What should people in the U.S. do to prevent/minimize risks for the development of thyroid cancer ?

Last week, the Pediatric Endocrine Society (formerly named in honor of Lawson Wilkins) published a letter summarizing the risk of exposure to radioiodine from Japan.  The letter was written by Andrew Bauer, a pediatric endocrinologist at Walter Reed Army Medical Center in Washington, D.C.    Dr. Bauer reviewed the situation and offered advice regarding the use of potassium iodine (KI) to high risk populations in the U.S. (i.e., young children and pregnant women).  Oral KI is highly effective in preventing radioiodine from being taken up by the thyroid, thereby effectively eliminating the risk of developing thyroid cancer from the exposure.  Dr. Bauer made clear in his letter, that at present, there is no reason to consider KI prophylaxis anywhere in the U.S.  I think it would be worthwhile for both pediatric endocrinologists and primary care doctors to read Dr. Bauer’s letter, but I haven’t yet figured out how to provide a link to the letter, unless you are a member of the Pediatric Endocrine Society, but I will try to do so.  Meanwhile, a number of other professional societies have published statements on-line (e.g., Radiation Risks to Health: a joint statement from the American Association of Clinical Endocrinologists, the American Thyroid Association, The Endocrine Society, and the Society of Nuclear Medicine, March 18, 2011).  So far all the experts are saying we should stay cool and avoid the temptation to stock up on KI.

Regulation of thyroid hormone levels

The thyroid gland synthesizes mostly tetraiodothyronine or T4 which is converted peripherally (mostly in the liver) to the “real” thyroid hormone, triiodothyronine, or T3 (also synthesized in the thyroid gland but most T3 is derived from T4).  Both T4 and T3 are part of a classic negative feedback system in which these hormones ( the “free” or non-protein bound hormones) bind to sites in the hypothalamus and in the pituitary gland, regulating their own synthesis by effects on thyrotropin-releasing hormone (TRH) and thyrotropin ( aka,  thyroid-stimulating hormone or TSH.   Normally the negative feedback system results in normal levels of TSH and T4.  If for whatever reason, the T4 level decreases,  release of TRH and then TSH are triggered which results in increased synthesis of T4 until the serum level is back to normal, assuming the thyroid gland is capable of responding appropriately.   Conversely, if the T4 level is elevated, this normally leads to low levels of TRH and TSH, in an effort to decrease the T4 level.  Of course, if the elevated T4 level is from a tumor secreting thyroid hormone or the result of  taking too much thyroid hormone, the feedback system corrections won’t help the situation.  So, what might result in either elevated TSH and FT4/T4 levels or low TSH and low or normal  FT4/T4 levels?  And, what, if anything can we do to fix the problem?

Case History # 1

The patient is a 9 year old female with a history of congenital hypothyroidism, diagnosed in the newborn period.  The initial laboratory studies at one week of age showed markedly elevated serum TSH (350 microunits/mL) and low serum T4 (1.5 micrograms/dL) and FT4 (0.3ng/dL).  The patient has been treated with L-thyroxine since about age 10 days (current dosage is 75 micrograms/d).  She has been generally health.  Height and weight have been consistently at about 50%.  She is a straight A student.   Thyroid laboratory studies over the years have consistently shown slightly elevated TSH levels (e.g., 6-7 microunits/mL) but high normal FT4 levels (e.g., 1.3-1.4 ng/dL).  Efforts to normalize the TSH level by increasing the dosage of L-thyroxine have resulted in high FT4  levels and symptoms and signs consistent with hyperthyroidism.

The differential diagnosis

So, what’s going on here?  In most instances when a patient’s thyroid test results show  elevated TSH and low or normal FT4 levels, it is safe to assume that the patient has either compensated hypothyroidism (if the FT4 is in the normal range) or frank hypothyroidism.  But, it would be unusual to find only a minimally elevated TSH level with a low FT4- that set of results would suggest secondary or tertiary hypothyroidism.  Thus if  a patient’s FT4 level is low on the basis of primary hypothyroidism, I would expect to find a very elevated TSH level (i.e., >25 microunits/mL).  So, things only get strange is when the TSH is slightly elevated yet the FT4 is high normal or even above the upper limit of normal for the laboratory.

