ENDOCRINE EXPLAINED

What is the thyroid gland? The thyroid gland is a gland, or factory, that produces thyroid hormones. In fetal life, it forms at the base of the tongue, and migrates to the front of the neck. It produces the thyroid hormone that circulates throughout the body as thyroxine (T4) and triiodothyronine (T3). How much thyroid hormone is produced and secreted depends on the action of thyrotropin, also known as TSH - Thyroid Stimulating Hormone. TSH is made in and secreted by the brain's pituitary gland, and is recognized by TSH receptors on cells within the thyroid gland to increase the production and secretion of T4 and T3.

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What are thyroid hormones, and what do they do? Thyroid hormones increase the rate at which most cells function. Thyroglobulin is made in thyroid cells, and is the scaffold to which thyroid hormones are made out of iodide and through enzymes to form T4 on one end, and T3 on its other. These are then secreted from the thyroid cells into the bloodstream, where they are available for use by other cells.

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Most of what is made and released by the thyroid gland is T4, and is taken up and used by cells after transformation into T3. Some of that T3 is then released back into the circulation, comprising up to 80% of the circulating T3! Each cell responds to T4 and T3 with a different action, generally increasing the work within a cell. In general, T4 and T3 thyroid hormones increase the rate of a cell's metabolism so that its actions and its rate of growth are increased. Thyroid hormones support normal body processes: if T4 and T3 are too low, the system works poorly, and too slowly, and if they are high, the system works overly rapid and intensively. Either way - too low or too high - people generally don't feel at their best, often feeling too tired.

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What is hypothyroidism? Hypothyroidism is the state of too little thyroid hormone. Signs and symptoms (what is observed and what is felt) include: Low energy, slow heart rate, low blood pressure, slow intestines (constipation), dry skin, thinning hair and brows, slow growth, weight gain, decreased urination and puffiness, depression and difficulty learning. When thyroid hormones are low, and the pituitary gland is healthy, TSH will rise to an abnormally high level. When the level of TSH is high, thyroid function is confirmed as low. 

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What is a high level of TSH? A normal TSH level is a little different for each laboratory, depending on the sensitivity of their test, or assay. Most endocrinologists will supplement thyroid hormone if a TSH is at least 10, but if someone has symptoms, especially with a low T4 level, they will consider treatment. In children, because development can be significantly affected over time with even mild hypothyroidism, pediatric endocrinologists may treat hypothyroidism when TSH is just above the normal range, somewhere between 4 and 10.

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How can you tell if a child has a thyroid problem? Most commonly, a doctor checks a child's thyroid levels if a child has a change in their growth pattern (read more about children's growth here), activity tolerance, emotional state, sleeping pattern, bowel habits, or skin health. There may be significant menstrual changes suggestive of PCOS/hormonal imbalance. There may be unusual or surprising weight gain (although also common and related to insulin resistance). If there is significant enlargement of the thyroid gland, a goiter, then the gland's function should be evaluated through blood tests, and its structure through ultrasound imaging. When the gland is protruding and becomes very large, it may be felt by a child to be uncomfortable as it interferes with their swallowing.

 

On the other had, a child can feel fine, but have only new school challenges, slowed growth, or a tendency toward constipation. These are difficult to distinguish from far more common childhood developmental changes, so it is important that you and your doctor consider its possibility if the usual treatments aren't working. It is very common for a child with a mild thyroid insufficiency that has been going on for years to "feel fine", yet once they are supplemented, realize that what they were used to wasn't normal.

 

The best way to check for a thyroid problem is a TSH blood test. If it is high or low, then antibodies, T4 (and sometimes T3), and an ultrasound are then performed to determine the appropriate treatment.

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How old are children when they're diagnosed with hypothyroidism? Children can be born without a gland or develop it in infancy due to an ectopic or poorly formed gland, termed congenital hypothyroidism. Autoimmune hypothyroidism, on the other hand, requires a well-functioning immune system, so doesn't typically develop in infancy. It is rare in children younger than 6 years old, but the prevalence rises with age.

