CASE REPORT
Diurnal Blood Pressure Variability in Mineralocorticoid Excess Syndrome William B. White and Carl
Malchoff
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wenty-four hour blood pressure (BP) monitoring has documented a diurnal BP variation in both normal and hypertensive individuals. Diurnal BP variation appears to be dependent upon catecholamine action by the autonomic nervous system and is strongly related to activity and the sleep/ wake cycle. " A loss of nocturnal decline in BP has been reported in patients with diabetic autonomic neuropathy, obstructive sleep apnea, and in Cushing's syndrome. Approximately 1 0 % of hypertensive patients fail to show a diurnal variation in BP, suggesting a disso1-3
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Received August 15, 1991. Accepted November 25, 1991. From the Section of Hypertension and Vascular Diseases, Division of Vascular and General Internal Medicine, and Division of Endocrinology and Metabolism, University of Connecticut School of Medicine, Farmington, Connecticut. Address correspondence and reprint requests to William B. White, MD, Section of Hypertension and Vascular Diseases, Division of Vascular and General Internal Medicine, University of Connecticut Health Center, Farmington, CT 06030.
tions of DOC and other adrenal steroids returned to normal values, the 24-h BP profile normalized with restoration of the nocturnal reduction in pressure. These findings document the effects of mineralocorticoid overproduction on diurnal BP regulation. Intensive investigation of individuals with a well-defined etiology of hypertension and the absence of diurnal variation of BP may lead to further hypotheses that will define the role of both autonomic and nonautonomic factors in BP control. Am J Hypertens 1992;5:414-418 KEY WORDS: Deoxycorticosterone-secreting tumor, mineralocorticoid excess syndrome, ambulatory blood pressure, circadian rhythm, secondary hypertension.
ciation of BP from the usual autonomic control mechanisms. In this report, we describe the diurnal BP variability in a patient with mineralocorticoid excess syndrome secondary to a deoxycorticosterone-secreting adenoma. The key finding was a loss of the usual nocturnal decline in BP despite a marked reduction in heart rate during sleep; tumor removal was associated with return of a normal 24-h BP and diurnal rhythm. 10,11
CASE REPORT A 43-year-old woman was evaluated for moderately severe hypertension with hypokalemia. She had been hypertensive for 2 years and was treated with sustained-release diltiazem and enalapril. There was no history of licorice ingestion, use of tobacco, or treatment with diuretics. On examination, the supine BP was 1 7 0 / 115 mm Hg with no postural change. Examination of the retina showed arteriolar narrowing and auscultation of the heart revealed a fourth heart sound. Sector-
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Noninvasive 24-h blood pressure (BP) monitoring has demonstrated a diurnal blood pressure profile in most individuals that is characterized by higher arterial pressures during wakefulness and lower pressures at night during sleep. Recently, reports suggest that this typical diurnal variation is absent in syndromes of autonomic dysfunction and in some forms of secondary hypertension. We investigated the 24-h BP, BP variability, and adrenal steroid concentrations in a patient with deoxycorticosterone (DOC)-secreting adrenal adenoma prior to and following adrenalectomy. Preoperatively, when the patient had a ten-fold increase in serum concentrations of DOC, there was no fall in nocturnal BP despite a marked reduction in heart rate during sleep. Postoperatively, when the concentra-
and during sleep. The BP load was also calculated as described previously. The relation between the heart rate and BP was assessed using Pearson's correlation test.
guided M-mode echocardiography showed left ventric ular hypertrophy with posterior and septal wall thick nesses of 12 and 13 mm, respectively. The serum potassium was 3.0 mmol/L (normal, 3.6 to 5.0 mmol/L) after termination of therapy for 2 weeks while urinary excretion of potassium was inappropri ately high at 51 mmol/day. Supine plasma renin activ ity (PRA) was suppressed at 0.03 n g / L / s e c . Supine serum aldosterone concentration was 444 pmol/L (nor mal, 83 to 694 pmol/L) while deoxycorticosterone (DOC) concentration was 7260 pmol/L (normal, 61 to 580). Plasma and urinary catecholamines were normal. An iodonorcholesterol scan following dexamethasone suppression showed a marked uptake in the region of the left adrenal gland. Computerized tomography of the abdomen revealed a large left adrenal mass. Subse quently, unilateral adrenalectomy was performed; the adrenal gland contained a tumor weighing 58 g and 5.0 cm in maximal diameter. Histologic diagnosis was con sistent with a benign adrenal cortical adenoma that pri marily differentiated as zona fasiculata. Two weeks postoperatively, the patient's BP fell to 1 3 0 / 9 0 mm Hg. Serum potassium became normal (4.0 mmol/L) without replacement and PRA rose to 0.22 n g / L / s e c (normal, 0.08 to 0.53 n g / L / s e c ) .
Endocrine Studies These studies were performed while the patient was fed a diet with an ad lib sodium and potassium intake. Serum aldosterone, 18-hydroxycorticosterone, deoxycortiocosterone (DOC), and 18OH deoxycorticosterone were measured by radioimmu noassay (RIA) after solvent partitioning, derivative formation, and chromatographic isolation. Plasma cor ticosterone, C o r t i s o l , 1 1 - d e o x y C o r t i s o l , pregnenolone, 17-OH pregnenolone, androstenedione, estrone, and progesterone levels were measured by high perform ance liquid chromotography, followed by RIA. PRA was measured by RIA of generated angiotensin I. Corti cotropin (ACTH) was measured by immunoradiometric assay at Nichols Institute (San Capistrano, CA). ACTH (0.25 mg, Cortrosyn, Organon, West Orange, NJ) was given as an intravenous bolus dose after base line samples were obtained in the early morning. A sec ond sample was obtained after 60 min. The ACTH test was performed approximately 4 weeks preoperatively and 4 weeks postoperatively.