What are the possibilities?  First, it could always be a laboratory error (more likely an error in transcribing the report than in the actual assay).  It could also be the result of an incorrect normal reference interval for either the TSH or the FT4 test.  More likely is the possibility of a high set-point for TSH.  This means that for whatever reason, the pituitary gland does not sense that the FT4 level is in the normal range until the TSH level is a bit higher than normal.  This situation is seen in about 10% of children with congenital hypothyroidism and I can’t tell you why it happens but it does.  The solution to the “problem” is to do nothing as long as the TSH level remains only mildly elevated AND the FT4 level remains in the normal range (just to be sure I prefer to keep the FT4 level at the high end of normal).

There are other possibilities to consider before assuming it’s just another one of those high set-point patients.  The laboratory findings could be a sign of a TSH-secreting pituitary tumor.  This disorder is rare during childhood but should be considered in patients with signs and symptoms suggesting hyperthyroidism, elevated thyroid hormone levels and normal or elevated TSH levels.  Most of these patients have  symptoms suggesting central nervous system disease.  Another possibility is thyroid hormone resistance.  This disorder is the result of genetic defects in the intracellular thyroid hormone receptors.  Most reported cases have shown autosomal dominant inheritance.  Clinical presentation varies considerably from no signs or symptoms to frank hyper or hypothyroidism.  In about 20% of reported  cases, patients have deafness,  while 50% have hyperkinetic behavior and are often diagnosed as having attention-deficit hyperactivity disorder.  In this condition, the pituitary gland has to work harder than usual in an effort to achieve normal intracellular signaling from thyroid hormone.  Typically, the TSH level is normal or slightly elevated while the T4 AND FT4 levels are above normal (remember that an elevated T4 could be merely the result of increased thyroid-binding proteins.  That is why measurement of FT4 is very important since that test is not generally affected by alterations in thyroid-binding proteins).  If I ever had a patient with both a high TSH set-point and thyroid resistance syndrome, I’m not sure how I’d figure it all out.

Case History # 2

The patient is a 16 year old female with chronic lymphocytic thyroiditis diagnosed several years earlier.  The patient had presented with swelling of the neck.  Evaluation revealed diffuse enlargement of the thyroid gland and a Delphian node present just above and to the left of the isthmus (as discussed in earlier entries, presence of a Delphian node  means it’s chronic lymphocytic thyroiditis until proven otherwise).  Laboratory studies showed slightly elevated TSH (8.5 microunits/mL), normal FT4, and sky high thyroid antiperoxidase antibodies.  The patient was treated with L-thyroxine.  The thyroid gland decreased somewhat in size.  Follow-up laboratory tests showed slightly low TSH and high-end normal FT4 (1.5 ng/dL).  The patient was clinically euthyroid.

The differential diagnosis

Here the question is whether the patient’s thyroid hormone dosage is a bit on the high side.  The patient’s FT4 is in the normal range and she shows no signs or symptoms of hyperthyroidism.  In this situation, I would tend to have faith in the negative feed-back system and lower the thyroid hormone dosage a bit but not bother to recheck labs for a while (i.e., 6 months or so).

There are some situations where a low TSH and a normal FT4 suggest other possibilities.   For example, maybe the patient has mild secondary (pituitary) or tertiary (hypothalamic) hypothyroidism?  Another fairly common situation is in patients with autoimmune hyperthyroidism who have received radioactive iodine ablation therapy.  Laboratory studies, particularly in the first few months after radioactive iodine treatment, may show low or normal TSH and low FT4 levels.  Here the answer lies in the T3 level which is typically normal or slightly elevated.  That clinical situation is one of the few in which I routinely monitor T3 levels in addition to TSH and FT4.

Is thyroid disease really as complicated as it seems?

Do not despair.  Diagnosis and treatment of thyroid disorders is generally very straightforward.  Once in a while, though, things can get a bit tricky.  But, one nice thing about clinical endocrinology is that if one understands the basic physiology, it is usually fairly to easy sort things out.

The other day I got into a discussion with a primary care physician (PCP) about a hypothetical patient.  We had been discussing a case history for an upcoming medical student examination.  The patient was a 40 year old female with a medical history suggesting hypothyroidism.  The physical examination revealed an enlarged thyroid gland.  The question was as follows: what thyroid function studies should be ordered?