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What is congenital hypothyroidism? Congenital hypothyroidism is hypothyroidism that is identified in the first months of life, often by way of the screen just prior to a newborn's discharge from the hospital. It is caused by the  absence of a normal thyroid gland, due to any of the following: 1. abnormal migration of the thyroid preventing its growth, 2. a gene mutation affecting one of the building blocks of thyroid cells preventing thyroglobulin's normal structure, its passage through the cell and/or storage, or an enzyme to create T4 and T3, 3. the mother's antibodies crossing the placenta and blocking thyroid function, or 4. the rare occurrence of abnormal pituitary gland development, so TSH is not secreted properly.

 

Treatment with levothyroxine is usually started prior to the development of any severe signs or symptoms of hypothyroidism, so intellectual impairment, poor growth, and weakness are prevented. Since it is initially difficult to tell which infants require support for only a short time, and who will require support for a lifetime, infants are typically treated through the age of 3 years. Until that time, they are monitored closely, but at 3 years, medication is reduced or discontinued, and its ongoing need is reevaluated.

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What is Hashimoto's thyroiditis? Thyroiditis means that there is inflammation of the thyroid gland. Hashimoto's thyroiditis is a description of a common autoimmune disorder named for Dr. Hashimoto, who, in 1912, identified a particular appearance of immune cells within the thyroid gland. These immune cells affect the gland due to the presence of thyroid peroxidase antibodies and anti-thyroglobulin antibodies - Hashimoto antibodies. Also known as Hashimoto disease, the presence of antibodies affects up to 5% of the population. The effects on the thyroid include: enlargement or goiter caused by lymphocyte immune cells growing within the gland, destruction of the gland through fibrosis and scarring, nodules consisting of normal and/or abnormal cells, and usually self-limited hyperthyroidism called "Hashitoxicosis."

 

Most often, Hashimoto antibodies are measured in blood tests, but have not led to any functional change to the thyroid. It is only when the destructive of the effects of the antibodies, particularly anti-thyroid peroxidase, override the thyroid's ability to overcome these effects, that they can cause impairment of thyroid function. This dysfunction is treated through replacement of thyroid hormone.

 

Parents often worry that a high level of antibodies is dangerous or concerning. Thankfully, elevated antibody levels do not correlate with the severity of thyroid dysfunction, and there is no treatment of the antibody levels themselves.  Indeed, thyroid hormone replacement is effective and rarely with intolerance or side effect. Even when there are side effects, alternative appropriate treatment can be found.

 

Why does my child have Hashimoto disease? Scientists aren't sure precisely what triggers the process of autoimmunity against the thyroid, but there are well-known genes that cause increased risk in some families. It is clear that certain viruses also cause inflammation of the thyroid gland, likely exposing proteins that usually remain inside the gland to the bloodstream, where the immune system learns to recognize these normal thyroid proteins, and attacks them. Many children have measurable Hashimoto antibodies for years before they develop hypothyroidism. While there are additional environmental forces that contribute to the development of Hashimoto and Graves' disease: smoking, high stress, high iodine intake - these factors are beyond the control of the child. It should be made clear to any child that it was not caused by anything they did, so there should be no blame placed on or felt by a child with this condition.

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How is medicine for hypothyroidism taken? Medication for hypothyroidism (levothyroxine (Synthroid, Levoxyl, Unithroid, Tirosint, Armour, Cytomel, levothyroxine and triiodothyronine) is typically daily. It should be taken at the same time every day, and on an empty stomach to avoid variable absorption due to its binding by food. This means it should be taken at least 30 minutes before, or at least two hours following food. Small changes in the timing of levothyroxine or in the amount absorbed can change its effect significantly, as do differences between brands. As a result, many endocrinologists encourage their patients to either discuss with their pharmacies using a generic brand continuously, or use a name brand. For many patients, T4 alone works well to correct their symptoms and normalize their TSH. For some, a small amount of T3 makes a difference in their treatment.

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If my child takes levothyroxine, how will they feel? If someone is taking the right amount of thyroid hormone, they should feel the same way that they would if they didn't have hypothyroidism. If they're taking too little, then TSH will be elevated, and they may have signs and symptoms of hypothyroidism. If they're taking too much, then TSH will be very low, and they may have signs and symptoms of hyperthyroidism. What is frustrating is when TSH and thyroid hormone levels are normal, and there are still signs and symptoms of hypo- or hyperthyroidism. 

