
Less Is More
March 16, 2020

Not All Hypertension Is a Lifelong Disease: A Teachable Moment

Author Affiliations
  • 1Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
JAMA Intern Med. Published online March 16, 2020. doi:10.1001/jamainternmed.2020.0361

Story From the Front Lines

A 63-year-old woman had a history of hypertension for 30 years. She was taking 3 medications (amlodipine, irbesartan, and indapamide) but still had not achieved optimal blood pressure control. She experienced a stroke 15 years ago but had no residual disability. She was found to have hypokalemia (serum potassium, 2.1 mEq/L [to convert to mmol/L, multiply by 1]) and was referred to a cardiologist, who discontinued her diuretic because of suspected diuretic-induced hypokalemia. Her hypokalemia persisted, and evaluation for primary aldosteronism was performed. The plasma aldosterone and renin levels were 19.0 ng/dL (to convert to pmol/L, multiply by 27.74) and 0.6 μIU/mL (to convert to pmol/L, multiply by 0.0375), respectively, resulting in an elevated aldosterone-to-renin ratio (31.7; reference: <2.0). The plasma aldosterone concentration after saline suppression testing was high (19.0 ng/dL; reference, <8.0 ng/dL), confirming a diagnosis of primary aldosteronism.

The patient underwent computed tomography of the adrenal glands followed by adrenal vein sampling, which revealed a left adrenal adenoma as the source of aldosterone excess. She underwent laparoscopic left adrenalectomy. After surgery, her serum potassium, plasma aldosterone–to–renin ratio normalized, as did her blood pressure level (110-130/60-70 mm Hg) despite discontinuation of all antihypertensive medications.

Teachable Moment

Hypertension is common, and most patients have essential hypertension responsive to lifestyle modification and medications. However, about 15% of patients have secondary hypertension, including 30% of those younger than 40 years.1,2 Primary aldosteronism is a common cause of secondary hypertension, occurring in 5% to 10% of patients with hypertension.3 The classic presentation of primary aldosteronism includes hypertension and spontaneous hypokalemia. However, 9% to 37% of these patients have hypokalemia.3 Guidelines recommend evaluation for primary aldosteronism in patients with severe hypertension (blood pressure level above 150/100 mm Hg on 3 separate days or with blood pressure level >140/90 mm Hg despite the concurrent use of 3 conventional antihypertensive drugs, including a diuretic, or controlled blood pressure requiring ≥4 antihypertensive drugs); spontaneous or diuretic-induced hypokalemia; adrenal incidentaloma; sleep apnea; family history of early-onset hypertension or stroke, or at least 1 first-degree relative with primary aldosteronism. Testing begins with measurement of plasma aldosterone, plasma renin, and aldosterone-to-renin ratio (Figure). Measurements should be performed in the morning and generally do not require stopping antihypertensive medications unless there is a concern for false-negative results because antihypertensive medications rarely cause false-positives. The finding of an elevated aldosterone-to-renin ratio strongly suggests primary aldosteronism, and these patients should be referred to an endocrinologist for further evaluation. Patients with aldosterone levels higher than 20 ng/dL, suppressed renin, and spontaneous hypokalemia do not require additional testing because only primary aldosteronism causes these findings. All other patients require confirmatory testing (eg, saline infusion test) to confirm the diagnosis.

Figure.  Flowchart for Diagnosis of PA
Flowchart for Diagnosis of PA

CT indicates computed tomography; MR, mineralocorticoid receptor; PA, primary aldosteronism.

This figure was used with permission.3

aOur recommended cutoff for positive ratio: 2.4 ng/dL per mIU/L if using chemiluminescence assay for direct renin concentration or 20 ng/dL per ng/mL/h if using radioimmunoassay for plasma renin activity; some investigators recommend checking both aldosterone-to-renin ratio and aldosterone.

bWith hypokalemia, undetectable renin, and plasma aldosterone level higher than 20 ng/dL (to convert to pmol/L, multiply by 27.74), confirmatory test could be skipped.

cIf surgery is not desired, mineralocorticoid receptor antagonist treatment is recommended.

dIf younger than 35 years, with marked PA and unilateral cortical adenoma on CT, adrenal vein sampling could be skipped.

Once primary aldosteronism is confirmed, most patients who are candidates for adrenalectomy should undergo computed tomography scanning of the adrenal glands and adrenal vein sampling to determine if elevated plasma aldosterone levels are owing to a unilateral adenoma or bilateral adrenal hyperplasia. Adrenal vein sampling can be skipped in patients younger than 35 years with spontaneous hypokalemia, markedly elevated serum aldosterone levels, and unilateral cortical adenoma on computed tomography. Because computed tomography results can be misleading in older patients, adrenal vein sampling is needed to localize the source of excess aldosterone secretion. Adrenalectomy is recommended for patients with a unilateral lesion, while treatment with mineralocorticoid receptor antagonists is warranted for those with bilateral adrenal hyperplasia, which accounts for most cases.