The Answer

The PCP said that he would order total thyroxine (TT4), free thyroxine FT4), and thyroid-stimulating hormone (TSH).  I was a bit surprised by his answer and asked if he didn’t also want to order thyroid peroxidase (TPO) antibodies?  He replied something to the effect that in the “real world” docs don’t mess with that kind of stuff.  I became even more surprised and then asked him whether he thought it was important to know what one was treating.  He got a bit hostile and replied that if the TSH were high and the FT4 and TT4 levels low, he would have a diagnosis, primary hypothyroidism.  He explained that the cost of the TPO antibodies (about $50-$80) depending on the laboratory) was not worth the benefit.  My response was “hmmmm.”

What did I really think?

I did not agree with the PCP’s approach to the hypothetical patient but I did not go ballistic since there was some merit to his argument.  On the other hand, it is my opinion that testing for TPO antibodies in the patient described above is worth the modest extra expense.  First of all, as a general principle it is important to know what one is treating.  While primary hypothyroidism is a diagnosis, there are many different causes for the condition and the approach to treatment might well be dictated by the specific etiology.  In those parts of the world where iodine deficiency is not endemic, the most common reason by far for primary hypothyroidism is chronic lymphocytic thyroiditis (CLT) or Hashimoto’s thyroiditis as it is commonly called.  This is an autoimmune disorder which is highly prevalent in females, particularly those over 40 years of age.  As I have discussed in previous entries, the physical examination often offers clues to the diagnosis; in my experience, careful examination of the thyroid gland will reveal a small lymph node on the left, just above the thyroid isthmus.  This node is called a delphian node and its presence means the patient has either CLT or autoimmune hyperthyroidism or Graves disease.  I can’t remember if I have ever had a patient with a delphian node who did not have positive thyroid antibodies.

Anyway, the differential diagnosis of primary hypothyroidism includes CLT, goitrogens (mostly iodine-containing products), familial inborn errors of metabolism (genetic abnormalities of the various steps to synthesis of thyroid hormones or their degradation), gland dysplasia (e.g., hemithyroids), and other rather uncommon entities.  I find thyroid antibodies most helpful when the TSH and FT4 come back normal (I can’t think of any reason to order TT4 but that’s a topic for another time).  The question becomes why is the gland enlarged (here we are assuming that the physician is skilled at telling when a thyroid gland is enlarged rather than there just being a prominent fat ring around the neck)?  It is still likely that the patient has CLT or possibly a so-called simple colloid goiter an entity I don’t understand; I don’t even know if the disorder exists even though almost all textbooks that cover thyroid disorders list it in the differential diagnosis of goiters (a goiter is just another way of describing an enlarged thyroid gland).  If the patient has CLT and enlargement of the thyroid, many endocrinologists will recommend treatment with replacement doses of L-thyroxine to “put the gland at rest.”  There are some data suggesting that such treatment can prevent progressive destruction of the gland which can occur; a number of studies have shown that TPO antibodies are cytotoxic even though most of the inflammation in CLT is lymphocyte-mediated.

So, it’s not so simple deciding what laboratory tests to order or not to order.   I will return to my original argument that whenever possible it’s good to know what specific disorder is being treated with medications, or  maybe, even if the treatment is just observation.  But I can sort of see the PCP’s point of view, sort of.

Back to basics

Before I tell you anything about the patient’s medical history and what I wrote in the e-mail (as well as a subsequent one, when I got the lab test result), I think we should review a bit about the anatomy of the thyroid gland.  The gland is in the neck just below the larynx or so-called Adams apple.  The gland is palpable in most people but it takes some practice to feel a normal-sized gland.  First have the person sit in front of you and just look at their neck.  If you notice a small protuberance just below the larynx go up and down when the person swallows, you have probably seen the thyroid gland.  In precise anatomic terms, the gland is situated just below the cricoid cartilage ring which is the first ring below the larynx.  The space between the bottom of the larynx and the cricoid cartilage is called the crico-thyroid membrane and it’s the place one is supposed to lance with a fountain pen cap to save a person’s life if there is an obstruction to airflow at the larynx.  I wonder if anyone has actually done such a thing?  I wonder how many people even own a fountain pen?  Anyway, the thyroid gland consists of an isthmus in the midline which connects the 2 lateral lobes.   With a normal-sized gland, the lateral lobes are quite small but most of the time the isthmus can be palpated with practice.  If one sits facing the patient and the light is right, it is usually possible to see a butterfly-shaped form move up and down the neck with each swallow; the body of the butterfly is the thyroid isthmus and the wings are the lateral lobes with the superior lobes much more prominent than the inferior ones.

