HYPERTENSION MYSTERY: A Case Study From ESAP™
A45-year-old woman presents with a nine-year history of hypertension. Her current antihypertensive medications include amlodipine, 10 mg daily; lisinopril, 20 mg daily; and KCl, 20 mEq twice daily. Her serum sodium concentration is 143 mEq/L, and her serum potassium concentration is 3.5 mEq/L. She has no family history of hypertension. She is keen to consider a surgical procedure if it would correct her hypokalemia and improve or cure her hypertension.
On physical examination, blood pressure is 150/90 mm Hg, heart rate is 88 beats/min, and BMI is 29.6 kg/ m2. Her excess body weight is diffusely and not centrally distributed. Findings from examinations of the heart and abdomen are normal, and peripheral pulses are intact.
Recent laboratory studies from her primary care physician’s office include the following:
• Aldosterone = 19 ng/dL
• Plasma renin activity = <0.6 ng/mL per h • 1-mg overnight dexamethasone suppression test = <1.0 μg/dL Urine • Urinary aldosterone excretion with oral sodium loading = 18 μg/24 h (urinary sodium = 222 mEq/24 h) • CT of the abdomen is performed, and a 7-mm right adrenal nodule is identified (arrow): Download PDF for chart QUESTION
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Which one of the following is the best next step in management?
A Perform laparoscopic right adrenalectomy
B Perform another adrenal venous sampling for aldosterone and cortisol
C Perform 6β- 131I-iodomethyl-19-norcholesterol (NP-59) scintigraphy
D Initiate medical therapy with a mineralocorticoid receptor antagonist
E Perform laparoscopic left adrenalectomy
Answer down below.
HYPERTENSION MYSTERY: A Case Study From ESAP™
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The answer is:
D. Initiate medical therapy with a mineralocorticoid
Aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism (IHA) are the two most common subtypes of primary aldosteronism—APA accounts for approximately 35 percent of cases and bilateral IHA accounts for approximately 60 percent of cases.
In patients with APA, unilateral adrenalectomy normalizes potassium levels in those who have hypokalemia on presentation, improves blood pressure in all, and normalizes blood pressure in approximately 30 percent to 60 percent. In patients with IHA, unilateral or bilateral adrenalectomy seldom corrects hypertension; thus, these patients should be treated medically with a mineralocorticoid receptor antagonist. In addition, lifelong treatment with a mineralocorticoid receptor antagonist is a reasonable alternative treatment strategy in patients with APA who are unwilling to undergo surgery, are elderly, or are afflicted by comorbid conditions that preclude the surgical option.
The treatment goals are to prevent the morbidity and mortality associated with hypertension, hypokalemia, and cardiovascular damage from aldosterone excess. Th us, a key diagnostic step in patients who want to pursue a surgical cure for primary aldosteronism is to distinguish between APA and IHA.
Because of the efficient mineralocorticoid synthetic processes, APAs can be small (less than 1 cm in diameter) and still cause clinical hyperaldosteronism. Th us, because of their small size, APAs may not be morphologically detectable on adrenal-directed CT or MRI. In addition, IHA adrenal glands may appear normal on CT or show nodular changes. To confuse the picture even more, the development of adrenocortical nodularity is common in healthy persons and is, in part, a function of aging. Thus, it is impossible for a clinician to know whether a solitary adrenal nodule observed on CT in a patient older than 40 years with primary aldosteronism has any role in the pathogenesis of the aldosterone excess—it may be an APA or it may be a nonfunctioning cortical nodule (thus, in this patient with a 7-mm right adrenal cortical nodule, laparoscopic adrenalectomy [Answers A and E] is incorrect).
If such a patient wants to pursue a surgical cure of primary aldosteronism, additional testing is required to determine the source of excess aldosterone secretion. Adrenal venous sampling (AVS) is essential to direct appropriate therapy in many patients with primary aldosteronism who have a high probability of having APA and who seek a potential surgical cure.
Th is patient has confirmed primary aldosteronism. CT shows a 7-mm cortical adenoma in the right adrenal gland. AVS was indicated on the basis of the patient’s desire for surgery and CT’s inaccuracy. The AVS findings in this patient are consistent with IHA, and medical therapy with a mineralocorticoid receptor antagonist (Answer D) is the correct answer. There are two steps in interpreting AVS data. First, the clinician must confirm that both adrenal veins were successfully catheterized. With the continuous cosyntropin infusion protocol, the gradient in cortisol from the adrenal vein to the inferior vena cava is more than 5:1 (indeed, it is usually >10:1). If the cortisol gradient between an adrenal vein and the inferior vena cava is absent, then that adrenal vein was not successfully catheterized and the AVS data are useless in most cases. In this patient, the adrenal vein to inferior vena cava cortisol gradients were 50 on the right and 25 on the left. Th us, AVS in this patient was successful, and another AVS (Answer B) is not needed. When both cortisol and aldosterone autonomous secretion from an adrenal adenoma is suspected (e.g., if the 1-mg dexamethasone suppression test results in this patient were abnormal), then adrenal venous epinephrine concentrations may be used to document successful adrenal vein sampling.
The cortisol concentration from the left adrenal vein is usually lower than the cortisol concentration from the right adrenal vein because of the diluting effluent from the inferior phrenic vein on the left. The second step in analyzing AVS data corrects for the dilution of the blood sample from the left adrenal vein—the adrenal vein aldosterone concentrations are divided by their corresponding cortisol concentrations. (The aldosterone to cortisol ratios in this patient were 3.2 on the right and 3.2 on the left.) The aldosterone to cortisol ratio from the high-side adrenal vein is divided by the aldosterone to cortisol ratio from the lowside adrenal vein (3.2 ÷ 3.2 = 1.0). Unilateral aldosterone excess is confirmed when the high-side adrenal vein aldosterone to cortisol ratio is more than four times higher than that of the low-side adrenal vein. AVS data are consistent with bilateral IHA when the high-side adrenal vein aldosterone to cortisol ratio is less than three times higher than that of the low-side adrenal vein. Ratios between 3:1 and 4:1 are an overlap zone between APA and IHA. In this patient, the cortisol-corrected adrenal vein aldosterone ratio was 1:1 (right-to-left), thus consistent with bilateral IHA. The right adrenal nodule was a nonfunctioning adrenal incidentaloma. Blood pressure markedly improved with the addition of a mineralocorticoid receptor antagonist (Answer D).
The 6β- 131I-iodomethyl-19-norcholesterol (NP-59) scintigraphy (Answer C), performed with dexamethasone suppression, has the advantage of correlating function with anatomic abnormalities. However, the sensitivity of this test depends heavily on the size of the adenoma. Because tracer uptake is poor in adenomas smaller than 1.5 cm in diameter, it is usually only helpful in determining whether unilateral aldosterone production is present in patients with bilateral adrenal macroadenomas. NP-59 scintigraphy is often not helpful in interpreting the clinical significance of micronodular findings observed on high-resolution CT.
In addition to its poor sensitivity, other reasons that NP-59 scintigraphy is rarely used in the U.S. include the following: (a) this methodology is not approved by the U.S. Food and Drug Administration, and its use requires institutional review board approval; (b) dexamethasone is administered at 1 mg every 6 hours starting 7 days before the NP-59 injection and is continued throughout the scanning period; (c) imaging starts on day 4 after the NP-59 injection and may continue daily through day 10; (d) a lateralizing scan can be seen in adrenal cortical adenomas that do not secrete aldosterone; and (e) no centers in the United States currently offer NP-59 scintigraphy. NP-59 is available and used in other countries to assist with the subtype evaluation of primary aldosteronism.