Clinical Challenge: An Underdiagnosed Cause of Resistant Hypertension

Once thought to be rare, the prevalence of primary aldosteronism is estimated to be 5% to 17%, although the condition remains underdiagnosed.

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Up to 10% of patients with hypertension have aldosteronism.

A30-year-old woman presents to the emergency department (ED) with headache, nausea, vomiting, diarrhea, and abdominal pain that started 1 day ago. The patient reports 3 episodes of nonbilious, nonbloody vomiting with concomitant bilateral extremity weakness lasting about 15 minutes and 2 episodes of nonbloody diarrhea.

She reports intermittent episodes of generalized body aches and lower extremity weakness over the last 2 months. She denies fevers, chills, weight loss, neck pain, shortness of breath, palpitations, chest pain, or paresthesias.

The patient has a medical history of hypertension for 3 years and type 2 diabetes for 4 years. She has been noncompliant with medications for these conditions for the last 6 months because of insurance issues. It is not known whether she was screened for a secondary cause of hypertension when she initially began treatment.

Her family history is noncontributory. She denies smoking as well as alcohol or drug use. She is a married stay-at-home mom with 2 daughters. She denies a history of gestational hypertension or preeclampsia but had a spontaneous abortion at 9 weeks’ gestation within the last year. The patient reports possible recent influenza exposure and is anxious that something is wrong.

Physical Examination

On arrival, her vitals are as follows: blood pressure, 195/126 mm Hg; respiratory rate, 18 breaths per

CLINICAL CHALLENGE: PRIMARY ALDOSTERONISM Primary aldosteronism is independent of the RAAS and is defined as excessive production of aldosterone by the adrenal glands.

minute unlabored; heart rate, 71 beats per minute; temperature, 98.4 °F; and oxygen saturation, 97% on room air.

On physical examination, the patient is somnolent but easily arousable. She is oriented, and her thoughts are coherent. She is of average build with a BMI of 24.8. Her skin is warm and her mucous membranes are moist. She has sweaty palms but no rashes or lesions. Her eyes appear normal with no proptosis. Visual acuity also is normal and extraocular movements are intact.

A small, diffusely enlarged goiter (grade 1 according to World Health Organization classification) is found. A bruit is audible over the goiter but no tenderness or lymphadenopathy is apparent. Her lungs are clear to auscultation. Her heart examination reveals clear S1 and S2 without murmur, rubs, or gallops. Her abdomen is flat; no tenderness, masses, or organomegaly are present. Bowel sounds are normoactive. Pelvic and rectal examinations are normal. Peripheral pulses are intact.

No edema is noted in the lower extremities. The patient has full range of motion, both active and passive, of the hands, wrists, elbows, shoulders, hips, knees, and ankles. Her strength is 5/5 in the upper and lower extremities bilaterally. Sensations of pain, light touch, proprioception, and vibration are intact. All reflexes are 2+.

Laboratory Results

Serum laboratory values are remarkable for a low potassium level, high arterial pH, and borderline high bicarbonate level (Table). Anion gap, blood glucose, hemoglobin A1c, and lowdensity lipoprotein cholesterol levels are elevated. Complete blood cell count, troponin level, and coagulation studies are unremarkable. Serum pregnancy test is negative.

The patient’s electrocardiogram reveals normal sinus rhythm at 71 beats per minute with left axis deviation and T-wave inversion in the inferior lateral leads. Lung fields are clear on chest radiograph.

The patient is admitted to the cardiology service and immediately is started on labetalol 100 mg orally for elevated blood pressure. She shows little improvement and standing orders for hydralazine and lisinopril are written. Her blood pressure remains elevated; the hydralazine dosage is increased from 50 to 75 mg and, finally, to 100 mg 3 times a day with the goal of lowering her blood pressure to less than 130/80 mm Hg.

She also receives acetaminophen for pain and ondansetron for nausea and/or vomiting as needed. The patient refuses prophylactic therapy for influenza exposure but consents to influenza vaccination.

An echocardiogram evaluation shows a left ventricular ejection fraction of 65% (normal range, 55%-70%); her valves and anatomy are of normal size and function.

An endocrinologist is consulted for her uncontrolled diabetes and goiter. The patient is started on insulin lispro and insulin glargine. An ultrasound of the thyroid shows a 1.7-cm nodule on the left lobe and a 5.2-cm nodule on the right. However, laboratory evaluation of thyroid status is unremarkable. The patient’s hypokalemia is treated with 3 doses of potassium chloride powder (40 mEq orally every 4 hours). The patient’s plasma aldosterone level is 24.7 ng/dL (normal range, 1-21 ng/ dL) and plasma renin concentration is undetectable (normal range with a normal sodium diet, 0.6-4.3 ng/mL/h).