Back to the patient

I was astonished when the patient asked me if I had ever noticed that she had an enlarged thyroid gland.  In fact, I had been caring for her type 1 diabetes for many years and had noticed first many years back that she had a very prominent neck.  She and I had talked about her neck on many occasions- that should tell all doctors just how much patients listen to what the doctors says at clinic visits!  I had known that the neck prominence was clearly not the result of a goiter since when she swallowed, the mass did not move up and down; the “problem” was simply a combination of large neck muscles and a fat ring that sat just above  the thyroid isthmus which was barely palpable.

I had obtained thyroid function studies on a number of occasions, all of which were normal.  The tests had been ordered as a routine since about 25% of patients with type 1 diabetes have chronic lymphocytic thyroiditis, an autoimmune disorder.  I had also ordered thyroid function studies about 2 years earlier when the patient developed menstrual irregularities.  Her thyroid test results had always been normal.  So, it was not a surprise when I got the faxed copy of the thyroid test the patient’s primary care doctor had ordered that it was normal.  I don’t know why the doctor told the patient the test result was abnormal.

So, I e-mailed the patient and told her not to bother with the ultrasound and that we would rediscuss her thyroid gland at the next appointment.  I also told the patient that the primary care doctor was just trying to do a good job and that sometimes it’s hard to tell if a thyroid gland is enlarged even though as we discussed above it’s pretty easy if one knows how.

One more thing: the value of medical histories and physical examinations

This case should serve to remind all physicians that obtaining good medical histories and performing appropriate physical examinations remains an important aspect of medical encounters.  Many years ago I found a cartoon in a throw-away medical journal for resident physicians.  The cartoon showed two young physicians entangled in x-rays and laboratory test reports looking puzzled.  One of the physicians was turned towards the other and said “maybe we should go back and get a medical history and do a physical examination.”  I saved the cartoon because even in “the old days” there was concern that physicians were relying too much on laboratory tests to “make the diagnosis” without first starting with the tried and true.  It amazes me how few of the younger physicians are skilled at obtaining medical histories and performing physical examinations.  The stethoscope has largely turned into just a prop to hang around the neck.  It’s time to resurrect the art and science of histories and physicals.  Patient care will be all the better for it.  I wonder how much my old cartoon would bring on E-Bay?

Why do we have newborn screening for congenital hypothyroidism?

The purpose of a screening test is to detect a specific medical condition in an asymptomatic patient. Screening tests are typically used if failure to make a timely diagnosis leads to a bad outcome. Obviously, there does need to be a test that can detect the condition without unreasonable frequencies of false positive and false negative tests (i.e., test results that falsely diagnosis the medical condition or fail to diagnose it). The part about “unreasonable frequencies” depends on many factors such as the cost of the screening test versus the cost of missing the diagnosis (e.g, chronic medical care costs for a missed diagnosis leading to a serious outcome).

CH is one of those medical conditions that most experts world-wide agree is “worth” screening for; we have an excellent and relatively inexpensive screening test, the number of false positive and false negative results is considered acceptably small (don’t ask me to quantify what “acceptably” means), and there is an inexpensive and effective treatment. Key to all of this is the fact that most cases of CH cannot be detected clinically until it is too late to prevent permanent central nervous system damage. Thus if the question is “what are the most common signs and symptoms in newborns with CH,” the correct answer is “nothing.” That’s why newborns screening for CH is so important.

“Classic” signs and symptoms of CH

Even though, most cases of CH are detected in timely fashion only because of newborn screening, there are some well-described signs and symptoms that are worth remembering. Signs include poor feeding, irritability, apnea spells, and constipation. Physical findings include large tongue, jaundice (yellowish skin from high levels of bilirubin), poor muscle tone, and edema (swelling of the hands and feet). The poor muscle tone is often exemplified by an umbilical hernia. Many other signs and symptoms have been described but remember, most often infants with CH provide no clues in the newborn period.

The timing of the newborn screening test

Immediately after birth, normal infants typically have a large “spike” in their TSH level (TSH is the pituitary hormone that controls the thyroid gland production of thyroid hormone). Thus, the TSH level used as a cut-off between normal and abnormal is much higher than what the upper limit of normal for the test would after the first week or so of life- after the TSH spike, the level does not return to normal until about day 4-5. Because, newborns are discharged from the hospital so quickly these days, it has become necessary to carry out 2 screening tests, one within 1-2 days of birth, and the other, 1-2 weeks later. This avoids the logistical (i.e., expensive) problem of too many false positive results. Of course, working out the details to be certain the follow-up screening test is performed, requires a high degree of organization in the medical care delivery system (it also requires a cooperative parent). This is one aspect of our shaky medical care system that seems to work pretty well- few cases of CH end up being missed in the U.S.

