Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia, or CAH, is a relatively "new" disease considering the fact that most of what is known about it today came from research that was done at Johns Hopkins Medical School in Baltimore in the middle of the 20^th century. It was Lawson Wilkins, founder of pediatric endocrinology, who figured out that it was the adrenal gland's impaired capacity for making cortisol that led to hyperplasia and overproduction of adrenal androgens (Daaboul, 2000). CAH is becoming more common as more advanced technology is allowing the medical community to diagnose more cases.

So what exactly causes CAH? Well, as Glatt, Garzon, and Popovic (2005) make clear, CAH is a rather complex disease and there is more than one type of CAH. Let's start at the beginning. All the problems begin with the adrenal gland which is a gland that sits comfortably on top of the kidney. While an adrenal gland is small, it's a rather complex structure. It consists of two parts: the outer cortex and the inner medulla. There are three very important pathways in the adrenal gland: the mineralocorticoid pathway, the Glucocorticoid pathway, and the androgen pathway. Each pathway produces a very important steroid hormone that is needed by the body.

The mineralocorticoid pathway secretes aldosterone. Aldosterone is essential for life because it is responsible for the release of potassium and sodium retention through the sodium potassium pump. Progesterone is converted to aldosterone by an enzyme known as 21- hydroxylase. If this enzyme is nonexistent (or there is a deficiency of it) then progesterone is not converted to aldosterone and it builds up in the adrenal gland. All of this excess progesterone ends up going into the androgen pathway. Essentially, the mineralocorticoid pathway is blocked off. This leads to a deficiency or even complete lack of aldosterone. At this point, the body is stimulated by the very small levels of this very important steroid and it keeps on increasing the process of aldosterone production. This has a negative impact as there is an increased production of androgens. The adrenal gland tries to make up for the increased demand for aldosterone by increasing cell growth (Glatt et al., 2005).

The second pathway of importance is the glucocorticoid pathway. A very important adrenal steroid manufactured in this pathway is called cortisol. Cortisol maintains stable blood pressure, wound healing, blood glucose levels, and what is known as the fight-or-flight mechanism. The synthesis of cortisol begins when cholesterol is converted to pregnenolone. Like a car that goes down a road, the pathway goes on as we then have the production of 17- hydroxyprogesterone. After this point, the enzyme 21- hydroxylase is needed for the conversion of 17- hydroxyprogesterone into 11- deoxycortisol and then to cortisol. Things end up turning sour if the 21- hydroxylase enzyme is missing. If there is a deficiency or absence of this enzyme, then there will not be normal amounts of cortisol. The adrenal gland will then be stimulated to increase the synthesis of cortisol and this will lead to a blocked pathway. It is this blocked pathway that will lead to the production of excessive androgens (Glatt et al., 2005).

Finally, we arrive at the androgen pathway. It is in the androgen pathway where testosterone is synthesized. If normal levels of 21-hydroxylase enzyme aren't present, then the levels of testosterone will end up being higher than normal (Glatt et al., 2005).

From what we have learned so far, the 21- hydroxylase enzyme is very important in the conversion of cholesterol to steroid hormones, one of the most important of which is cortisol. It's interesting to note that approximately ninety percent of patients do not have the 21-hydroxylase enzyme. Could this be related to genetics? That is definitely a high possibility. According to Deaton, Glorioso, and McLean (1999), CAH is an autosomal recessive disease. Each parent is an unaffected heterozygote. In other words, they carry the gene for the disease but they don't exhibit the symptoms. If both parents carry the gene, each child will have a twenty five percent chance of getting CAH.

There are three types of CAH present: classical salt-losing CAH, non salt-losing CAH, and late onset CAH. The most dangerous of the three is the Classical salt-losing CAH. This type of CAH accounts for about seventy five percent of all CAH cases. In this case, the sodium retaining hormone known as aldosterone is lacking. Because of the loss of salt from the body, one with this type of CAH will experience dehydration, low blood pressure, and vomiting if they are not taking the required medications. These are symptoms of what has come to be known as 'adrenal crisis.' Another symptom of Classical salt losing CAH is that females may be born with ambiguous genitalia because of the fact that the fetus is subjected to high levels of androgens and testosterone during the period of external sexual differentiation. Also, excessive androgen levels can cause both sexes to grow rapidly. This rapid growth results in advanced bone age which can cause kids to be short when they become adults. Also, people with classical salt losing CAH are prone to more illnesses because there is not enough cortisol being produced to mount a stress response (Glatt et al., 2005).

