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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 137-142
Copyright © 2007 by The Endocrine Society

Aldosterone-to-Renin Ratio as a Marker for Disease Severity in 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia

Saroj Nimkarn, Karen Lin-Su, Niklas Berglind, Robert C. Wilson and Maria I. New

Department of Pediatrics (S.N., K.L.-S., R.C.W., M.I.N.), Adrenal Steroid Disorders Program, and Department of Community and Preventive Medicine (N.B.), Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Maria I. New, M.D., Director, Division of Adrenal Steroid Disorders, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1198, New York, New York 10029. E-mail: maria.new{at}mssm.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency (21 OHD) is classified clinically in decreasing order of severity into salt-wasting, simple-virilizing, and nonclassical forms. Causative mutations in the CYP21A2 gene dictate the degrees of adrenal enzyme defect. Salt-wasting crises due to aldosterone deficiency are clinically apparent in the salt-wasting form but not in other forms of 21 OHD.

Objectives: This study examined the ratio of serum aldosterone to plasma renin activity as an index of sodium wasting in patients with 21 OHD CAH, heterozygotes, and normal individuals.

Design: This was a cross-sectional, retrospective, noninterventional study.

Patients and Other Participants: A total of 402 individuals were included: 224 patients affected with 21 OHD CAH and 178 unaffected subjects. Classification into each diagnostic group was made primarily on the basis of clinical and hormonal features. Affected or unaffected status was confirmed by genotype of CYP21A2. All subjects were on ad lib diets without restrictions. Salt-wasting status was examined by sodium deprivation testing in 32 salt-wasting subjects and 14 simple virilizing subjects.

Results: The ratio of serum aldosterone to plasma renin activity was found to discriminate well between the different groups of disease severity. The lowest ratios, indicative of the least sodium conservation, were seen in the salt-wasting group with increasing ratios in the simple virilizing, nonclassical, and unaffected groups. This ratio remained stable with age.

Conclusion: The ratio of serum aldosterone to plasma renin activity provides a simple index to compare groups of patients with varying degrees of 21 OHD.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN PATIENTS AFFECTED with 21-hydroxylase deficiency (21 OHD) congenital adrenal hyperplasia (CAH), the degree of enzyme deficiency is governed by mutations in the CYP21A2 gene. Adrenal glucocorticoid and mineralocorticoid biosynthesis are both diminished due to defective enzyme activity, and the severity of hormonal abnormalities and clinical symptoms largely depends on the extent of the deficiency (1). Steroid 21 OHD CAH is categorized into classical and nonclassical (NC) forms. Classical 21 OHD can be further subdivided into the simple-virilizing (SV) and salt-wasting (SW) forms.

Salt wasting is a distinctive feature of the SW form due to inadequate aldosterone synthesis despite high renin activity (2). However, the determination of salt wasting is ill defined. Many female infants who present with ambiguous genitalia, as well as males and females prenatally diagnosed or identified through positive newborn screening, are treated with fludrocortisone, a salt-retaining hormone, from birth, before any salt-wasting symptoms or signs actually occur. These patients then remain characterized as salt wasters only because such treatment was initiated in early life. Although the importance of aldosterone as the most potent salt-retaining hormone and its deficiency as a cause of salt wasting is recognized, aldosterone is not routinely measured to distinguish a SW patient from a SV patient. It is recognized that salt deprivation studies are the gold standard to establish salt wasting based on the failure of sodium conservation. These studies are, however, labor intensive and require an inpatient admission because of the risk of a salt-wasting crisis.

In this report, we present a simple test to define salt wasting based on the adrenal capacity to produce aldosterone in response to renin stimulation. We report that the aldosterone to plasma renin activity (PRA) ratio is abnormal in all forms of 21 OHD CAH, but most abnormal in SW CAH.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

In this cross-sectional study, we examined the ratio of serum aldosterone to plasma renin activity (ARR), determined from blood drawn in an upright position, as an index of sodium wasting in a total of 402 affected and unaffected individuals up to 40 yr of age. This included 224 patients diagnosed as affected with 21 OHD CAH (74 SW, 43 SV, 107 NC) on the basis of hormonal profile (3), clinical findings (4), knowledge of two CYP21A2 mutations, and 178 genotyped individuals who were unaffected [111 heterozygotes (HET) and 67 homozygous normal (NL)]. Informed consent was obtained for all participants who were enrolled from July 1977 to June 2005. Detailed information is provided in Table 1Go.


