Thyroid problems can be worrisome, but relatively few children referred for workup for an abnormal thyroid test have clinically significant disease. Choosing the right screening tests can prevent these costly encounters without compromising children whose test results warrant close follow-up and possible intervention.
DR. KAPLOWITZ is chief of endocrinology, Children's National Medical Center, and professor of pediatrics, George Washington University School of Medicine, Washington, D.C.
Referrals for evaluation of "abnormal" thyroid tests account for at least 25% of appointment requests in our department of pediatric endocrinology. The great majority of these patients do not actually have thyroid disease, need no therapy, and in many cases, no follow-up testing. They nevertheless arrive at the endocrinologist's office for three basic reasons:
This article will review some basic thyroid pathophysiology, pinpoint the indications for thyroid testing in children, and offer examples of test results that (most of the time) do not require referral to an endocrinologist.
Thyroid hormones l-thyroxine (known as T4) and triiodothyronine (known as T3) have many important functions, but those that are most critical in children are promotion of normal myelination during brain development in the first two to three years of life and normal skeletal growth. In addition, thyroid hormones regulate the rate of metabolism. Thus a severe deficiency may result in fatigue, feeling cold, low heart rate, constipation, and slow growth if the problem has been present for long enough. It is important to note that mild but biochemically detectable deficiency is often asymptomatic, and that the actual symptoms of thyroid hormone deficiency (or excess) vary greatly from child to child.
T3 is more potent as a thyroid hormone than T4, but its blood levels are lower. About 20% of T3 comes directly from thyroid synthesis and 80% from peripheral metabolism, since many tissues can convert T4 to T3 by removing an iodine atom.
Thyroid hormone production is tightly regulated by pituitary secretion of thyroid stimulating hormone (TSH), which is in turn regulated by hypothalamic thyrotropin-releasing hormone (stimulatory) and somatostatin (inhibitory). The pituitary senses the level of unbound (free) T3. When that level falls below a critical set point, TSH increases which then stimulates the thyroid gland to produce and release more thyroid hormones. When thyroid hormone levels normalize, they induce feedback inhibition of TSH release, and TSH levels return to normal. Thus a mildly increased TSH (6 to 15 µIU/mL) may be an appropriate response to a transient decrease in thyroid hormone production, and does not always signify an immediate need to start thyroid hormone replacement.
By far the most common cause of a progressive decline in thyroid function is autoimmune or Hashimoto's thyroiditis. The hallmark of this condition is a progressive rise in TSH (usually to levels above 20 µIU/mL), accompanied by a gradual fall in circulating thyroid hormone levels. In the early stages, thyroid hormone levels may still fall within the low-normal range, but eventually, as the thyroid fails, the free T4 level will become subnormal. In most but not all cases, the rise in TSH stimulates growth of the gland itself, resulting in a goiter palpable on physical examination. Goiter may appear early in the course of disease, while symptoms are absent. Eventually, as thyroid hormone levels fall well below normal, the classic symptoms noted above will appear, although their onset is so insidious they may go unrecognized. In about 90% of cases, elevated levels of anti-thyroid antibodies, particularly thyroid peroxidase (TPO) antibodies, will be present at the time of diagnosis, thus confirming a suspicion of autoimmune thyroiditis.
The other autoimmune problem that alters thyroid function is the production of antibodies directed at the TSH receptor on thyroid follicular cells. Often, these antibodies stimulate the thyroid cells as effectively as TSH, resulting in an increase in both T4 and T3 secretion. However, as T4 and T3 levels rise and TSH production is shut down by negative feedback, production of antibodies continues unabated, resulting in sustained elevation of T4 and T3 and, eventually, many of the classic symptoms of hyperthyroidism. These include inability to sit still and focus, heat intolerance, rapid heart rate, weight loss despite increased appetite, and occasionally excessive stooling. Exophthalmos is not related to elevation of T4 and T3, but to antibodies directed against the extraocular smooth muscles. This type of hyperthyroidism, also known as Graves disease, is at least five times more common in girls than in boys. Most school-aged patients will have a significant decline in their academic performance, due to their inability to focus, concentrate, and sit still.
Thyroid tests should be ordered mainly in these situations:
Thyroid tests are not likely to be helpful in these situations:
Thyroid testing is one of those situations where less is more. More tests increase the chances of finding a trivial abnormality but are not more likely to uncover actual thyroid disease. In general, only two tests are needed for initial thyroid screening:
The following tests are not relevant or not worth ordering except under certain cirmstances:
The following six cases discuss what to do in some common situations when thyroid test results are abnormal.
Case 1.You are evaluating a child for short stature (or fatigue, or a positive family history of thyroid disease), and find that the free T4 is mid-normal, but the TSH is 0.3 (lab normal range 0.5-5.5). What should you do?
Case 2. What if, on screening, the free T4 is normal but the TSH is 0.05 and the child has no clinical signs of hyperthyroidism?