The second type of CAH is non salt-losing CAH (classic simple virilizing CAH). This case is less severe than the previous mentioned because enough aldosterone is released so that there is not enough salt loss to cause adrenal crisis. There is still, however, a deficiency in cortisol. Therefore, there is still an excessive amount of androgens. Females are usually diagnosed with at birth when signs of ambiguous genitalia are present. Secondary sexual characteristics such as pubic and axilliary (armpit) hair, acne, and body odor appear later on (Glatt et al., 2005).

The third type of CAH is known as late onset CAH (nonclassical CAH). This is the mildest form of CAH and overproduction of androgens result in unwanted hair growth and irregular periods in women. Nonclassical CAH can go unrecognized in men as the only noticeable symptom may be short stature (Glatt et al., 2005).

So exactly how common is CAH? Well, actually, it's not all that common. CAH occurs in about 1 in 14000 or 15000 births. Classical CAH is believed to be most frequent in Madagascar and parts of Alaska while the milder forms are thought to be more common in Ashkenozi Jews and in Hispanic, Slavic, and Italian populations. There is obviously a genetic component to this (Deaton et al., 1999).

It has become easier than ever to diagnose CAH. The physical characteristics we have discussed are just a few things that can be used to diagnose CAH. According to the work of Glatt et al. (2005), the procedure which has been used the most in diagnosing CAH is the ACTH (adrenocorticotroin hormone) stimulation test. After ACTH is injected into the individual, "serum levels of 17-hydroxyprogesterone are measured at time intervals" (p. 109). If the person has CAH, the administration of ACTH will cause a rather significant increase in the levels of 17-hydroxyprogesterone. Excess amounts of 17-hydroxyprogesterone indicate that not enough cortisol is being produced. There is also newborn screening which involves a heelstick on filter paper. By doing this, the levels of 17-hydroxyprogesterone are measured. If there is an excess amount of this then this may point to a deficiency of the 21- hydroxylase enzyme. Unfortunately, this method of diagnosis is not the best way to go because of the fact that it turns out a rather high number of false-positives and false negatives. Because of this, it's important that all babies suspected of having CAH get laboratory work done.

As is noted in the work of Glatt et al. (2005), it is important that treatment in the form of glucocorticoid replacement therapy be done as soon as possible. This therapy will help reduce the amount of androgens being released into the body and it will help the body mount a stress response. Hydrocortisone is typically given to children with CAH and is given before they reach their final height. After the child has stopped growing, a switch to dexamethosone or prednisone occurs. The goal of this glucocorticoid therapy is to "replace physiologic glucocorticoid production" (p. 110). The amount of glucocorticoid given is "based on interval growth, body surface area, bone age, and hormone levels" (p. 110). It's important to note that more glucocorticoid must be given when an individual becomes sick or gets injured. Another important medication that is given is Fludrocortisone and it's essential for people with salt wasting CAH. Fludrocortisone helps to replace salt and it is especially needed by infants and toddlers.

Daaboul, J. (2000, May 19). Does the study of history affect clinical practice? Intersex as a case study: The physician's view. Intersex Society of North America. Retrieved October 4, 2006, from http://www.isna.org/articles/daaboul_history

Deaton, M., Glorioso, J., & McLean, D. (1999). Congenital Adrenal Hyperplasia: Not really a zebra.American Family Physician. 59 (5). 1190-6, 1172. Retrieved October 4, 2006, from http://www.aafp.org/afp/990301ap/1190.html

Glatt, K., Garzon, D., & Popovic, J. (2005). Congenital Adrenal Hyperplasia due to 21-hydroxylase
Deficiency. Journal for Specialists in Pediatric Nursing, 10 (3), 104-114. Retrieved Wednesday
October 4, 2006, from the Academic Search Premier Database.