Transient CH

Most pediatric texts include a a disorder called “transient CH” in the differential diagnosis of CH. Apparently some newborns have abnormal TSH screens and on follow-up have normal thyroid function studies. In my experience, most of the cases are the result of newborn TSH spikes that were unusually high or testing that was too early but it is relatively easy to sort these cases out. If the blood level of thyroid hormone (T4) is normal and the TSH level is modestly elevated (i.e, <20 with a normal level <5), careful follow-up testing can usually sort things out and determine if the infant needs to be treated with thyroid hormone life-long or not at all .

Congenital Hypothyroidism: The Basics

Congenital hypothyroidism (CH) is a very important pediatric endocrinology diagnosis. About 1/3000-4000 children are born with this condition; the prevalence is higher in females (about 2:1), much lower in blacks (about 1/20,00) and higher in Hispanics (about 1/2000 ). The condition is most commonly caused by abnormal development of the thyroid gland, called thyroid dysgenesis, which in most cases means that the gland is missing or only a remnant. The specific cause of this form of CH is unknown but is only rarely on a genetic basis (I have cared for 2 sets of identical twins where only one of each of the twin pairs had CH). It must be some intrauterine insult quite early on since the thyroid gland is fully formed and “in place” (the gland migrates from the base of the tongue to the anterior neck) by day 50 in utero.

There are other causes of CH which include disorders of thyroid hormone syntheses and disorders of the pituitary or hypothalamus (called secondary and tertiary hypothyroidism, respectively). The disorders of thyroid hormone synthesis are called “dyshormonogenesis” and are mostly on well described genetic bases (all are autosomal recessive disorders). The dyshormonogenesis causes of CH can be differentiated from “classic” CH because most are associated with enlargement of the thyroid gland at birth.

What is such a big deal about CH?

CH is important to diagnose as soon as possible after birth because thyroid hormone is critical for postnatal brain development as well as growth and various metabolic processes. CH will result in permanent brain damage if not treated within a few months after birth. Unfortunately, many patients with CH do not show any signs or symptoms of CH until it is too late to prevent developmental disorders. That is why, throughout the U.S. and most of the rest of the world, newborn screening programs test for CH from dried blood spots, easily obtained from heel stick blood samples. Once diagnosed, the condition (whatever the specific cause) can be easily treated with thyroid hormone replacement. Mental retardation from CH is now quite unc0mmon, a true triumph for modern medicine.

Enter the zebra

A recent article in the New England Journal of Medicine (Moreno, J.C., and Associates- 358:1811-18, 2008) reported 4 cases of a dyshormonogenesis cause for CH, a mutation in a gene responsible for recycling iodine within the thyroid gland; iodine, in the form of iodide, is necessary for thyroid hormone syntheses (each molecule of thyroid hormone has 4 molecules of iodine). In effect, if the gland cannot recycle iodine from thyroid hormone precursor molecules, the iodine is lost in the urine and stool and causes iodine deficiency which results in enlargement of the thyroid gland- a “goiter,” and hypothyroidism. The article was actually mostly about the sophisticated studies defining the specific genetic disorder in the 4 cases but the authors also discussed the clinical implications of their findings.

As it turns out, most cases of CH due to dyshormonogenesis are detected by the newborn screens or by an astute clinician finding a goiter. But, the authors documented that at least 1 of the cases had a normal newborn screen. When finally diagnosed, all cases had goiters. The authors concluded that clinicians should not rely on newborn screening tests to detect all cases of CH.

In an accompanying editorial, P.A. Kopp (pages 1856-59) emphasized the importance of careful clinical observation of infants and children to avoid making a diagnosis of CH after permanent brain damage has occurred. It isn’t so hard- infants and children with clinically significant hypothyroidism (i.e., where the blood level of thyroid hormone is abnormally low) will demonstrate slowed linear growth and maybe other signs and symptoms too. These days with our medical care system in disarray, some parents do not seek medical care for their children unless there are acute problems. Routine medical care for infants and children following some routine is the best way to prevent preventable catastrophes.  Without a first class medical care system we will miss both zebras and horses.