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  		TABLE 1. Characteristics of the study population included in analysis

 
The majority of the subjects (356 of 402 or 88.5%) had not been treated with glucocorticoids or mineralocorticoids at the time of study. For the purpose of evaluating age of the subjects as a possible confounding factor, we evaluated the ARR at various ages up to 40 yr of age. In the older patients who had received treatment for SW or SV, we obtained the ARR data retrospectively after salt deprivation to study the ability to conserve sodium (5, 6, 7, 8). Forty-six classical patients were included, 32 SW (male to female 11:21) and 14 SV (male to female 8:6), for this purpose. These study subjects have been designated as SW2 and SV2, in contrast to those whose data were derived from the time of diagnosis before treatment was initiated (SW1 and SV1). Data from those past sodium deprivation studies were used as a minor part of this report (22 classical patients comprised approximately 5% of total subjects of the report). Previous publications of salt deprivation studies reported ratios of PRA to either urinary aldosterone or its metabolites, not to serum aldosterone as in this report. Most of these patients did not have molecular genetic analysis of CYP21A2. In those past studies, mineralocorticoid treatment in SW patients was discontinued during sodium deprivation. They were admitted to the hospital, during which time they were given a restricted amount of dietary salt (maximum of 10 mEq of sodium per day) and were under close observation for signs of clinical decompensation. In SW2 and SV2 groups, aldosterone, PRA, and ARR were evaluated at the end of the study.

Baseline and stimulated levels of 17-hydroxyprogesterone (17OHP) after the administration of synthetic ACTH were used to classify patients as affected with either classical or nonclassical 21 OHD CAH (3, 9). The diagnosis of SW, SV, or NC disease was assigned by the primary endocrinologist (M.I.N.) based on history, physical examination, presence or absence of electrolyte abnormalities, hormonal data, and genotype. Overt evidence of sodium depletion, i.e. hyponatremia (sodium < 130 mEq/liter), hyperkalemia (potassium > 5.5), metabolic acidosis, hypovolumia, or shock (adrenal crisis), identified patients as having the SW form. Those with no clinically apparent salt wasting but markedly elevated 17OHP and normal to elevated aldosterone levels were classified as SV. NC patients have lower levels of 17OHP, normal aldosterone levels, and no evidence of prenatal virilization. Unaffected subjects included HET and NL CYP21A2 individuals. Medical records and laboratory tests were thoroughly reviewed. All subjects were on ad lib diets without restriction except for those studied in the salt-deprivation protocol (as described above).

Blood samples were taken in an upright position in an outpatient setting, except for SW newborns, whose blood samples were taken in a supine position in the hospital. Affected status was confirmed by direct CYP21A2 analysis or human leukocyte antigen typing with subsequent identification of mutations in CYP21A2 in all subjects. Identification of the CYP21A2 mutations was performed in our molecular genetic laboratory according to the published protocol (10, 11). To diagnose the patients genotypically, the mutations were classified into severe (i.e. large deletion, 656 A/C-G, clustered I236N, V237E& M239K, Q318X, R356W, and R483P), moderate (I172N), and mild (P30L, V281L, R339H, and P453S) based on in vitro enzyme activity (12). The combination of the two mutations was a part of phenotypic determination. Salt-wasting patients have two severe mutations, simple virilizing patients have severe/moderate or moderate/moderate mutations, and nonclassical patients have severe/mild, moderate/mild, or mild/mild mutations. Serum aldosterone was measured by RIA (13), using the same antibody in all assays, and PRA was assayed by the method of Sealey and Laragh (14).

Statistical analysis

Because of the skewed distribution of the outcome measurements, the nonparametric Kruskal-Wallis rank test was used to compare the overall difference, and pair-wise Mann-Whitney rank-sum tests were used to compare parameters between the groups in the 356 individuals without prior treatment at the time of diagnosis. All results of the nonparametric tests are shown as P values adjusted for multiple testing with Bonferroni’s method. The median, 25th, and 75th percentile of each group are presented.

To investigate the relationship between the outcome variables and age of the individuals in our study, we included the 14 SV2 and 32 SW2 with prior treatment and used linear models on the transformed outcome variables (square root transformation for aldosterone and ARR and log transformation for PRA). The results from these analyses are presented as P values for the slope of age, in which a low P value can be interpreted as a strong relationship between age and the outcome variable, and a high P value indicates no relationship. The levels of the observed outcome variables in the untreated and treated groups were compared with pair-wise Mann-Whitney rank-sum tests. A P value of less than 0.05 was considered statistically significant. All statistical analyses were performed with Stata version 9.1 (StataCorp, College Station, TX).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics

Table 1Go summarizes the baseline characteristics of the subjects. Females comprised the majority in all the groups except SV. The distribution of the age at diagnosis for each 21 OHD CAH group also differed, SW1 being the youngest, followed by SV1 and NC. Within the SW group, untreated subjects (SW1) were younger (0.1 ± 0.24 yr) than previously treated subjects (SW2) (17.8 ± 12.4 yr) in whom outcome variables were derived from the salt deprivation study. Similar differences in age distribution were also found in SV groups, between untreated (SV1) and previously treated subjects (SV2) (3.0 ± 2.0 and 20.0 ± 11.7 yr, respectively). Mean ages of the previously treated subjects in both SW2 and SV2 were similar to those of NC, HET, and NL groups. The majority of HET and NL subjects were enrolled in our study during the time of the probands’ family evaluation. Subjects affected with 21 OHD CAH in our study were the patients referred to our research center; this was not a population-based study. Therefore, the difference in quantities in each group did not conform to the estimated incidence in general populations. However, SV accounted for 36.7%, whereas 63.3% were SW, in our classical 21 OHD CAH patients. This percentage is similar to the overall estimation that one third to one fourth of classical 21 OHD CAH cases are SV (4, 15).

Aldosterone and PRA

Aldosterone levels were significantly higher in the SV1 group than the other groups (Fig. 1Go and Table 2Go). PRA levels declined with decreasing disease severity from the most affected SW1 to the unaffected. All pair-wise comparisons between groups were statistically significant except within the unaffected groups HET and NL. ARR increased with decreasing severity from SW1 to unaffected. All comparisons were statistically significant except between groups HET and NL


Figure 1
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  		FIG. 1. Box plots describing the distribution of aldosterone, PRA, and ARR in the different groups. Aldosterone, ARR, and PRA are shown. The boxes at the lower and upper ends represent the lower and upper quartiles, and the horizontal line inside the boxes represents the median. The vertical bars reach from the box to the nonoutlier minimum and maximum values. The circles represent outliers, which are defined as values more than 1.5 times the height of the box from the nearest quartile.

 

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  		TABLE 2. Pair-wise and overall comparisons of the outcome measurements between groups

 
Age distribution

The age distribution of each group in our study differed substantially, with SW presenting at an earlier age than SV and NC (Table 1Go). To investigate whether the difference in levels of the outcome variables could be explained by the difference in age distribution, we included previously treated subjects (SW2 and SV2) in a linear regression analysis of age against the transformed outcome variables. Figure 2Go shows the relationship between age and the outcome variables in logarithmic scale. In each plot the regression line is drawn, and the P value for the slope is given. Aldosterone levels decreased slightly with age, but this decrease was statistically significant only in the HET group. PRA decreased with increasing age with a statistically significant slope in all groups except SV, in which the slope was borderline significant. ARR, on the other hand, increased slightly with age but was only statistically significant in the NL group.


Figure 2
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  		FIG. 2. Scatter plots of aldosterone, PRA, and ARR against age in the different groups. In each plot, the linear regression line is drawn.

 
Effects of treatment

To investigate whether prior treatment had any effect on the outcome variables, we compared the untreated and treated subjects who underwent salt deprivation in the SW and SV groups with a nonparametric test. Aldosterone levels were not statistically different between the treated and untreated groups, whereas the difference in PRA levels were of borderline significance (P = 0.098 and 0.066 for SW1 vs. SW2 and SV1 vs. SV2, respectively). ARR did not differ significantly between untreated and treated in both SW and SV groups. ARR after sodium deprivation in salt wasters who require treatment throughout life was different from the normal subjects who were never treated.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Phenotypically, the disease severity of 21 OHD CAH can be classified into the most severe SW form, the moderately severe SV form, and the least severe NC form (9). Although the aldosterone synthesis defect is clinically apparent only in the SW form, we have shown that some degree of aldosterone deficiency is present in all the forms of 21 OHD CAH. Our data indicate that ratio of aldosterone to plasma renin activity is a better indicator of disease severity than either measure of aldosterone or PRA alone. As demonstrated, the aldosterone level itself is not a discriminatory measure between groups because it may be inappropriately normal in the presence of sodium depletion at the expense of a markedly increased PRA. In fact, previous studies have shown that aldosterone levels in patients with SW CAH can either be low, normal, or elevated, depending on sodium status and level of PRA (2, 6, 8, 16, 17, 18, 19, 20, 21, 22, 23, 24). Aldosterone levels may also be affected by renal tubular function and treatment.

