Once the diagnosis of 21-OH deficiency CAH has been established, what are the current therapeutic approaches at different times of life and, by extension, what are the unmet therapeutic needs?
So I'm thinking about uh how to treat uh cah owing to 21 hydroxy deficiency. Uh anyway, is it's uh useful to uh consider what you do in the neonatal period in the first uh two or three years of life during childhood, during adolescence and during adulthood. So, the clinician first encounters, uh the uh child affected with cah under two related um but not identical circumstances. Uh The first is uh that you get paged to the nursery because there is a uh child born with ambiguous genitalia. And assuming that uh that child was born and affect his pediatric endocrinologist is uh is, is we we're getting called in uh pretty quickly or the child is gonna get transferred to us. Uh uh Also pretty quickly. The uh other circumstance is that the, the baby trips the newborn screen and it felt to have a reasonable uh likelihood to effect have uh cah uh that kid uh may in some cases get a confirmatory screen um uh at the pediatrician's uh office. But if there is any clinical concern, uh the child would be uh referred to uh the nearest emergency room and those clinical concerns would include uh problems with gaining weight, um and ill appearance, uh low low blood glucose uh and elec electrode abnormalities including a low sodium and potassium. And any of those things are likely to in the context of an a an abnormal newborn screen are are likely to lead to referral into the uh uh emergency room. So, uh what we do then is uh to do con con con confirm what we do then is to do confirmatory testing as, as seems appropriate. We may measure steroid levels. In some cases, if the child appears medically stable is we will do provocative testing. A coin from stimulation test which is designed to jazz up the adrenal glands to make asthma uh cortisol as they possibly can. And we can see how much cortisol goes up and uh it comes back a couple of days later, but we can see what happens to levels of precursors and particularly 17 hydroxy progesterone, which is the substrate for the 21 hydroxylase enzyme. If a normal 17 hydroxy progesterone is up to um 150 or 200 nanograms per deciliter. Uh is somebody with a nonclassic form of ch Michael up to 1500. Um somebody with um the simple paraly form of ch michael up to 10 to 20,000, someone with more severe disease might go up as high as 100,000. So, so really almost 1000 times uh normal uh levels. And so that test in and of itself could give us a pretty good idea. Uh What, what we're dealing with, uh in general, if we have a reasonable uh index of suspicion that the child has classic cah is we will uh begin treating uh the patient while we are waiting for those labs to return, uh admit them and, and, and watch them for a couple of days and, and, and give them a moderate dose of hydrocortisone. Uh It generally starts uh uh some food or cortisone to uh remedy uh the possible alster deficiency. And also um uh if, if there are ec uh electrode abnormalities, uh also give the kids some sodium chloride uh supplements just as uh just as some additional uh salt drops that, that one can add to uh to the baby's uh formula. Uh newborns uh as, as a, as a general rule, are relatively insensitive to uh to aldosterone. And therefore, hilu a cortisone and the doses that you have to use of that early on are uh quite high. They're higher. In fact, for, to kill a baby, they're higher than, than you would need to use for uh for and uh for an adult due to immaturity of the kidneys, uh treat the baby with uh with high doses of uh of, of both uh hydrocortisone and, and fluid or, and, and use salt supplementation because you're trying to, to get things normalized uh as rapidly as possible to stabilize the patient as rapidly as possible. Over the short term, you cannot overtreat somebody with hydrocortisone. It's not possible. Ok. Uh II I it is uh hydrocortisone and related drugs like predniSONE and dexamethasone are used in other clinical contexts like uh like leukemia chemotherapy or neurosurgery or, or, or a doses that are hundreds of times what, what, what we, the endocrinologists are, are, are using uh so the cryptos dose that's high enough and, and, and, and, and, and we don't worry about, about overtreatment over, over the short term, the, the uh the most like the most likely effect over the very short term might be slightly elevated blood glucose or uh or blood pressure. But suddenly that, that's, that's not, that's not a big deal. So, um uh you get your test back, uh you uh you determine what the patient has, let's say they have fault wasting disease. Um Even so, as I said, is uh we expect sensitivity to Pluto cortisone to rapidly improve over the first few months of life. Um So we keep a careful eye on the patient and we rapidly uh in general wean off uh the salt supplements, we reduce the dose of Pluto