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Original Studies |
Hypertension Unit, University Department of Medicine, Greenslopes Hospital, Brisbane, 4120, Australia
Address correspondence and requests for reprints to: Dr Michael Stowasser, Hypertension Unit, University Department of Medicine, Greenslopes Hospital, Brisbane, Australia 4120. E-mail: m.stowasser{at}mailbox.uq.edu.au
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Abstract |
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Introduction |
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Hypertension in FH-I is often of early onset and may be of sufficient severity as to result in early death, commonly due to intracerebral hemorrhage (3, 4, 5). The development of genetic tests capable of reliably detecting the hybrid gene in DNA extracted from a peripheral blood sample (1, 6) collected anytime after birth (4, 7) has greatly facilitated the screening of families with FH-I and the detection of less floridly affected family members with only mildly elevated, or even normal blood pressure levels (2, 7, 8, 9, 10). Normal blood pressure levels are encountered frequently among affected children, but in only a small proportion of adults found to have the condition by family screening (4, 9), suggesting that hypertension is likely to develop in most affected individuals following a variable normotensive phase. However, the presence and severity of hypertension varies considerably between affected individuals within any given age group, even among members of a single family sharing a common genetic abnormality (2, 4, 7, 8, 9), and some have remained normotensive until well into the 5th decade of life (11).
In the current study, we examined in detail the biochemical characteristics of normotensive individuals with FH-I, to see if they were different from those described in hypertensive individuals with this disorder. Any such differences might expose factors important in the development of hypertension in this condition.
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Methods |
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In all subjects studied, the diagnosis of FH-I was confirmed by demonstrating the presence of the hybrid gene in peripheral blood leucocyte DNA using a "long-PCR"-based method developed in this laboratory (4, 6) and validated against the Southern blot technique (1).
Blood pressure was measured using a mercury sphygmomanometer after
subjects had been quietly seated for at least 5 minutes. Three
measurements, separated by at least 1 minute, were recorded. Subjects
were regarded as normotensive if: 1) the mean of the last two systolic
and diastolic measurements was within the normal range for age and sex
(12); 2) they were not receiving antihypertensive medication; and 3)
there was no previous history of hypertension. Subjects were considered
to be hypertensive if: 1) the mean of the last two systolic and
diastolic measurements was above the normal range for age and sex; or
2) they were receiving medications as treatment for previously
documented hypertension. Ten subjects (six females; median age when
last assessed, 16.0 ± 12.3 yr SD; range, 11–43 yr)
of a series of 30 patients with FH-I in whom blood pressure status has
been assessed according to these methods, were normotensive. Blood
pressures remained normal in these individuals over 4.5 ± 0.6 yr
(range, 2.9–5.0 yr) of follow-up. All except one (patient 10, Table 1
) of these 10 individuals belonged to a
single large family (21 known affected members).
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25 µg per
24 h]. During the biochemical studies, dietary salt intake was unrestricted.
Midmorning upright plasma potassium, aldosterone and PRA, and urinary sodium and 18-oxo-cortisol levels
Levels of plasma potassium, plasma aldosterone, PRA, and aldosterone to PRA ratios were measured in blood collected without stasis midmorning after at least 2 h of upright posture and compared with ranges established in our laboratory for normal subjects studied under similar conditions. Immediately after each collection, the blood was centrifuged and the plasma component was snap-frozen on dry ice and stored at -20 C pending assay.
Levels of sodium and 18-oxo-cortisol (corrected for creatinine excretion) were measured in a 24-h urine collection.
Aldosterone response to posture
Plasma aldosterone was measured in blood collected at 0800 h following overnight recumbency and again at 1000 h following 2 h of upright posture (sitting, standing, or walking). Aldosterone was considered to be responsive to upright posture if the 1000-h upright levels were at least 50% higher than the 0800-h recumbent levels.
Angiotensin II (AII) infusion studies
AII infusion studies were performed during midmorning hours following at least 30 min of recumbency. AII was infused at a rate of 2 ng/kg·min, and blood was collected basally and 60 min after commencement of the infusion for measurement of plasma aldosterone. Aldosterone was considered responsive to AII if levels rose by at least 50% during the infusion.
Aldosterone, PRA, and cortisol day-curve studies
For each day-curve study, a cannula was inserted into a forearm vein in the cubital fossa for blood sampling. Blood (15 mL) was collected every 2 h for 24 h from 1000 h to 1000 h for measurement of plasma aldosterone, PRA, potassium, and plasma cortisol. Posture was unrestricted until midnight, after which subjects remained recumbent until 0800 h and then assumed an upright posture until the completion of the day-curve at 1000 h.