Screening for primary aldosteronism should have been considered when the patient in this case developed resistant hypertension.4 Earlier diagnosis may also have reduced her risk of stroke because primary aldosteronism is associated with increased cardiovascular risk independent of blood pressure. Unfortunately, appropriate evaluation for primary aldosteronism is uncommon, resulting in marked underdiagnosis.5 Clinicians, especially general internists, should be aware of the high prevalence of primary aldosteronism and should consider screening in appropriately selected patients.

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Article Information

Corresponding Author: Qifu Li, MD, PhD, Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Street, Chongqing 400016, China (liqifu@yeah.net).

Published Online: March 16, 2020. doi:10.1001/jamainternmed.2020.0361

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank the patient for granting permission to publish this information.

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    1 Comment for this article
    Most/all primary aldosteronism is bilateral; it’s too soon to say this patient was cured
    J David Spence, M.D. | Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Canada
    Yang et al.[1] report a case of a “cure” of hypertension by adrenalectomy for primary aldosteronism, emphasizing that hypertension is not a lifelong disease. They describe identification of primary aldosteronism by an aldosterone/renin ratio, and say “Once primary aldosteronism is confirmed, most patients who are candidates for adrenalectomy should undergo computed tomography scanning of the adrenal glands and adrenal vein sampling to determine if elevated plasma aldosterone levels are owing to a unilateral adenoma or bilateral adrenal hyperplasia.” That approach, though perhaps common, is not supported by my experience of treating resistant hypertension for more than 40 years. In my view the best reason to measure plasma renin and aldosterone is to identify the appropriate medical therapy.[2] Adrenalectomy should be reserved for patients not controlled medically, because many/most cases of primary aldosteronism are due to bilateral adrenocortical hyperplasia.

    In 1977 I opened the third hypertension clinic in Canada; our approach was to follow Laragh’s renin-based therapy,[3] with a twist; we used stimulated renin as recommended by Keith Dawson’s group.[4] In those days it was possible to do an iodocholesterol scan before and after dexamethasone to distinguish unilateral adrenal adenomas from bilateral hyperplasia (that protocol was developed in Ann Arbor by Conn’s group). In the early 1980’s we did those scans in a hundred patients with a stimulated plasma renin activity < 1 ng/mL/hour; >80% of those patients had hot adrenal glands bilaterally, and <20% were normal. Not a single one was unilateral. (I presume the patients with normal scans had a Liddle phenotype; at the time we did not have access to plasma aldosterone to sort that out). Usually the patients could be well controlled medically once the diagnosis was evident; [2] over the years less than 5% have required adrenalectomy. (It helps to have eplerenone available now.)

    Ed Biglieri described his first 4 cases of primary aldosteronism due to bilateral hyperplasia in 1984;[5] by then I had 10 such cases who had required adrenalectomy because they could not be controlled medically. Several of those cases are described in the 1999 paper of my talk at John Laragh’s festschrift.[6] They became normotensive for a while after the first adrenalectomy, but the hyperaldosteronism recurred, sometimes as long as 5 years later.

    This condition is probably mostly or always bilateral; it is too soon to say this patient was “cured”.

    1. Yang S, Hu J, Li Q. Not All Hypertension Is a Lifelong Disease: A Teachable Moment. JAMA Internal Medicine. 2020.
    2. Akintunde A, Nondi J, Gogo K, Jones ESW, Rayner BL, Hackam DG, et al. Physiological Phenotyping for Personalized Therapy of Uncontrolled Hypertension in Africa. Am J Hypertens. 2017;30(9):923-30.
    3. Laragh JH. Modern system for treating high blood pressure based on renin profiling and vasoconstriction-volume analysis: a primary role for beta blocking drugs such as propranolol. Am J Med 1976;61: 797-810. Am J Med. 1976;61:797-810.
    4. Wallach L, Nyarai I, Dawson KG. Stimulated renin: a screening test for hypertension. Ann Intern Med. 1975;82:27-34.
    5. Biglieri EG, Kater CE, Arteaga EE. Primary aldosteronism is composed of primary adrenal hyperplasia and adenoma. J Hypertens. 1984;2 (Suppl):S259-S61.
    6. Spence JD. Physiologic tailoring of therapy for resistant hypertension:20 years' experience with stimulated renin profiling. Am J Hypertens. 1999;12:1077-83.