cortisone. We reduce the dose of uh uh of, of uh hydrocortisone and try to uh position the kid for uh for uh as normal as possible. A childhood. Uh We have a few goals here. The first is to keep the patient out of the hospital. Uh The, the risk of being rehospitalized with adrenal insufficiency is highest during the first two years of life. Uh little Children tend to get sick. Uh The, the, the their idea of personal hygiene is, is, is, is not that of, of a grown up. Uh they, they, they, they get all kinds of viruses as the immune system is, is getting uh built up. And so any patient, uh if they get, if they get, let's say significant gastroenteritis may uh develop uh some uh degree of, of adrenal insufficiency and require rehospitalization. And that risk goes down gradually after the first couple of uh years of uh o of life. Uh We need to wean down on uh fluto Cortisone and salt relatively quickly because if we don't is uh as uh the baby becomes more sensitive to uh to uh the salt retaining effects of fluto cortisone. Um they can in fact become quite uh hypertensive and so this requires fairly close monitoring over the first few months of life. Uh then, but then we're uh concerned with making sure that, that the child can, can grow. And that means using enough hydrocortisone but not too much. Uh And this is where um uh cah is a little bit different from other uh forms of adrenal insufficiency. Um in all cases is we're trying to uh compensate for uh the inability to make a cortisol and aldosterone. Well, but in addition with uh cah, is we are trying to uh suppress with the con with cah, we are trying to suppress uh abnormal secretion of uh androgens and androgen precursors by the abnormal uh adrenal glands. It is important to not over normalize uh steroids and that uh uh uh so it's important to not over normalize um 70 hydroxy progesterone uh levels. Uh This is a common mistake that many clinicians make and it's made. Not just for ch in fact, is, is, is it's made uh uh for other forms of uh of uh adrenal insufficiency is um uh clinicians tend to want to minimize the likelihood of uh of a child developing adrenal insufficiency. And so I think there is a tendency amongst many clinicians to uh to overtreat. Um So uh we uh monitor uh adequacy of uh hydrocortisone replacement largely by looking at something hydroxy progesterone uh levels. As I said, that's, that's the precursor for uh for the enzyme. You can look at a um uh androgen uh at a weak androgen made by the, by the adrenal glands, andros Dion. And you can uh monitor the adequacy of food or cortisone treatment by looking at uh renin, which is a partic enzyme secreted by the kidney in response to uh to uh diminished volume that um uh uh generates uh uh anti intens uh uh it generates angiotensin and uh which is converted by a gi tens too and then that stimulates uh aldosterone uh secretions. So you aim to have 17 hydroxy pro levels, maybe at the upper end of the reference range or up to maybe 10 fold elevated. So let's say very roughly uh levels of 100 nanograms per deciliter to 1000 nanograms per deciliter. Those are not hard limits. But that's kind of the uh the range that you're looking for. You are not looking to have a kid at the lower end of the reference range for 17 hydroxy progesterone that is overtreating. Similarly, for Renan is you want that to be at the upper end of the, of the reference range or uh or a little bit elevated, you have to keep track of the uh age specific uh reference ranges for uh that particular uh test because little kids have high levels of ring compared with uh with adults. But uh analogous to 7017 hydroxy project is you want for ring it to be high normal or uh relatively low abnormal. You do not want uh low or suppressed levels of rent. And that means that you are overtreating with uh with uh fluid or cortisone. So our goal during childhood is to um make sure that you're not overtreating uh with, with, with steroid, you want the child to be growing along uh along uh appropriate uh high percentiles. Uh But obviously, as you also do want to uh to, to minimize the uh to minimal, minimize the frequency of uh of hospitalization. And uh you also want to minimize the effects of uh excess androgen levels. Now, in K, you are unlikely to see um uh uh effects such as uh hers or acne. It takes a pretty serious, pretty seriously poor control to see those. Ok. Uh Sometimes you'll uh notice an adolescent body odor but by and large, it's not like you're dealing with a lot of pubic hair and little kids. But uh even without that, you can end up with high enough um uh androgen levels um that they get a rum to estrogen in the bone and they can cause acceleration of the skeleton uh which can and lead to a shortened uh window in, in which the child can grow and can ultimately lead to short stature. And, and so, uh I do recommend that one regularly uh monitor bacia every uh year or so and make sure that that is not uh advancing on, on July.