In contrast to measurements of aldosterone, PRA has historically served as the method of choice in determining sodium homeostasis (19, 25, 26, 27) and has been accepted as a sensitive index for salt-wasting tendency (28, 29). A rise in PRA, proportional to the degree of sodium loss represents an indirect reflection of aldosterone deficiency; however, PRA is not a stable measure and can fluctuate depending on salt intake and other factors. ARR more accurately depicts the degree of aldosterone synthesis capability as it relates to PRA stimulation, regardless of age or sodium status. This ratio was chosen to demonstrate the degree of aldosterone deficiency driven by the renin activity level.

Previous studies involving relatively small numbers of patients have also suggested a spectrum of salt loss in the various forms of 21 OHD CAH (19, 27). Although adrenal zona glomerulosa function in sodium homeostasis has been the subject of interest since the 1960s, to our knowledge, there have been no systematic studies of ARR status in genetically classified 21 OHD CAH. One study used the ratio of PRA to urinary aldosterone in a scoring system for phenotypic severity and showed fair correlation with genotypic severity (7). In contrast, we chose to study the inverse (ARR) because aldosterone is often unmeasurable in SW patients. Furthermore, ARR has been used reliably in the hypertensive population to screen for hyperaldosteronism and has been shown to be stable regardless of position, dietary salt intake, or time of day (30, 31).

Our study demonstrated an evident decrease in ARR with increasing phenotypic severity in patients with 21 OHD CAH. However, the data on ARR are sufficiently overlapping that we cannot assign a salt-wasting status, nor can we distinguish SV from NC, based on ARR in an individual patient. This is especially true in the newborn infant. The median ARR in the HET group was slightly lower than the NL group, but it was not a statistically significant difference. Our finding is in line with a previous study showing that obligate heterozygote parents of SW patients do not express a partial defect in aldosterone biosynthesis as demonstrated in PRA/urinary aldosterone, although they do demonstrate changes in cortisol biosynthesis in the zona fasciculata (8).

As expected, the age at diagnosis differed among the forms of 21 OHD CAH. Severe enzyme deficiency leads to clinical symptoms earlier in life; therefore, SW patients present at a younger age than SV patients, who are in turn younger at the outset than NC patients. Due to genital ambiguity, female SV are diagnosed at an earlier age than SV males. Although it is known that aldosterone and PRA both vary with age (32, 33, 34), our study showed a clear positive relationship only between age and PRA. There was a slight increase in ARR with age seen only in the NL group. This lends support to our conclusion that the ability of ARR to discriminate between the groups is not explained by age differences among the groups.

Although dexamethasone treatment during salt deprivation studies may have altered the levels of aldosterone and PRA independently (6), the only way to include older SW to investigate how age differences affected our results is to add these treated subjects. We did observe some differences in PRA between treated and untreated subjects, but this effect is expected considering the strong negative relationship between PRA and age, and the large age difference between the treated and untreated subjects. The fact that we found no difference in ARR between treated and untreated subjects allowed us to include older SW and SV subjects in the analysis to demonstrate that age does not affect ARR trends.

In conclusion, our study revealed that all forms of 21 OHD CAH have varied degrees of the adrenal capacity to produce aldosterone in response to renin stimulation. In view of the fact that a salt-wasting crisis in nonclassical patients is extremely rare, it is surprising to find the ARR in NC patients to be lower than normal. This suggests that, compared with normal individuals, even patients with the mild form of 21 OHD CAH require a greater degree of renin activity to stimulate an adequate level of aldosterone to maintain normal sodium conservation. Because salt-wasting crises have not been observed in our experience in nonclassical patients, we do not believe that administration of mineralocorticoids is indicated. Sodium deprivation studies, which are labor intensive and require hospitalization, provide information about the salt-wasting status of 21 OHD CAH patients on an individual basis. ARR, on the other hand, provides a simple index to evaluate disease severity among clinically classified groups of 21 OHD CAH, but not among individual patients. Our data indicate that ratio of aldosterone to PRA is a better indicator of disease severity than either measure of aldosterone or PRA alone.


   Footnotes
 
This work was supported by Grants HD00072 and RR19484 and the General Clinical Research Center Grant RR00071.

Disclosure Summary: The authors have nothing to disclose.

First Published Online October 10, 2006

Abbreviations: ARR, Ratio of serum aldosterone to plasma renin activity; CAH, congenital adrenal hyperplasia; HET, heterozygotes; NC, nonclassical; NL, normal; 21 OHD, 21-hydroxylase deficiency; 17OHP, 17-hydroxyprogesterone; PRA, plasma renin activity; SV, simple virilizing; SW, salt wasting.

Received May 5, 2006.

Accepted October 3, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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