Severity of Hypertension in Familial Hyperaldosteronism Type I: Relationship to Gender and Degree of Biochemical Disturbance¹

Abstract

In familial hyperaldosteronism type I (FH-I), inheritance of a hybrid 11␤-hydroxylase/aldosterone synthase gene causes ACTHregulated aldosterone overproduction. In an attempt to understand the marked variability in hypertension severity in FH-I, we compared clinical and biochemical characteristics of 9 affected individuals with mild hypertension (normotensive or onset of hypertension after 15 yr, blood pressure never Ͼ160/100 mm Hg, Յ1 medication required to control hypertension, no history of stroke, age Ͼ18 yr when studied) with those of 17 subjects with severe hypertension (onset before 15 yr, or systolic blood pressure Ͼ180 mm Hg or diastolic blood pressure Ͼ120 mm Hg at least once, or Ն2 medications, or history of stroke). Severe hypertension was more frequent in males (11 of 13 males vs. 6 of 13 females; P Ͻ 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 Ϯ SD, 27.4 Ϯ 9.0 vs. 35.2 Ϯ 12.9 nmol/mmol creatinine⅐day), higher plasma potassium (4.0 Ϯ 0.3 vs. 3.6 Ϯ 0.4 mmol/L), and lower recumbent (0800 h after overnight recumbency) plasma aldosterone levels (498 Ϯ 279 vs. 744 Ϯ 290 pmol/L). Upright (midmorning after 2-3 h of upright posture) plasma aldosterone levels were similar (mild, 485 Ϯ 150; severe, 474 Ϯ 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 Ϯ 1.4; severe, 3.7 Ϯ 3.2 pmol/ L⅐min) and aldosterone/PRA ratios (mild, 199.5 Ϯ 133.4; severe, 200.6 Ϯ 150.9) as severe subjects. During angiotensin II (AII) infusion studies (n ϭ 6 mild and 10 severe), performed during recumbency, aldosterone levels were lower in the mild group both basally (404 Ϯ 144 vs. 843 Ϯ 498 pmol/L; P Ͻ 0.05) and after 60 min AII (2 ng/kg⅐min; 261 Ϯ 130 vs. 520 Ϯ 330 pmol/L; P Ͻ 0.05). Aldosterone was unresponsive (rose by Ͻ50%) to AII in all subjects. Day curve studies (blood collected every 2 h for 24 h; n ϭ 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. (J Clin Endocrinol

Molecular phenotyping for analyzing subtle genetic effects in mice: Application to an angiotensinogen gene titration

“…A support of this interpretation is our preliminary observation that the plasma levels of Ang II and of aldosterone are both increased in the Agt 2͞2 animals to about 1.4 times their levels in wild-type animals. Human patients with glucocorticoid-remediable aldosteronism carry an additional chimeric gene that fuses the regulatory sequences of steroid 11␤ hydroxylase to the coding sequences of AS; these patients have 1.5 times plasma aldosterone levels and are hypertensive (13,14).…”

New Perspectives On The Role Of Aldosterone Excess In Cardiovascular Disease

“…It is also probable that other genes involved in blood pressure regulation influence the phenotypic expression of the hybrid gene. Our two oldest normotensive individuals with FH‐I demonstrated PRA levels that differed from those of other affected subjects, with one showing basal levels that were high/ normal and the other having levels that were suppressed basally, but showed a much brisker rise in response to correction of hyperaldosteronism by dexamethasone 73,74 . Neither had ever received diuretics nor had 24 h urinary sodium levels suggestive of marked dietary salt restriction to explain increased PRA levels or responsiveness.…”

“…Whereas some of these individuals are still in childhood and may become hypertensive with time, many have remained normotensive into adulthood. Among our series of patients with FH‐I, females have been relatively protected against the development of hypertension 74 . Five of six individuals who have remained normotensive into their third decade of life and all three subjects who are still normotensive in their fifth decade are females.…”

Familial Varieties Of Primary Aldosteronism

“…In our largest family, one affected male who had been severely hypertensive since the age of 13 years died at 21 years of haemorrhagic stroke, whereas a 45‐year‐old affected female has remained normotensive. Seeking explanations for this marked variability in phenotypic expression, we found that: (i) females appear to be relatively protected, being less likely to have severe hypertension and tending to live longer than males; 26 (ii) even normotensive individuals demonstrate biochemical evidence of hybrid gene expression, with suppressed PRA, high aldosterone/PRA ratios and urinary 18‐oxo‐cortisol levels and tight correlation of circadian aldosterone levels with cortisol rather than PRA, suggesting that lack of hypertension is not explained by lack of expression of the hybrid gene; 27 and (iii) the degree of hybrid gene expression may help determine hypertension severity, because patients with more severe hypertension have tended to demonstrate lower plasma potassium and higher urinary 18‐oxo‐cortisol and recumbent plasma aldosterone levels 26 …”

“…The severity of hypertension varies widely in FH‐I, even within the same family 8,26 . In our largest family, one affected male who had been severely hypertensive since the age of 13 years died at 21 years of haemorrhagic stroke, whereas a 45‐year‐old affected female has remained normotensive.…”