Interview: After an Abnormal Heel Prick, Rapid Diagnosis Is Very Important

Paul van Trotsenburg (50) is a pediatrician-endocrinologist at the AMC (Academic Medical Centre) in Amsterdam. He specializes in thyroid gland disorders and abnormalities in thyroid hormone regulation.

How long have you worked as a pediatric endocrinologist?

In started in 1992 as a pediatric resident, and four years later, I started on the sub-specialty of pediatric endocrinology. At that time, the program took 2.5 years. So, by 1999, I was a pediatric endocrinologist.

Which thyroid problems do you encounter most often?

It is useful to make a distinction between congenital and acquired disorders of thyroid hormone regulation. With congenital disorders, you usually have a thyroid hormone deficiency that is diagnosed shortly after birth. This deficiency occurs because the thyroid gland was not properly formed or does not work as it should. In a small percentage of cases, the patient has a deficiency of thyroid hormone caused by a pituitary gland that does not function properly. The pituitary is the regulating gland of the body. In these cases, the pituitary does not direct the thyroid gland to produce thyroid hormone as it should.
With acquired disorders, it is often a matter of a thyroid gland that works too slowly, or hypothyroidism. This is the case with Hashimoto's thyroiditis, where the immune system attacks the thyroid gland. There are also children with a thyroid gland that works too quickly, hyperthyroidism, because the immune system speeds up the thyroid gland. This is the case with Graves' disease. Then, there are other children with exceptional problems, such as a thyroid gland that is too large or nodules in the thyroid gland. Sometimes, the unfortunate diagnosis of thyroid cancer is the cause of these problems. What we also encounter fairly often is a newborn whose mother has an overactive thyroid gland. These newborns almost always have temporary thyroid gland disruptions, because the mother's thyroid problems affect the child.

How many children have thyroid problems?

That is a difficult question. I have figures for how many children have congenital thyroid problems. Every year, some three hundred children in the Netherlands have an abnormal heel prick result. Some seventy to eighty children have a true congenital thyroid hormone deficiency. This is due to an improperly formed thyroid gland or to a thyroid gland that does work as it should. Acquired hyperthyroidism occurs in about one hundred children per year, especially teenagers. A small percentage of these children are younger than that. For a thyroid gland that really does not function properly, like with Hashimoto's thyroiditis, it is much less clear. I estimate that this disease occurs two to three times more frequently than Graves' disease. But that is a rough estimate. How many children in the Netherlands have an enlarged thyroid gland or a thyroid gland with nodules every year, I don't dare to say. In the Netherlands, approximately eight to ten children are diagnosed with thyroid cancer per year.

When do children come to see you?

The diagnosis is usually made by the general practitioner or the pediatrician. The children go to the general practitioner with specific complaints or if they find a lump in the throat. This could be a swollen thyroid gland or a visible or palpable lump in the throat. If the laboratory results confirm the diagnosis or make it probable, the child is referred to a pediatrician or, occasionally, directly to a pediatric endocrinologist. Children with hypothyroidism, Hashimoto's thyroiditis, often remain with the general pediatrician. If there is doubt about the correct diagnosis or if the treatment is not working, they are then referred to us.
We see children with hyperthyroidism somewhat earlier, since the accuracy of their diagnoses is more often called into question. In those cases, we are called by a pediatrician who wants to consult with us about the treatment.
We see children with an enlarged thyroid gland or with nodules very soon after this is discovered. We are usually able to quickly reveal whether the cause of this is serious or something benign.

Are general practitioners quick to think of diagnoses like Hashimoto's thyroiditis or Graves' disease?

They are when it comes to Hashimoto's thyroiditis, due to the clear-cut symptoms associated with hypothyroidism: fatigue, generally not feeling well, feeling cold, dry skin and sudden weight gain. This particularly applies in the case of tiredness, because the general practitioner's protocols for fatigue state that they must consider thyroid function and that they must measure the TSH in the blood. Hyperthyroidism is somewhat more difficult. Everyone knows that you have to consider a hyperactive thyroid gland with symptoms like heart palpitations, feeling warm, increased perspiration, weight loss and feeling agitated. But this set of symptoms occurs less frequently. However, in and of itself, the diagnosis is not difficult.