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What is hyperthyroidism? Hyperthyroidism is the state of too much thyroid hormone. Signs and symptoms include: Overactive reflexes, fatigue with exertion, increased anxiety, difficulty falling asleep, high blood pressure, rapid heart rate, diarrhea, soft and smooth skin, frequent urination especially noticed at night, thinning hair, rapid growth, weight loss (although not always!), menstrual absence or irregularity, inattention and difficulty learning. When thyroid hormones are high, then TSH will decline to an abnormally low level. 

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What is Graves' disease? It is hyperthyroidism that is caused by antibodies that stimulate the TSH receptor, so thyroid cells increase their production and release of T4 and T3. Since T4 and T3 are secreted without regulation, T4 and T3 levels are elevated, and the pituitary gland responds by suppressing its release of TSH. These antibodies cause the thyroid gland to enlarge and secrete hormones, but also have effects beyond the thyroid, especially to affect the muscles and supporting tissue behind the eyes, causing protrusion - sometimes severe - of the eyes, called exophthalmos, or Graves' Orbitopathy. There is rarely Graves' Dermopathy, or pretibial myxedema, where there is inflammation and swelling of the tissue in the front of the lower legs and the tops of the feet. Lastly, there is an entity called Acropachy, where inflammation of the small bones of the hands and feet cause pain and swelling, as well as the appearance of clubbing of the fingertips and nails noted by doctors.

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Treatment for hyperthyroidism is usually with an oral medication called Methimazole for the first 1-3 years, if needed that long. If hyperthyroidism is severe, then oral beta-blocker medications are also used for both symptoms and to reduce T4 and T3 levels. If hyperthyroidism continues beyond this time frame in an older child, then the option of radioactive iodine ablation (RAI) to destroy, vs surgery to remove the gland, are often discussed. If there is Graves' orbitopathy or nodules within the thyroid gland, it is considered prudent to use surgery to treat the ongoing hyperthyroidism rather than RAI.

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What side effects are associated with thyroid treatment? In hypothyroidism, levothyroxine (occasionally with triiodothyronine) are used. If the thyroid hormone levels become normal with levothyroxine, then there shouldn't be hypothyroidism, so a person should have resolution of hypothyroid symptoms. If medication is at too low a dose, there will be ongoing hypothyroidism. If the dose is too high, a child may develop hyperthyroidism. The medication itself is rarely a problem in itself, as it has only a few ingredients, although allergies to the components occur, especially to the food dyes used to differentiate the different doses. 

 

Some people report that a particular brand is effective for them whereas another is not. It is possible that an additive in one causes enough irritation that the medication isn't absorbed well, so a more easily absorbed form - like Tirosint - should be tried. Some individuals like the idea of a natural origin of thyroid hormone. The only one on the market, Armour brand, has a relatively high T3 amount in relation to T4. For those who need T3 in addition to T4, it can sometimes be used successfully.

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In hyperthyroidism, thionamide medications - Methimazole is used in the United States - can rarely cause severe side effects, like liver failure, vasculitis, and agranulocytosis (low neutrophil white blood cell count) leading to infection. While the occurrence of these are relatively uncommon, parents are encouraged to call and seek an urgent evaluation for their child whenever there is a fever, or if a new rash or abdominal pain develop. Beta blockers are used in significant hyperthyroidism, and fatigue can develop if the hyperthyroidism improves and the medication isn't reduced. Other medications - steroids for moderate to severe Graves' orbitopathy, or SSKI in a preoperative setting for surgical thyroidectomy - should be discussed with the prescribing doctor in these rare situations. 

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How do we treat high thyroid antibody levels? Levels of antibodies are checked if there is concern that someone is at risk for thyroid disease, when there is a goiter, and to confirm a diagnosis of Hashimoto or Graves' disease. The levels themselves do not typically influence treatment, but parents and doctors often are uneasy when the levels of antibodies are high, or increase over time. 

 

Treatments have been tried to reduce antibody levels, including certain diets, medications, herbs and supplements. While some people find that symptoms correlate with antibody levels, questions remain regarding the general usefulness of trying to reduce antibody levels in all people with Hashimoto's. It isn't clear whether proposed treatments reduce antibodies in large groups of people - as would be demonstrated in a scientific study - or whether shifts in antibody levels are due to their normal fluctuations. Most of all, it isn't at all clear that reducing the levels of antibodies reduces hypo- or hyperthyroidism, or whether their side effects are worthwhile. 

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Can a child have both Hashimoto AND Graves' antibodies? Yes they can. It can cause fluctuation between alternating hypo- and hyperthyroidism. Children may require a combination of therapies, and more frequent follow-up than if they had just one form of thyroid antibody.