Dexamethasone suppression testing
Plasma aldosterone, plasma cortisol, and PRA were measured in blood collected at 1000 h after 2 h of upright posture following overnight recumbency, basally and also daily, during 4 days of dexamethasone administration (0.5 mg every 6 h).
Assays
Plasma aldosterone was measured by RIA (Coat-A-Count 125I-Aldosterone RIA Kit; Diagnostic Products Corporation, Los Angeles, CA), in a modification of the method of Mayes et al. (13), with intra- and interassay coefficients of variation of 4.0% and 6.0%, respectively, and a lower detection limit of 69 pmol/L. PRA was measured by RIA (Gamma Coat [125I] Plasma Renin Activity RIA Kit; INCSTAR Corp., Stillwater, MN) of generated angiotensin I in a modification of the method of Haber et al. (14), with intra- and interassay coefficients of variation of 4.3% and 7.2%, respectively, and a lower detection limit of 1.3 pmol/L/min. Plasma cortisol was measured by RIA (Quanticoat 125I-Cortisol RIA Kit; Kallestad Diagnostics, Chaska, MN), with intra- and interassay coefficients of variation of 4.5% and 9.6%, respectively, and a lower detection limit of 28 nmol/L. Urinary 18-oxo-cortisol levels were determined by RIA using a method described previously (15).
Data analysis
Group data for the 10 normotensive subjects with FH-I are presented as median ± SD unless otherwise indicated. Results for hypertensive patients with FH-I have also been included, with the number value given in each case, for comparative purposes. For each day-curve study, Spearman rank correlation coefficients were determined for correlations between aldosterone and cortisol levels as a reflection of ACTH-dominated aldosterone regulation and between aldosterone and PRA levels as a reflection of AII-dominated regulation of aldosterone.
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Results |
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)Plasma potassium levels were within the normal range (3.5–5.0 mmol/L) for all 10 normotensive individuals, with a median ± SD for the group of 3.7 ± 0.4 mmol/L (compared with 3.6 ± 0.5 mmol/L in 19 hypertensive subjects with FH-I).
Upright plasma aldosterone levels were within the normal range
(140–1100 pmol/L) in all except one (1412 pmol/L) of the normotensive
subjects (patient 3, Table 1). The median level for the group was
478 ± 333 pmol/L (compared with 458 ± 174 pmol/L in 19
hypertensive subjects with FH-I). Upright PRA levels (median, 3.3
± 30.5 pmol/L·min compared with 2.6 ± 3.0 pmol/L·min in 19
hypertensive subjects with FH-I) were suppressed below the lower limit
of the normal range (13 pmol/L.min) and aldosterone to PRA ratios
elevated (median, 169.0 ± 308.3 compared with 135.9 ± 151.0
in 19 hypertensive subjects with FH-I) above the upper limit of normal
(65.0) in all but one subject (patient 4, Table 1). This 38-yr-old
woman with normal plasma potassium (3.6 mmol/L) and aldosterone (646
pmol/L) levels, elevated PRA (99.0 pmol/L·min), and low/normal
aldosterone to PRA ratio (6.5) had never received diuretics,
angiotensin-converting enzyme inhibitors, dihydropyridine calcium
antagonists, or angiotensin type 1 receptor blockers, and did not
demonstrate evidence of marked dietary salt restriction (24-h urinary
sodium excretion 13.2 mmol/mmol creatinine) to explain the high PRA
level, but was taking an estrogen and an androgen inhibitor. Repeat
testing 3 months after changing her sole medication (a combination oral
contraceptive medication containing 2000 µg cyproterone acetate/35
µg ethinylestradiol daily) to 150 µg levonorgestrel/30 µg
ethinylestradiol daily gave similar results (blood pressure 110/80,
plasma potassium 3.6 mmol/L, plasma aldosterone 755 pmol/L, PRA 74.6
pmol/L/min, and aldosterone to PRA ratio 10.1).With the exception of
PRA and the aldosterone to PRA ratio, other biochemical findings in
this patient (urinary 18-oxo-cortisol levels and results of posture
studies, AII infusions, and day-curve studies) resembled those
characteristic of FH-I.
Urinary levels of 18-oxo-cortisol (median, 34.3 ± 11.2 nmol/mmol creatinine compared with 32.5 ± 12.9 nmol/mmol creatinine in 15 hypertensive subjects with FH-I) were above the normal range (0.8–6.5 nmol/mmol creatinine) in all subjects.
