Fall 2007 Newsletter

CARES Foundation, Inc.

Hypertension in Children with 21-Hydroxylase Deficiency

Todd D. Nebesio, M.D.

Department of Pediatrics, Section of Pediatric Endocrinology/ Diabetology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN

Hypertension is the medical term for elevated blood pressure. Until recently, few reports have attempted to characterize and describe hypertension in children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). Unlike other forms of CAH, such as 11-hydroxylase or 17-hydroxylase deficiencies, hypertension is not typically mentioned in discussions about 21OHD. However, there are several aspects of 21OHD that may impact blood pressure.

Children with the salt-wasting form of 21OHD are treated with salt in infancy as well as both a mineralocorticoid and glucocorticoid throughout life. Depending on the dose, either of these medicines may potentially cause hypertension (1). Excessive amounts of mineralocorticoid, such as fludro- cortisone, may result in hypertension due to salt and fluid retention. If this occurs, a reduction in the dose of mineralocorticoid will often normalize the blood pressure. Excessive amounts of glucocorticoids, such as hydro- cortisone, prednisone, or dexa--methasone, may also result in hypertension along with many other unwanted side effects, such as growth suppression, bone disease, and weight gain. However, undertreatment with glucocorticoids may result in excessive male hormone production, which leads to bone age advancement and short stature as an adult. The goal in CAH is to give the minimum dose of glucocorticoid needed to adequately suppress the adrenal glands while avoiding the negative consequences of overtreatment.

In all children as well as adults, the percentage of those who are overweight in the United States has increased significantly over the last several years (2). If a child is overweight, there is a high likelihood that they will also be overweight as an adult. Similarly, a higher blood pressure in childhood is predictive of hypertension in early adulthood (3). There is a significant association between body mass index (BMI) and blood pressure in all childhood age groups (4). In other words, with an increasing BMI, there is a significant increase in blood pressure. Therefore, healthy lifestyle choices and regular exercise are important for all children in order to avoid complications associated with obesity, such as hypertension.

BMI is a calculated number which allows one to determine if a person is or at-risk for being overweight or obese. BMI is affected by height, weight, and body composition. Currently, those children with a BMI between the 85th to 95th percentile for age are classified as “at-risk for overweight” and those with a BMI > 95th percentile for age are classified as “overweight”. New pediatric obesity guidelines presented at the 2007 Endocrine Society in Toronto will soon be published. Among the guideline’s new recommendations include changing the old terminology of “at-risk for overweight” to “overweight” and the previous term of “overweight” to “obese” (5).

It is well known that patients with 21OHD are at risk for increased weight gain and the development of obesity. Even in children with 21OHD who are medically well controlled, their BMI tends to increase throughout childhood, which is predominately a result of weight gain due to increased fat mass (6). In one study of 89 children and adolescents with CAH, it was noted that children and adolescents with 21OHD have a higher risk of obesity. Interestingly, glucocorticoid dose, chronological age, advanced bone age maturation, and parental obesity all positively correlated with an elevated BMI. However, the type or form of glucocorticoid as well as the dose of fludrocortisone were not associated with obesity (7). Researchers have attempted to implement alternative medical regimens in the treatment of CAH to decrease the daily gluco-corticoid dose so as to avoid complications of overtreatment, such as obesity. Such regimens include bilateral adrenalectomy (8), the use of anti- androgens and aromatase inhibitors (9), and most recently the use of calcium channel blockers (10). Many of these strategies are experimental and still being studied.    

There have been a few prospective studies investigating blood pressure profiles in children and adolescents with 21OHD. In the first study which looked at 38 children from the United Kingdom, the majority had elevated blood pressures as well as loss of the normal, physiologic overnight drop in blood pressure. Blood pressure measurements were not related to laboratory markers of CAH control, such as 17-OHP, androstenedione, or renin. However, hypertension was associated with an elevated BMI, particularly in females (11). In a second study looking at 11 children from Australia, prolonged glucocorticoid treatment was not associated with hypertension (12). In a third study looking at 55 children from Germany, elevated blood pressure was correlated with the degree of overweight and obesity (13). As in the previous studies, there was no correlation between blood pressure and renin levels, which suggests that an excessive dose of mineralocorticoid was not the reason for hypertension.    

Recently, we sought to categorize the prevalence of hypertension in our CAH patient population at Riley Hospital for Children in Indianapolis, Indiana (14). We defined hypertension based on reference values for age and gender, and each child had to be on an anti-hypertensive medication and under the care of a blood pressure specialist. Over the last 20 years, we identified 91 children (54% female) with CAH due to 21OHD. Overall, 6.6% of the children were found to have hypertension. Of these 6 children, one had hypertension as a result of acute renal failure after presenting in an adrenal crisis and shock. Therefore, 5 children or 5.5% had essential hypertension, which means that no identifiable cause for the elevated blood pressure was identified. Three children had salt-wasting CAH, and none had a suppressed renin level at the time of diagnosis of hypertension. Family history for blood pressure problems was negative in all children with 21OHD and hypertension.

We hypothesized that an elevated BMI would be predictive of those who had hypertension. Interestingly, this was not the case. Only one child with essential hypertension had an elevated BMI (Body Mass Index) at the 95th percentile for age. In those children with 21OHD and hypertension, 40% were at risk for overweight and 20% were overweight. In those children with 21OHD and no hypertension, 16% were at risk for overweight and 48% were overweight. Although there were more children with a BMI > 95th percentile for age who were not hypertensive, the difference between the two groups was not statistically significant (14).

In the general population of healthy children, the overall prevalence of hypertension is around 1% (15-17). A more recent study examined the prevalence of hypertension in a pediatric population where 20% of children were overweight. In this heavier population, the prevalence of hypertension was 4.5% (18). In our study of infants, children, and adolescents with 21OHD, we found an even higher prevalence of hypertension (14). One needs to consider that it is often difficult to measure blood pressure accurately in children in an outpatient clinic environment. However, in children with CAH, other studies have shown that blood pressures obtained in outpatient subspecialty clinics are an accurate and reliable method to detect tendencies of blood pressure elevations (19). It is not clear why our patients had an increased prevalence of hypertension. Animal research suggests that ACTH or abnormalities in glucocorticoid metabolism may contribute to some forms of essential hypertension (20), but additional studies in children with 21OHD are needed.

In conclusion, children with 21OHD are at an increased risk for the development of hypertension. Excessive amounts of mineralocorticoid and glucocorticoids should be ruled out as the cause of elevated blood pressure. Obesity is also prevalent in children and adolescents with 21OHD. Therefore, healthy lifestyle choices and daily exercise are important to decrease the development of complications associated with increased weight gain, including hypertension. However, other undefined factors besides obesity may be at fault for the increased prevalence of hypertension in children and adolescents with 21OHD. This is definitely an area in which more investigation is needed!   

It is well known that patients with 21OHD are at risk for increased weight gain and the development of obesity.

References omitted due to space constraints. Available upon request.