Newborns: don’t wait for clues

The majority of newborns with hypothyroidism have absolutely no signs or symptoms. That is why we have newborn screening for hypothyroidism. If there was severe prenatal hypothyroidism, a newborn might present with “classic” signs and symptoms that include hoarse cry, poor feeding, lethargy, constipation, enlargement of the tongue, and overall decreased muscle tone including an umbilical hernias. Lab tests would show very low serum free T4 and very high TSH (often as high as the lab assay goes, 200-300). Lab tests might also show hypoglycemia (low blood sugar levels) and hyperbilirubinemia, a high level of bilirubin in the blood. Bilirubin is a yellowish pigment found in bile and if elevated in the blood can cause the skin and whites of the eyes to take on a yellowish color called jaundice- almost all newborns have some degree of hyperbilirubinemia but it tends to be worse and last longer in hypothyroidism.

Children and adults with hypothyroidism can also have a yellowish tint to the skin due to high levels of carotene in the skin called hypercarotenosis. This is due to slow metabolism of the yellow pigment carotene, found in a variety of foods, particularly carrots. People who eat huge amounts of vegetables that contain carotene can have this yellow staining of the skin even if they do not have hypothyroidism. The pigmentation is harmless and will go away when hypothyroidism is treated (or the carrot-lover cuts back). One way to tell if a yellowish tint to the skin is due to hyperbilirubinemia (high bilirubin levels in the blood) or simply due to carotene in the skin is to look at the sclera (the whites of the eyes). If the sclera do not have a yellowish tint to them, it’s hypercarotenosis (you’ll be just as clever as Dr. House- the guy from the TV show called “House,” for those of you enlightened people who do not watch much TV).

Children: think poor growth and excellent school performance

In children, the signs and symptoms of hypothyroidism are similar to those in adults with one major exception, growth. Linear growth (growth in height) is markedly impaired in children with hypothyroidism (only if the free T4 level is low). In addition, these children may be overweight. It is interesting that school performance usually does not suffer; children with hypothyroidism have a much slower metabolism than normal and they are not very distractible- they can really concentrate on their schoolwork! In fact, one of the difficulties in treating children with longstanding severe hypothyroidism is that they can go from being the perfect child, quiet and well-behaved, to a hyperactive, highly distractible child. Thank goodness the hyperactive “phase” does not last forever, although the child may never go back to being so easy to deal with. I always warn parents about this temporary “side effect” of treating severe hypothyroidism in the hopes of avoiding telephone calls from angry parents asking what have I done to their wonderful child! Please note that this Jekyll and Hyde personality/behavior change occurs only when the hypothyroidism has been severe and longstanding.

Sometimes the diagnosis is delayed for quite a long time while doctors are trying to figure out why their patients have dry skin, anemia, constipation, and poor growth. In severe cases, the thyroid gland is usually not enlarged (it has been destroyed by the autoimmune process found in Hashimoto’s thyroiditis).

Adults with hypothyroidism

In adults, signs and symptoms are not really much different than those found in children. Of course, in adults one cannot assess linear growth as a clue to the disorder. Fatigue and weight gain are common but, unfortunately, most people with those symptoms do not have hypothyroidism. Remember it’s easy to tell from two simple laboratory tests, free T4 and TSH.

Problems within the thyroid gland: congenital hypothyroidism

Congenital hypothyroidism affects about one in every 5000 newborns. In most instances, the condition is the result of some mix-up in utero that affects development of the gland. Most often the gland is simply mssing or just a small remnant. Sometimes there is a gland, or part of a gland, but it is ectopic; the gland normally migrates from the base of the tongue down the neck to its usual location, but once in a while it “parks” before it gets to where it is supposed to go- sometimes still at the base of the tongue which is called a lingual thyroid. Anyway, congenital hypothyroidism is very important to detect and to detect quickly since hypothyroidism can cause irreversible brain damage during the first two years of life. It is not surprising that all 50 States in the U.S. require newborn screening for hypothyroidism. Treatment is easy- just a little pill every day for life (if you are wondering, the pill is crushed up and given with liquid in infants). A delay in treatment for even a month or two can be disasterous.