Urinary sodium excretion (14.7 ± 7.4 mmol/mmol creatinine) was unremarkable in this group of normotensive patients with FH-I, and was not, specifically, consistent with marked dietary sodium restriction.
Dynamic tests and day-curve studies
Only two (patients 8 and 10, Table 2) of the seven subjects so studied
demonstrated normal increases in plasma aldosterone of at least 50%
above basal levels during assumption of upright posture (median
response for the group, 14.2 ± 135.4% compared with 10.2 ±
41.8% in 19 hypertensive subjects with FH-I). However, in both of
these responsive individuals, plasma cortisol also unexpectedly rose
(by 130% and 59%, respectively), consistent with a concomitant rise
in ACTH, and fell as expected (by 22%, 20%, 33%, and 8%,
respectively) in the four unresponsive individuals in whom it was
measured (patients 1, 4, 7, and 9). Although levels remained low, PRA
rose during assumption of upright posture in five subjects (patients 1,
4, 5, 8, and 10; by 247%, 275%, 100%, 9%, and 97%, respectively),
did not change in one (patient 9) and fell in one (patient 7, by
50%).
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; median response,
-39.1 ± 18.0% compared with -33.1 ± 73.1% in 19
hypertensive patients with FH-I). Six subjects (patients 1, 4, and 7–10) underwent day-curve studies. In all six subjects, aldosterone correlated strongly with cortisol (r = 0.79 to 0.97, median 0.91 ± 0.07; P < 0.01 to < 0.001), but not with PRA levels (r = 0.13 to 0.40, median 0.24 ± 0.10; not significant).
Two subjects (patients 5 and 10) underwent dexamethasone suppression
testing (Fig. 1). Dexamethasone
administration resulted in marked, persistent suppression of plasma
cortisol, as expected. Within 24 h of dexamethasone
administration, upright plasma aldosterone had fallen to less than 110
pmol/L (4 ng/dL), and PRA levels had begun to rise in both individuals.
In both subjects, aldosterone to PRA ratios fell rapidly after
commencement of dexamethasone and were still very low by day 5 (0 in
patient 4, 1.9 in patient 10). One of the two individuals (patient 10)
demonstrated evidence of early, partial recovery of AII-dependent
aldosterone production, with plasma levels rising progressively from
day 3 to day 5 of dexamethasone. This early recovery followed an
earlier, marked rise in PRA levels, which by day 4 had reached 187.8
pmol/L·min (compared with corresponding levels ranging from 1.3–63.0
pmol/L·min in 15 other patients with FH-I studied within our unit).
Patient 10 was a 40-yr-old normotensive female who was receiving
treatment with 2 mg transdermal estradiol (designed to release 25
µg per 24 h) twice weekly at the time of dexamethasone
suppression testing. She demonstrated a sodium excretion rate of 9.4
mmol/mmol creatinine (in the middle of the range of values for subjects
in the current study) and gave no history of previous treatment with
diuretics to explain her brisk PRA response to dexamethasone.
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Discussion |
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None of the normotensive patients with FH-I in this study were hypokalemic. However, several investigators have recently pointed out that hypokalemia is, in fact, uncommon in this condition, even when the patients are hypertensive, because it has been possible through genetic testing to identify all affected members of families, rather than identify only those with gross clinical or biochemical disturbances (2, 3, 8, 9). The same, more complete family studies have shown upright plasma aldosterone to be frequently within the normal range (2, 3, 9) in affected family members, even in hypertensive patients with FH-I. Only one of the normotensive patients in the present study demonstrated an elevated upright plasma aldosterone level. Patients with other forms of primary aldosteronism also frequently lack hypokalemia (2, 21, 22, 23) and demonstrate normal upright plasma aldosterone levels (2, 24, 25, 26, 27).
Excessive production of 18-hydroxy- and 18-oxo-cortisol (so-called "hybrid steroids") in FH-I is thought to result from aberrant expression of aldosterone synthase activity in zona fasciculata, where cortisol is available as a substrate (28, 29). Although an elevated urinary level of 18-oxo-cortisol is a sensitive biochemical marker of FH-I (3, 9), this steroid has only weak mineralocorticoid activity (30) and is believed not to play a major role in the development of hypertension in this condition (30). All normotensive subjects with FH-I showed elevated urinary levels of 18-oxo-cortisol. All but one subject (patient 4, who is discussed more fully below) in the current study demonstrated suppressed upright PRA levels and elevated aldosterone to PRA ratios, which are both biochemical indicators of hyperaldosteronism, evident in these individuals despite the absence of hypertension.
