Severity of Hypertension in Familial Hyperaldosteronism Type I: Relationship to Gender and Degree of Biochemical Disturbance1
Michael Stowasser,
Anthony W. Bachmann,
Phillip R. Huggard,
Tony R. Rossetti and
Richard D. Gordon
Hypertension Unit, University Department of Medicine, Greenslopes
Hospital, Brisbane 4120, Australia
Address all correspondence and requests for reprints to: Prof. Richard D. Gordon, Hypertension Unit, University Department of Medicine, Greenslopes Hospital, Brisbane 4120, Australia. E-mail:
med.gslopes{at}mailbox.uq.edu.au
In familial hyperaldosteronism type I (FH-I), inheritance ofa hybrid
11ß-hydroxylase/aldosterone synthase gene causesACTH-regulated
aldosterone overproduction. In an attempt tounderstand the marked
variability in hypertension severity inFH-I, we compared clinical and
biochemical characteristics of9 affected individuals with mild
hypertension (normotensiveor onset of hypertension after 15 yr, blood
pressure never >160/100mm Hg, 1 medication required to control
hypertension, no historyof stroke, age >18 yr when studied) with
those of 17 subjectswith severe hypertension (onset before 15 yr, or
systolic bloodpressure >180 mm Hg or diastolic blood pressure >120
mmHg at least once, or 2 medications, or history of stroke). Severe
hypertensionwas more frequent in males (11 of 13 males
vs. 6 of 13 females;P < 0.05). All
4 subjects still normotensive after age 18yr were females. Of 10 other
affected, deceased individuals(7 males and 3 females) from a single
family, all six who diedbefore 60 yr of age (4 by stroke) were males.
Biochemical studieswere conducted in 6 mild and 16 severe subjects.
The 2 groupswere similar in terms of urinary sodium excretion. Mild
subjectstended, although not significantly, to have lower urinary
18-oxo-cortisol(mean ± SD, 27.4 ± 9.0
vs. 35.2 ± 12.9nmol/mmol creatinine·day),
higher plasma potassium (4.0± 0.3 vs. 3.6 ±
0.4 mmol/L), and lower recumbent(0800 h after overnight recumbency)
plasma aldosterone levels(498 ± 279 vs. 744
± 290 pmol/L). Upright (midmorningafter 2–3 h of upright posture)
plasma aldosterone levelswere similar (mild, 485 ± 150; severe,
474 ± 188pmol/L). In 1 normotensive female, upright PRA was much
higher,and the upright aldosterone/PRA ratio was much lower than that
inthe other subjects. The remaining mild subjects had similarupright
PRA levels (mild, 2.8 ± 1.4; severe, 3.7 ±3.2
pmol/L·min) and aldosterone/PRA ratios (mild, 199.5± 133.4;
severe, 200.6 ± 150.9) as severe subjects.During angiotensin II
(AII) infusion studies (n = 6 mild and10 severe), performed
during recumbency, aldosterone levelswere lower in the mild group both
basally (404 ± 144vs. 843 ± 498 pmol/L;
P < 0.05) and after 60 min AII(2 ng/kg·min;
261 ± 130 vs. 520 ± 330 pmol/L;
P< 0.05). Aldosterone was unresponsive (rose by
<50%) toAII in all subjects. Day curve studies (blood collected
every2 h for 24 h; n = 2 mild and 7 severe)
demonstrated abnormalregulation of aldosterone by ACTH rather than by
AII in bothgroups. In conclusion, in this series of patients with
FH-I,males had more severe hypertension, and the degree of hybrid
gene-inducedaldosterone overproduction may have contributed to the
severityof hypertension.
This article has been cited by other articles:
B. Xue, D. Badaue-Passos Jr, F. Guo, C. E. Gomez-Sanchez, M. Hay, and A. K. Johnson Sex differences and central protective effect of 17{beta}-estradiol in the development of aldosterone/NaCl-induced hypertension
Am J Physiol Heart Circ Physiol,
May 1, 2009;
296(5):
H1577 - H1585.
[Abstract][Full Text][PDF]
I. Quack, O. Vonend, L. Sellin, J. Stegbauer, G. Dekomien, and L. C. Rump A Tale of Two Patients With Mendelian Hypertension
Hypertension,
March 1, 2008;
51(3):
609 - 614.
[Full Text][PDF]
M. Stowasser, J. Sharman, R. Leano, R. D. Gordon, G. Ward, D. Cowley, and T. H. Marwick Evidence for Abnormal Left Ventricular Structure and Function in Normotensive Individuals with Familial Hyperaldosteronism Type I
J. Clin. Endocrinol. Metab.,
September 1, 2005;
90(9):
5070 - 5076.