The typical form of congenital hypothyroidism is not considered genetic and we actually do not know what causes it. Rarely, congenital hypothyroidism is due to a genetic disorder. For example, some people have thyroid glands but are unable to make thyroid hormones. There are a number of steps in the formation of thyroid hormone and abnormalities in each of the steps have been described. The most common of these genetic causes of congenital hypothyroidism is called Pendred syndrome and was first described in a Swiss family. In this syndrome, congenital hypothyroidism is associated with deafness. Generally it is easy to tell if a newborn infant with congenital hypothyroidism has an abnormality in thyroid hormone synthesis- the thyroid gland is enlarged. Anyway, the treatment is exactly the same whatever the cause of the hypothyroidism.

Occasionally we do see congenital hypothyroidism that is transient; examples would include hypothyrpoidism due to a medication the mother took during pregnancy (e.g., medications to treat maternal hyperthyroidism, ingestion of large amounts of iodine during the pregnancy).

Chronic lymphocytic thyroiditis

By far the most common cause of hypothyroidism after the newborn period is chronic lymphocytic thyroiditis, or Hashimoto’s thyroiditis as it is usually called. This condition is an autoimmune disorder, where the body’s immune system attacks this or that part of the body. In this instance, the autoimmune process directs lymphocytes, a type of white blood cell, to attack the thyroid gland. In some instances this leads to complete destruction of the gland; in other cases, the gland shows only minor damage and its ability to crank out normal amounts of thyroid hormones is unaffected. I have made the diagnosis in children as young as 6 months of age, but typically the disorder is found much more often in older children and adults. The thyroid gland is usually enlarged but rarely tender. The diagnosis is usually easy to make once suspected; blood levels of free T4 and TSH (as discussed in my last posting) and thyroid antiperoxidase antibodies. The presence of the thyroid antibodies in the blood test pins down the diagnosis even if the free T4 and TSH are normal.

The condition is seen quite frequently in certain medical conditions including type 1 diabetes mellitus (about 25-30% of patients), the Turner syndrome (about 50% of patients), and Down’s syndrome (about 40% of patients). It is much more common in females than males as are all thyroid disorders except for thyroid cancer and congenital hypothyroidism. Treatment is generally simple- a small pill every day.

Other causes of hypothyroidism due to problems within the gland

There are many other causes of hypothyroidism but they are relatively rare compared to congenital hypothyroidism and Hashimoto’s thyroiditis. For example, subacute thyroiditis is a condition that can cause hypothyroidism. Typically, people develop pain and swelling in the thyroid gland which generally subsides over 2-3 months. Hypothyroidism is transient, lasting only a month or so and people with the condition often present with evidence of an overactive thyroid gland early on: the damaged gland releases large amounts of stored thyroid hormone. So the “classic” pattern is early hyperthyroidism leading to hypothyroidism after a few weeks, and eventually, back to normal. Much is written about this condition in endocrinology textbooks. I confess that I am not sure if I ever saw a single case in a child during the past 40 years.

Other causes of hypothyroidism include certain drugs, iodine deficiency (basically unheard of in the U.S.), and consumption of certain foods such as large amounts of soybean products: soy products inhibit absorption of iodine which is critical for thyroid hormone synthesis. Nowdays there is so much iodine in our diets (e.g., salt, bread) that even aggressive tofu eaters need not worry (in the 1940s when soy milks were first introduced for baby formulas, there was an “epidemic” of iodine-deficiency goiters- a goiter just means enlargement of the thyroid gland. The problem was sorted out very quickly and eliminated by adding iodine to soy milk formulas.

Hypothyroidism caused by problems outside the thyroid gland

Just for completeness, you should know that hypothyroidism can be caused by problems in the messenger system that controls how much throid hormone the gland produces. Up in the brain, the hypothalamus normally sends a hormone signal, thyrotropin-releasing hormone or TRH to the pituitary gland which in turn sends a hormone signal, thyrotropin, or thyroid-stimulating hormone or TSH to the thyroid gland (it’s not as complicated as it may seem). If there is anything wrong with this signalling system in getting the proper message to the thyroid gland, the person will develop hypothyroidism. This is called secondary hypothyroidsim to distinguish it from primary hypothyroidism, where the problem is with the thyroid gland itself. Typically causes of seconary hypothyroidism include a variety of brain tumors, radiation to the brain, head trauma, and hypopituitarism (often with a variety of hormone deficiencies which we will discuss in a future posting).