Failure of plasma aldosterone to rise normally in response to upright posture or during AII infusion in FH-I is consistent with aldosterone production being predominantly regulated by ACTH (levels of which are falling during the morning hours when these tests are conducted) rather than by AII. In the current study, aldosterone responses to upright posture were seen in only two of seven subjects so studied and were attributable to concurrent unexpected rises in ACTH. Aldosterone failed to respond to AII infusion in these two patients, as well as in the other normotensive subjects with FH-I. Predominant regulation by ACTH also explains the strong tendency for circadian levels of aldosterone to tightly follow those of cortisol rather than PRA levels in this disorder (11 and the present study), and the ability of dexamethasone to rapidly induce marked suppression of plasma aldosterone, which usually lasts at least several days (9, 19, 20, and the present study). All the above features of FH-I were apparent in all of the subjects studied, despite the fact that they were normotensive.
Two female subjects (patients 4 and 10) demonstrated PRA levels and responses that differed from those of other normotensive individuals with FH-I, with one showing basal levels that were considerably higher and the other having levels that were suppressed basally, but showed a much brisker rise in response to dexamethasone administration. These two subjects were also the oldest among the current series of normotensive individuals with FH-I, suggesting that they might share factors rendering them particularly capable of resisting development of hypertension. At the time of assessment, both of these subjects were receiving treatment with preparations of estrogen. In normal females, the administration of estrogen preparations markedly increases hepatic synthesis and plasma levels of angiotensinogen (31). Reported effects of estrogen preparations on PRA levels have been variable, with earlier studies describing elevated levels (32, 33) and more recent studies (31, 34) reporting normal levels and reduced plasma renin concentrations, which presumably compensated for the increase in angiotensinogen production induced by these agents. It is possible, therefore, that the aberrant PRA findings in patients 4 and 10 can be explained solely on the basis of estrogen treatment. Cessation of the cyproterone acetate (an inhibitor of androgen action) component of patient 4’s combined oral contraceptive medication had no effect on her plasma aldosterone or PRA levels. Neither subject had ever received diuretic medications, and in neither subject were 24-h urinary sodium levels suggestive of marked dietary salt restriction to explain increased PRA levels or responsiveness. Reduced expression of the hybrid gene in certain patients with FH-I could result in higher PRA levels. However, urinary 18-oxo-cortisol levels were elevated in both subjects, and both demonstrated evidence of ACTH-regulated aldosterone production with plasma aldosterone levels falling during the early morning period (when ACTH falls as part of its normal diurnal rhythm) despite infusion of AII and tight correlation of circadian aldosterone levels with those of cortisol (but not PRA), suggesting functioning hybrid genes. An alternative explanation might be the coexistence in these subjects of a state of aldosterone resistance, perhaps genetically determined, which could protect them from the hypertensive and renin-suppressing effects of excessive aldosterone production.
In conclusion, biochemical evidence of excessive, abnormally regulated aldosterone production characteristic of hypertensive individuals with FH-I was also present in normotensive individuals with FH-I. The absence of hypertension in such individuals cannot, therefore, be attributed to lack of expression of the hybrid gene. Given that urinary sodium excretion was unremarkable, the lack of hypertension in these individuals did not seem to be attributable to strict low dietary sodium intakes. Other investigators have reported more severe hypertension in this condition to be associated with lower urinary kallikrein levels (35) and maternal origin of the hybrid gene (8), but a lack of association of hypertension severity with urinary sodium excretion (35), urinary hybrid steroid levels (35), degree of hyperaldosteronism (8, 35), or position of the hybrid gene crossover point (8). The results of the current study exclude a complete lack of hybrid gene expression to explain the normal blood pressure levels. They do not exclude the possibility of a lower level of hybrid gene expression and of aldosterone overproduction contributing toward normality of blood pressure in normotensive individuals with FH-I. However, it is more likely that other genes involved in blood pressure regulation may determine whether an individual with this disorder develops hypertension.
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Footnotes |
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Received March 3, 1999.
Revised June 4, 1999.
Accepted August 3, 1999.
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References |
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), and PRA (
) in response to dexamethasone
administration (0.5 mg every 6 h) in two normotensive subjects
with FH-I [patient 5 (a) and patient 10 (b)]. Levels were measured in
blood collected at 1000 h after 2 h of upright posture. The
shaded portion represents plasma aldosterone levels of
110 pmol/L (4 ng/dL) or less.