Primary aldosteronism (PA) is identified as a potential cause of the patient’s illness and a contrast-enhanced computed tomography (CT) of the abdomen is ordered to evaluate for adrenal masses. The CT shows a left-sided adrenal mass measuring 2.5 cm × 1.8 cm.

To confirm the diagnosis of PA, a saline infusion test is ordered. Consistent with PA, the plasma aldosterone

TABLE. Abnormal Laboratory Results

Measure Result Normal Range

Anion gap, mEq/L 13 3-10

Arterial pH 7.48 7.35–7.45

Bicarbonate, mEq/L 28 21-28

Glucose, mg/dL 322 70-99

Hemoglobin A1c, % 13.1 4-5.6

LDL-C, mg/dLa 146 <100a

Potassium, mEq/L 2.1

LDL-C, low-density lipoprotein cholesterol aOptimal level 3.5-5.1

PA is a leading cause of secondary hypertension, accounting for 5% to 10% of patients with hypertension and 20% of those with resistant cases.

concentration increases to 38.7 ng/dL at the 4-hour mark. The patient’s symptoms improve and she is discharged on an angiotensin-converting enzyme (ACE) inhibitor for hypertension and a potassium supplement.

She receives diabetes nutritional education during the hospitalization and insulin training. She is discharged on insulin injection and instructed to follow up as scheduled with the endocrine clinic. The patient is considering the recommendation to biopsy the thyroid nodules. A moderate-intensity statin, (atorvastatin 20 mg daily) is prescribed for hyperlipidemia. She is counseled to follow a low-fat, heart-healthy diet and avoid pregnancy while taking the statin. The patient has an intrauterine device for contraception.

Discussion

Once considered a rare condition, PA has emerged as a primary cause of secondary hypertension, accounting for 5% to 10% of patients with hypertension and 20% of those with resistant hypertension.1-4 The prevalence of PA is estimated to be 5% to 17%, although this condition is underdiagnosed.1,2

Hyperaldosteronism can be classified as primary or secondary. Secondary hyperaldosteronism is caused by excessive activation of the renin-angiotensin-aldosterone system (RAAS) caused by extra-adrenal stimuli, such as a renin-producing tumor, renal artery stenosis, or edematous disorders (eg, heart failure, pregnancy).2,4

Primary aldosteronism is independent of the RAAS and is defined as excessive production of aldosterone by the adrenal glands.2,4 Excessive production of aldosterone leads to increased activity of the sodium-potassium pumps in the cortical collecting ducts of the nephron, which, in turn, causes sodium retention and potassium loss.4 Hyperaldosteronism also causes increased loss of hydrogen ions in medullary collecting ducts, resulting in metabolic alkalosis.2

Causes of PA include: • Aldosterone-producing adrenal adenomas (Conn syndrome): these adenomas typically are unilateral but may be bilateral4 • Adrenal hyperplasia: this may be unilateral or bilateral; hyperplasia is more common among older men2,4 • Familial PA: this condition is rare and often related to germline mutations of electrolyte channels2,5 • Ectopic aldosterone-secreting tumors2 • Aldosterone-producing adrenocortical carcinoma2

The most common clinical manifestation of PA is hypertension that often is resistant to treatment.2,5 Hypertension may lead to complaints of headaches and, if left untreated, may cause hypertensive retinal changes, stroke, renal insufficiency, hypertensive encephalopathy, and cardiac failure.6 Despite having an elevated blood pressure, patients with PA do not exhibit peripheral edema.4 Patients may be hypokalemic, even in the absence of potassium-depleting diuretics.4 Individuals who are severely hypokalemic may present with fatigue, muscle weakness, ileus, and palpitations.2 Severe loss of potassium may lead to hypokalemia-induced nephrogenic diabetes insipidus, which can cause polydipsia and/or polyuria.2 Other signs and symptoms include constipation, decreased deep tendon muscle reflexes, and hypomagnesemia.2

Diagnosis of Primary Aldosteronism

The diagnostic approach to PA begins with routine laboratory studies to assess serum levels of sodium, potassium, magnesium, bicarbonate, glucose, blood urea nitrogen, and creatinine. Plasma aldosterone concentration (PAC) and plasma aldosterone to renin ratio (ARR) serve as screening tests for PA and play an important role in distinguishing between primary and secondary hyperaldosteronism.5 Normal levels of PAC are less than 10 ng/dL2; however, in PA, elevated levels of plasma aldosterone with decreased or normal renin activity increase the ratio. An ARR greater than 30 ng/dL and PAC greater than 20 ng/dL are highly suspicious for PA, with sensitivity and specificity of greater than 90%.2