[Abstract][Full Text][PDF]
O. Olivieri, A. Ciacciarelli, D. Signorelli, F. Pizzolo, P. Guarini, C. Pavan, A. Corgnati, S. Falcone, R. Corrocher, A. Micchi, et al. Aldosterone to Renin Ratio in a Primary Care Setting: The Bussolengo Study
J. Clin. Endocrinol. Metab.,
September 1, 2004;
89(9):
4221 - 4226.
[Abstract][Full Text][PDF]
P. Mulatero, S. M. di Cella, T. A. Williams, A. Milan, G. Mengozzi, L. Chiandussi, C. E. Gomez-Sanchez, and F. Veglio Glucocorticoid Remediable Aldosteronism: Low Morbidity and Mortality in a Four-Generation Italian Pedigree
J. Clin. Endocrinol. Metab.,
July 1, 2002;
87(7):
3187 - 3191.
[Abstract][Full Text][PDF]
H.-S. Kim, G. Lee, S. W. M. John, N. Maeda, and O. Smithies Molecular phenotyping for analyzing subtle genetic effects in mice: Application to an angiotensinogen gene titration
PNAS,
April 2, 2002;
99(7):
4602 - 4607.
[Abstract][Full Text][PDF]
M. Stowasser, R. D Gordon, J. C Rutherford, N. Z Nikwan, N. Daunt, and G. J Slater Review: Diagnosis and management of primary aldosteronism
Journal of Renin-Angiotensin-Aldosterone System,
September 1, 2001;
2(3):
156 - 169.
[PDF]
J. W. Funder Editorial: Sex and the Single Gene--FH-1
J. Clin. Endocrinol. Metab.,
June 1, 2000;
85(6):
2158 - 2159.
[Full Text]
H.-S. Kim, G. Lee, S. W. M. John, N. Maeda, and O. Smithies Molecular phenotyping for analyzing subtle genetic effects in mice: Application to an angiotensinogen gene titration
PNAS,
April 2, 2002;
99(7):
4602 - 4607.
[Abstract][Full Text][PDF]
1 medication required to control
hypertension, no history of stroke, age >18 yr when studied) with
those of 17 subjects with severe hypertension (onset before 15 yr, or
systolic blood pressure >180 mm Hg or diastolic blood pressure >120
mm Hg at least once, or 
2 medications, or history of stroke). Severe
hypertension was more frequent in males (11 of 13 males
vs. 6 of 13 females; P < 0.05). All
4 subjects still normotensive after age 18 yr were females. Of 10 other
affected, deceased individuals (7 males and 3 females) from a single
family, all six who died before 60 yr of age (4 by stroke) were males.
Biochemical studies were conducted in 6 mild and 16 severe subjects.
The 2 groups were similar in terms of urinary sodium excretion. Mild
subjects tended, although not significantly, to have lower urinary
18-oxo-cortisol (mean ± SD, 27.4 ± 9.0
vs. 35.2 ± 12.9 nmol/mmol creatinine·day),
higher plasma potassium (4.0 ± 0.3 vs. 3.6 ±
0.4 mmol/L), and lower recumbent (0800 h after overnight recumbency)
plasma aldosterone levels (498 ± 279 vs. 744
± 290 pmol/L). Upright (midmorning after 2–3 h of upright posture)
plasma aldosterone levels were similar (mild, 485 ± 150; severe,
474 ± 188 pmol/L). In 1 normotensive female, upright PRA was much
higher, and the upright aldosterone/PRA ratio was much lower than that
in the other subjects. The remaining mild subjects had similar upright
PRA levels (mild, 2.8 ± 1.4; severe, 3.7 ± 3.2
pmol/L·min) and aldosterone/PRA ratios (mild, 199.5 ± 133.4;
severe, 200.6 ± 150.9) as severe subjects. During angiotensin II
(AII) infusion studies (n = 6 mild and 10 severe), performed
during recumbency, aldosterone levels were lower in the mild group both
basally (404 ± 144 vs. 843 ± 498 pmol/L;
P < 0.05) and after 60 min AII (2 ng/kg·min;
261 ± 130 vs. 520 ± 330 pmol/L;
P < 0.05). Aldosterone was unresponsive (rose by
<50%) to AII in all subjects. Day curve studies (blood collected
every 2 h for 24 h; n = 2 mild and 7 severe)
demonstrated abnormal regulation of aldosterone by ACTH rather than by
AII in both groups. In conclusion, in this series of patients with
FH-I, males had more severe hypertension, and the degree of hybrid
gene-induced aldosterone overproduction may have contributed to the
severity of hypertension. 