What happens in the case of a lump or an enlarged thyroid gland?

Usually, the general practitioner refers the child to a pediatrician in the area. If there is actually an abnormality, most pediatricians will very quickly contact us or our colleague pediatric endocrinologists at the VU University Medical Center. We then quickly make an appointment for an ultrasound and needle biopsy of the thyroid gland. Thyroid cancer is a very serious diagnosis with serious consequences. The treatment is rather radical. And the psychological burden of the thought of possibly having cancer means that we want to quickly give the patient clarity about the situation.

What happens after an abnormal heel prick?

In those cases, the neonatal screening organization contacts the general practitioner. The general practitioner will then immediately contact the nearest pediatrician. Then, the goal is for the pediatrician and/or pediatric endocrinologist to see the child as soon as possible. Preferably the same day or that evening, if necessary. The aim is to talk with the parents, take a blood sample and to start diagnostics. To see if the level of thyroid hormone production is actually too low. The most important results are usually received within one to two hours. Then, you decide whether you need to start thyroid hormone treatment. If supplemental diagnostics are necessary, they are usually arranged within a few days.

What else do you look for if thyroid gland problems are diagnosed?

After the first blood tests, it is usually clear whether the problem is a thyroid gland disorder or whether the pituitary is the probable culprit. You can see this by looking at the free thyroxine (FT4) as well as the thyroid-stimulating hormone (TSH) concentrations in the blood. But sometimes this can be more difficult with newborns. Then it becomes a puzzle to which we need to dedicate some extra time, several days, sometimes weeks, to be sure. Especially in cases when we suspect that the pituitary gland is not functioning properly and controlling the thyroid gland, we will then also look at the other functions of that gland.

Why is a rapid diagnosis so important?

If there is a severe thyroid hormone deficiency or if other pituitary hormones are also not being synthesized properly, then that must be treated immediately, as quickly as possible. With pituitary abnormalities, quite a few newborns who have a TSH deficiency also have a deficiency of ACTH, the hormone that controls the adrenal glands, or growth hormone. If you do not produce enough ACTH, then you will not produce enough cortisol, the stress hormone that is synthesized by the adrenal glands, and that can lead to life-threatening situations. You must treat this quickly. So, if a newborn comes to the pediatrician via the general practitioner after an abnormal heel prick, and the pediatrician suspects that the thyroid gland is not being properly controlled by the pituitary gland, then the child must be immediately referred to the pediatric endocrinologist.

What do you do in the case of minor abnormalities of the thyroid gland?

That is the most complicated group: newborns and young children with slightly abnormal thyroid function. This relates to cases where the thyroid gland works, but just not optimally. With low, but not too low, thyroid hormone levels, and with slightly increased TSH. In the Netherlands, we have decided to treat these children anyway up until the age of three years. After that, we investigate the system again without treatment. In the first two to three years of life, the development of the brain is dependent on thyroid hormone, and we think that a thyroid hormone deficiency can have a negative effect on brain development. On the international level, this is still a matter of discussion. Not everyone is in favor of treatment.

Has any research been done in this area?

As far as I know, none has been done so far. A large-scale study should actually be carried out in which babies with these types of mild values are studied. Preferably a European study. In a randomized clinical trial, for example, one half of a group of newborns with slightly abnormal thyroid function should be given a placebo, and the other half a thyroid hormone treatment until the age of two or three. Then at around the age of six, neurocognitive development, growth and things like that should be examined. Then we would have an answer. We did this with young children with Down's syndrome. Because, as a group, babies with Down's syndrome have somewhat elevated TSH levels in combination with normal thyroid hormone concentrations. We saw that the children who had received thyroid hormone treatment since their first weeks of life had shown better development and had grown better by the age of two years.

Did you publish this study?