Confirmatory diagnostic tests include a saline infusion test or oral sodium loading. • Saline infusion test: Patient is either sitting or lying down for at least 1 hour before and during a 4-hour infusion of IV normal saline. Plasma levels for renin, aldosterone, cortisol, and potassium are drawn at hours 0 and 4. Aldosterone levels of less than 10 ng/dL after the infusion can rule out the diagnosis of PA because levels do not decrease as they should in patients with PA. Cortisol levels are taken to exclude adrenocorticotropic hormone is not causing elevations in aldosterone levels.2 • Oral sodium loading test: Patients ingest 10 g to 12 g of sodium chloride orally for 3 days before testing. At the end of 3 days, serum and 24-hour urine are collected and tested for aldosterone, sodium, and potassium levels. Urine aldosterone levels greater than 14 µg/24 hours are confirmatory for PA. Urine sodium levels are tested to ensure adequate salt loading for proper interpretation of the test.2

To distinguish between causes of PA, thin-sliced adrenal CT with contrast is the most common initial diagnostic test to

CLINICAL CHALLENGE: PRIMARY ALDOSTERONISM For unilateral adrenal adenomas or hyperplasia, surgical resection is often curative. Bilateral adrenal hyperplasia requires a medical approach.

identify aldosteronomas and adrenal cell carcinoma.5 Levels of aldosterone in adrenal venous blood may be measured in patients in whom there is high suspicion of unilateral PA despite normal imaging.⁵

Treatment of Primary Aldosteronism

The overall treatment goal in PA is to reduce the morbidity and mortality associated with hypertension, hypokalemia, and other associated symptoms.5 The approach to treatment depends on the etiology of the PA. For unilateral adrenal adenomas or adrenal hyperplasia, surgical resection often is curative.5

Patients diagnosed with bilateral adrenal hyperplasia and familial PA require a medical approach. They should be started on an aldosterone antagonist such as spironolactone or eplerenone.5 For patients with persistent hypertension, clinicians should initiate another antihypertensive agent, such as hydrochlorothiazide or an ACE inhibitor. In addition, they should advise patients to follow a low-salt diet.6

Early diagnosis and treatment of PA can improve a patient’s overall long-term morbidity and mortality. Patients with PA have a higher risk of developing chronic kidney disease than individuals with essential hypertension. However, when surgical adrenalectomy is performed, there is no difference in kidney morbidity.7 Patients with PA also have an increased risk for stroke, atrial fibrillation, heart failure, coronary artery disease, diabetes, and metabolic syndrome than patients with essential hypertension.8

Conclusion

Primary aldosteronism should be considered in any patient with treatment-resistant hypertension, especially in a hypokalemic patient who is not taking a diuretic. Hypertension, unexplained hypokalemia, and metabolic alkalosis are the most common findings. The workup includes serum electrolytes (to evaluate for hypokalemia, metabolic alkalosis, hypernatremia, and hypomagnesemia), ARR screening, as well as a saline infusion or oral sodium loading test and adrenal CT with contrast. Individuals with PA have increased long-term cardiovascular and renal risks, making early diagnosis and treatment essential. ■

Corinne I. Alois, MS, PA-C, is an assistant professor at St. John’s University Physician Assistant Program in Jamaica, New York; Alyssa C. Quinlan, PA-C, MPAS, is an assistant professor at St. John’s University Physician Assistant Program.

References

1. Monticone S, Burrello J, Tizzani D, et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol. 2017;69(14):1811-1820. 2. Dominguez A, Muppidi V, Gupta S. Hyperaldosteronism. In: StatPearls. StatPearls Publishing; 2021. Updated November 21, 2020. Accessed June 22, 2021. https://www.ncbi.nlm.nih.gov/books/NBK499983 3. Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized prevalence of primary aldosteronism: a cross-sectional study. Ann Intern Med. 2020;173(1):10-20. 4. Grossman AB. Primary aldosteronism (Conn syndrome). In: Merck Manual Professional Version. Merck & Co, Inc; 2020. Updated September 2020. Accessed June 22, 2021. https://www.merckmanuals.com/professional/ endocrine-and-metabolic-disorders/adrenal-disorders/primary-aldosteronism 5. Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. 6. Iqbal AM, Jamal SF. Essential hypertension. In: StatPearls. StatPearls Publishing; 2021. Updated July 10, 2020. Accessed June 22, 2021. https://www. ncbi.nlm.nih.gov/books/NBK539859/ 7. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Renal outcomes in medically and surgically treated primary aldosteronism. Hypertension. 2018;72(3):658-666. 8. Monticone S, D’Ascenzo F, Moretti C, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2018;6(1):41-50.