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Can a child be cured of Hashimoto or Graves' disease? It is clear that some children have resolution of their antibodies over time. Of these children, some work with their doctors to monitor their thyroid function as they discontinue their medication, and their TSH and thyroid hormone levels remain normal. Should levels remain normal off medication, I would consider their autoimmune disease in remission, as opposed to cured. This is because children and teens who once were treated for their thyroid are more likely to develop abnormal thyroid function again. As a result, for these children and teens, it is appropriate to screen TSH yearly, or if signs or symptoms of hypo- or hyperthyroidism recur. 

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How often will I need to see a doctor for monitoring? While it depends on the severity of a child's condition at the start of treatment, usually a child will be seen within 4 weeks after starting treatment for hyperthyroidism, and within 6 weeks after starting treatment for hypothyroidism. Once a child is thought to be on an appropriate dose of medication, then monitoring is often reduced to every 2-6 months - more often if a child is growing or there are weight fluctuations, and less often towards the end of the teenage years. One important consideration for sooner evaluation than anticipated is if there is the development of new signs or symptoms of hypo- or hyperthyroidism, and urgently - that day - should a child on Methimazole develop a concern for one of the severe side effects outlined above.

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What are other conditions to know about that could be related to autoimmune thyroid disease? While most individuals who have autoimmune thyroid disease don't develop other autoimmune concerns, its presence does increase the possibility of other autoimmune diseases. Typically, endocrinologists screen for celiac disease, Type 1 diabetes, and Addison's disease, along with autoimmune anemias, hepatitis, and nephritis. Children and parents should be asked about patches of hair loss, decreased skin pigment, and pain in joints or rashes that could be early signs of alopecia areata, vitiligo, lupus or scleroderma. When concerns are raised, referrals to the appropriate specialist should be made in conjunction with the child's general doctor. 

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Should my child be on a special diet because of their thyroid condition? There have not been any peer-reviewed scientifically conducted and published studies demonstrating a particular diet effective in reducing autoimmunity or thyroid conditions. The only studies performed looking at gluten free diets in thyroid disease have been in individuals with celiac disease, where there is a clear benefit beyond their thyroid disease. That said, some people describe significantly improved well-being when their diet changed to exclude gluten, sugar, and/or dairy. However, these diets are very restrictive and can have significantly negative psychological effects on a child's socialization and self-perception as being ill, when they are truly otherwise healthy, and only require thyroid hormone supplementation.

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Are there supplements that are helpful to support the thyroid? Thyroid cells require iodine, selenium and zinc to make T4 and T3. Both iodine deficiency and iodine excess increase the risk of autoimmune thyroid disease, so it is recommended that no large iodine doses are given as supplements. However, a small amount daily, as in a multivitamin or as is supplemented in iodized salt, ensures that enough is available for normal thyroid function in most people. Several small studies do not demonstrate a benefit in giving additional selenium and zinc. That said, if someone is known to have a deficiency, then providing support seems warranted. Low dose naltrexone is a new dose of an old medication, with little but promising data. It is not yet generally prescribed, since data aren't yet clear regarding long-term effects and risks of opioid-receptor blockade, especially in children, whose neurological pathways are still developing. 

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If it's not a thyroid problem, why is my child tired?  If the level of TSH is between 0.6 and 3, and the T4 and T3 levels are at least average, it is unlikely that the fatigue - or slow growth, hair loss, or weight gain - is related to the thyroid function. Most often, a child is tired due to inadequate sleep - or poor quality of sleep due to apnea, inadequate conditioning and muscle strength, low iron/food intake, or anxiety and depression. Each of these possibilities should be considered and treated appropriately so that a child can return to optimal energy and health.

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Resources for learning around the web:

1. https://www.hormone.org/your-health-and-hormones/glands-and-hormones-a-to-z/glands/thyroid

2. https://emedicine.medscape.com/article/122393-overview

3. Di Jeso B, Arvan P. Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology. Endocr Rev. 2016;37(1):2-36. doi:10.1210/er.2015-1090

4. Kahaly GJ. Management of Graves Thyroidal and Extrathyroidal Disease: An Update. J Clin Endocrinol Metab. 2020;105(12):3704-3720. doi:10.1210/clinem/dgaa646