Recently, in December 2014, we published the results of a follow-up study of this group of children. At the age of almost eleven years, there was no longer a (clear) difference in development between the children with Down's syndrome who were treated with thyroid hormone up until the age of two and the children who were treated with a placebo. The children who were treated with thyroid hormone were somewhat taller. The difference was most significant, 3 cm, in the children who had the highest TSH concentrations at birth. Of course, three centimeters is not a huge difference, but in a child with Down's syndrome, who as an adult is on average 20 cm shorter than an adult without Down's, it is not insignificant! Soon, we hope to publish other results of the study we performed with this group of children.

How do you treat Graves' disease?

We start with a medicine that inhibits the production of thyroid hormone, so that the thyroid hormone levels in the blood can drop to normal levels within a few weeks. Generally speaking, we administer enough of this medication so that the thyroid stops producing virtually all thyroid hormone. This is referred to as blocking the thyroid gland. Then, we perform a blood test after two to three weeks and again after four to five weeks to verify whether the thyroid hormone levels in the blood have decreased. If they have, then thyroid hormone treatment is started. Otherwise, the thyroid levels will continue to drop, and they will become too low. After that, you must check once every four weeks until you reach a new balance. Once that has happened, you only need to do blood tests once every three to four months, but you must have a stable balance first.

Do the children who have Graves' disease have problems with their eyes?

Eye abnormalities in children and teenagers occur less frequently than they do in adults. But they do occur. A feeling like there is sand in the eyes, redness or a slight bulging. That is very bothersome for those who have it. I have not yet seen it where it was so bad that it had to be treated. The AMC has a special outpatient clinic for people with eye problems from Graves' disease.

How long is the treatment for Graves' disease?

As a rule, this medicinal treatment lasts two years. Then we stop it and hope that the treatment has contributed to the cessation of the immune reaction against the thyroid gland and that this results in the thyroid working normally again. However, in seventy to eighty percent of the children, the hyperthyroidism comes back very quickly after the treatment is stopped. In adults, this happens in fifty percent of the cases. Unfortunately, the problem remains. But in one in four cases, it disappears completely. Three of the four patients get Graves' disease again. Then we usually start the medication again. With longer treatments, the chance that the problem disappears definitively is somewhat greater. However, in fifty to sixty percent of the cases it never goes away. We then speak to the child and the parents about definitive treatment. Unfortunately, we cannot fix the immune reaction. We can only block the thyroid gland by radiating it from the inside with radioactive iodine. We can also surgically remove the thyroid gland. In most cases, radioactive iodine is preferred by patients and their parents. I explain the advantages and disadvantages of each treatment very clearly. We make the decision together. Luckily, this does not have to happen immediately. You can continue the medicinal treatment for a while. It is important that the child is also involved in the decision. However, one child will be mature enough for this earlier than another.

How do you treat Hashimoto's thyroiditis?

The treatment for Hashimoto's thyroiditis is simpler. With this disorder, the thyroid gland does not function at all or it functions very poorly. In these cases, you are given thyroid hormone. Very often, this works very well, but unfortunately there is a small percentage of children whose symptoms do not abate. Such symptoms include fatigue or less than optimal functioning. I am reasonably convinced that this has something to do with the immune reaction, the cause of the destruction of the thyroid gland. Slowly but surely more research into this is being done. I think that we will hear a lot more about it in the coming years.

What kind of scientific research do you do?

At the AMC, we perform research into children with thyroid-regulation problems due to a structural or functional disorder of the pituitary gland. We try to discover which genes, and especially which errors in these genes, are responsible for these disorders. In the Netherlands, we find children with this problem by means of the heel prick mentioned above. And we have been doing this for a number of years. However, we do not know enough about how these children are doing. Do they do just as well as their brothers and sisters, for example, if they are treated properly? We have a reasonably good idea about this in children with thyroid hormone deficiency due to a problem in the thyroid gland but not in children with a pituitary problem. There are now two doctoral students working on this study.

What fascinates you about thyroid hormone?

During my studies, Professor Drexhage, who then worked at the VU University Medical Center, gave an impassioned lecture on Graves' disease and the autoantibodies that made the thyroid gland work harder. I thought this was fascinating. After that lecture, I went to him to ask if he had an interesting bit of research for me to do. Almost thirty years later, I am still right in the middle of it. And, given the choice, I would do the same all over again!