METHODS
RESULTS
24-hour Ambulatory Blood Pressure Monitoring Ambulatory BP determinations were made on a week day with the Accutracker II portable recorder (Suntech Medical Instruments, Raleigh, N C ) . Readings were obtained at 15-min intervals for the entire 24 h of study. Editing of the data was performed as reported previously. The studies were performed after with drawal from all medications for 2 weeks. Data that were analyzed included the 24-h BP pattern, the mean BP, and the BP variability over the 24 h and while awake
Pre- and Postoperative Steroid Concentrations Plasma concentrations of deoxycortisol, DOC, corticos terone, and 18-OH DOC were all markedly elevated and returned to normal 4 weeks postoperatively (Table 1). Aldosterone levels were normal. Urinary 17-ketosteroid excretion was normal (34 μιηοΐ/day). Serum ACTH was normal (3.11 pmol/L). Progesterone was moder ately (3243 pmol/L) elevated but 17-OH progesterone, estrone, androstenedione, pregnenolone, and 17-OH pregnenolone were all normal.
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TABLE 1. BASAL AND ACTH-STIMULATED PLASMA ADRENAL STEROID LEVELS BEFORE AND 4 WEEKS AFTER REMOVAL OF ADENOMA Preoperative
Postoperative
Normal Values*
Steroid
Basal
Post-ACTH
Basal
Post-ACTH
Basal
Post-ACTH
DOC (pmol/L) 18-OH DOC (pmol/L) Corticosterone (pmol/L) Aldosterone (pmol/L) Progesterone (pmol/L) 17-OH progesterone (pmol/L) 11 -Deoxycortisol (pmol/L) Cortisol (nmol/L)
7260 3492 43,694 444 3243 2481 12,673 386
63,540 12,237 361,154 2497 99,331 54,463 72,950 772
424 837 21,097 139 1653 2935 2945 469
1725 1443 72,237 222 2162 5144 10,855 717
61--580 87--694 3752--26,147 83--694 477--2703 666--4418 346--4561 193--579
363--2723 1212--3752 31,890--137,143 165--777 1081--9146 1967--7141 1963--6841 469--1076
DOC; deoxycorticosterone. Studies were performed at 8:30 AM in the supine position following an ad lib sodium intake; all medications were withdrawn for 2 weeks prior to the preoperative studies. The patient was in the follicular phase of the menstrual cycle. * Normal values are derived from adult women (n = 14) using an ad lib sodium diet and in the follicular phase of the menstrual cycle.
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Systolic Blood Pressure
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FIGURE 1. Twenty-four hour profiles of the systolic (top) and diastolic (middle) blood pressures and heart rates (bottom) preopera tive^ and following left adrenalectomy. PREOP: preoperatively; POST-OP: postopera tively; SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate.
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Relationship between heart rates and blood pressures preoperatively and postoperatively. Systolic blood pressures are shown on the left and diastolic blood pressures on the right. F I G U R E 2.
The plasma Cortisol response to ACTH was normal both pre- and postoperatively. Preoperatively, DOC, deoxycortisol, corticosterone, and 18-OH DOC were all sensitive to ACTH stimulation. Four weeks after the removal of the adrenal tumor, the responses to ACTH were normal. Blood Pressure Monitoring The untreated casual (clinic, seated) blood pressure was 170 to 1 8 0 / 1 1 0 to 120 mm Hg preoperatively and fell to high normal values (125 to 1 3 0 / 8 8 to 90 mm Hg) 1 month postopera tively. The 24-h blood pressure and heart rate profiles are shown in Figure 1. Preoperatively, the mean 24-h blood pressure was 1 7 1 / 1 0 7 ± 1 3 / 9 mm Hg and there was little difference in the awake ν sleep blood pressure (Δ awake-sleep BP = — 2 / 4 mm Hg). Postoperatively, the mean 24-h blood pressure fell to 1 3 1 / 7 9 ± 1 3 / 1 1 mm Hg and there was a substantial difference in awake ν sleep blood pressure ( Δ awake-sleep BP = 1 4 / 1 5 mm Hg). Both awake and sleep blood pressure were mark edly lower postoperatively and blood pressure load was reduced to normotensive values postoperatively. Blood
pressure variability and heart rate profiles were similar pre- and postoperatively (Figure 1). Analysis of the relationship between the heart rates and blood pressures over the two 24-h study periods are shown in Figure 2. Preoperatively, there was no rela tionship between heart rate and systolic or diastolic blood pressure. Postoperatively, a strong positive corre lation between heart rate and blood pressure was noted (r = 0.65, Ρ < .001 for systolic BP and r = 0.66, Ρ < .001 for diastolic BP). DISCUSSION In the present study, we have demonstrated that second ary hypertension induced by excessive mineralocorti coid hormones markedly alters the diurnal variation of BP. The 24-h BP profile showed both elevated BP values and loss of the expected nocturnal decline (Figure 1) associated with reduced sympathetic nervous system activity during sleep. " The alterations in the relation ship between the heart rate and BP were of particular interest. Preoperatively, the heart rate at night fell by an average of 23 beats/min, yet there was no change in BP 1
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