It is generally easy to diagnose secondary hypothyroidism ,although maybe not so easy to determine the underlying cause: blood levels of free T4 will be low and the TSH normal or low. It is important to measure the free T4 not just the “total T4″ since the latter can be affected by the levels of the serum proteins that carry most of the circulating thyroid hormones; if the serum proteins that carry thyroid hormones are low, the total T4 level will be low but the free T4 level will not be affected. Now that we have reliable free T4 assays, life is good for pediatric endocrinologists.

The thyroid gland is normally located in the neck just a bit below the thyroid cartilage, the “adams apple.” If you are intensely curious to actually locate your thyroid gland or someone else’s, you need to first put your thumbs on the thyroid cartilage (gently). Next, slide them down the front of the neck about half an inch until you reach a lump, this is the cricoid cartilage. Next. slide your thumbs down a bit and you should be feeling the isthmus of the thyroid, the part of the thyroid that bridges the right and left lobes. The lobes have upper and lower poles but the upper ones are more prominent. The thyroid gland looks a lot like a butterfly. You may not be able to feel the thyroid gland as it is normally quite small. Watch someone swallow and see if a small butterfly-like shape slides up and then down in the neck where you would expect the thyroid gland to be.

In many medical schools, students are taught to feel the thyroid gland standing behind the patient. The idea is that one can use the fingers the feel the gland rather than the opposed thumbs; the fingers are supposed to be more sensitive than the thumbs for feeling nodules and who know what. In my opinion, any advantage in sensitivity is off-set by one’s being unable to see what is going on.

What does the thyroid gland do?

The thyroid gland is basically a factory for thyroid hormones, called T4 and T3 (mostly T4). Think of thyroid hormones as the gas pedal on a car, which controls the speed of the vehicle. Thyroid hormones control the body metabolic rate. If the thyroid hormone levels are low, the metabolic rate decreases and this is called hypothyroidism. Typical signs and symptoms include fatigue, weight gain, swelling of the feet, constipation, and dry skin. Severe hypothyroidism is very serious and can lead to heart failure. The other side of the coin, hyperthyroidism, is associated with rapid heart rate, nervousness, weight loss, heat intolerance, and excessive sweating. In some forms of hyperthyroidism there is prominence of the eyes, called exophthalmos. In adults, hyperthyroidism can be associated with an arrhythmia of the heart called atrial fibrillation.
Thyroid testing

It is relatively easy to diagnose thyroid conditions. thyroid hormones circulate in the blood and can be measured very accurately by most laboratories. Generally the best test to assess blood levels of thyroid hormone is called “free T4.” This is the portion of the circulating thyroid hormone, tetraiodothyronine (a thyronine molecule with 4 iodine molecules attached) that is not tightly bound to serum proteins and best reflects the metabolic state. One other hormone, thyrotropin, or TSH (thyroid-stimulating hormone) is also useful to measure. TSH is produced by the pituitary gland in the brain and regulates thyroid hormone production. If there is too much circulating free T4, the pituitary gland decreases the secretion of TSH thereby slowing down the production of T4 in the thyroid gland. Conversely, if the circulating level of free T4 is too low, TSH levels go up in an effort to drive the thyroid gland to produce more T4. If the gland is damaged or affected by certain drugs, it can’t respond to the pituitary message and the free T4 level stays low. Sometimes, the TSH message succeeds in stimulating the thyroid gland to make enough T4 to get the free T4 level back to normal but only if the TSH stays elevated. That condition is called compensated hypothyroidism.

So what’s the bottom line?

In summary, except in very rare circumstances, if the blood levels of free T4 and TSH are in the normal range, hypothyroidism is highly unlikely (as is hyperthyroidism). If a person has compensated hypothyroidism (normal free T4 and elevated TSH) it would be very unusal for them to have any symptoms due to hypothyroidism- they might have signs or symptoms that suggest hypothyroidism, such as fatigue and weight gain, yet not have them the result of hypothyroidism.

Mysticism and the thyroid gland

Some physicians believe that many patients have hypothyroidism even though the test results are normal. Their reasons vary but in my experience, they don’t make any sense and are inconsistent with our very firm understanding of thyroid gland physiology and pathophysiology. Quite a number of people who do not have hypothyroidism are treated long-term with thyroid hormone. The other side of the coin are the many people who do have hypothyroidism and are not being treated. For example, hypothyroidism is very common in people over the age of 40 years, mostly women. It’s easy to diagnose, right? Just have your physician order a serum free T4 and a serum TSH.