Case 3.A patient who is being screened for thyroid disease due to obesity has a normal free T4 of 1.2, but the TSH is slightly increased to 7.0. There is no goiter. How aggressive should one be in further testing and treatment?
Pediatric endocrinologists are split on whether to treat children with normal free T4, TSH of 5.5 to 10, and no goiter. Some believe that any slightly elevated TSH that is present on more than one test should be treated aggressively, while others believe this is usually a normal variation. My own experience is that few of these patients become overtly hypothyroid, at least in the short term (one to two years). I ask referring physicians to repeat the free T4 and TSH in six to 12 months, or sooner if a goiter appears or there are classic hypothyroid symptoms. About half the time, TSH levels fall back into the normal range, and half the time they remain in the 5.5 to 10 range. In only a few cases do TSH levels increase to more than 10, and even then overt hypothyroid symptoms are rare, but at that point the child should be seen. Parents need to be informed there are generally no signs or symptoms (obesity, fatigue, short stature) that can be attributed to a slightly elevated TSH when the free T4 is normal. Even though thyroid hormone replacement is safe and not very expensive, most parents would prefer to wait to see if the child develops more clear-cut hypothyroidism before starting treatment.
Case 4.A 10-year-old boy with hyperactivity is screened for thyroid disease and is found to have a slightly low free T4 of 0.82 (normal is 0.9 to 1.6) with a normal TSH of 2.7. How should one interpret such tests and is treatment or additional evaluation warranted?
One situation in which a low free T4 with normal TSH may be meaningful is in the child with significant short stature and a decreased rate of growth. Since pituitary deficiencies are often multiple, such a child could have a deficiency of both TSH and growth hormone-particularly if the insulin-like growth factor-1 level is also low. Certain drugs may also cause a low free T4 without a compensatory rise in TSH. The drugs which do this most often are carbamazapine (Tegretol) and the structurally similar anticonvulsant oxcarbazepine (Trileptal).
If you see a child with this problem, I suggest waiting a few months and repeating the test. If a direct free T4 was ordered the first time, order a free T4 by equilibrium dialysis the second time. If both are low, the child can be referred to a pediatric endocrinologist, but unless there is either a poor growth rate or a history of central nervous system (CNS) disease or new CNS symptoms, the chance of pinpointing a cause (e.g. a tumor near the pituitary) is quite low. Children with a low free T4 level who are taking the seizure medications just mentioned may not have true hypothyroidism; the test result may be due to displacement of T4 from thyroid-binding globulin. Most endocrinologists will treat to normalize the free T4 but will try to withdraw treatment if the child is taken off the seizure medication.
Case 5.A 3-week-old child who had a birth weight of 7 lb 6 oz is sleeping a lot, feeding poorly, and not gaining weight well. The child passed his newborn thyroid screening but you want to rule out hypothyroidism anyway. The free T4 comes back 2.1, the total T4 is 15.5 (both slightly elevated), and the TSH is 8.0 (also slightly elevated). What does this mean? Can the child be hypo- and hyperthyroid at the same time?
Case 6. You find an enlarged, symmetric, and non-tender thyroid on a routine exam and obtain a free T4 and TSH, which are both normal. Should this child be referred?
By urgent referral, I mean not simply asking the parents to call and schedule an appointment but faxing the test results to your local pediatric endocrinologist in the hope that the child can be seen on an expedited basis. This list, you will notice, is short.
Target patients for referral who are most likely to need evaluation and possibly treatment with either thyroid hormone or antithyroid medication. This will eliminate or greatly decrease the parental anxiety aroused by being told their child has a thyroid problem when none exists. It will also allow those patients who truly need to be seen by a pediatric endocrinologist to be given appointments more promptly-the best of all possible worlds.
1. Glass AR, Kushner J: Obesity, nutrition, and the thyroid. The Endocrinologist 1996;6:392
2. Hollowell JG, Staehling NW, Flanders WD: Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2005;87:489
3. Nabhan ZM, Kreher NC, Eugster EA: Hashitoxicosis in children: Clinical features and natural history. J Pediatr 2005;146:533
4. Moore DC: Natural course of 'subclinical' hypothyroidism in childhood and adolescence. Arch Pediatr Adol Med 1996;150:293
5. Diez JJ, Iglesias P: Spontaneous subclinical hypothyroidism in patients older than 55 years: An analysis of natural course and risk factors for development of overt thyroid failure. J Clin Endocrinol Metab 2004;89:4890
6. Knudsen N, Laurberg P, Rasmussen LB, et al: Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab 2005;90:4019
7. Soldin SJ, Morales A, Albalos F, et al: Pediatric reference ranges on the Abbott IMx for FSH, LH, TSH. T4, T3, free T4, free T3, and T-uptake. Clin Biochem 1995;28:603
After reviewing this article, the physician should be able to:
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Target audience: Pediatricians and primary care physicians
Understand the basic pathophysiology of thyroid dysfunctionj
Describe the indications and limitations of available tests of thyroid function
Recognize what symptoms and test results do and do not warrant referral to a pediatric endocrinologist
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Author Paul Kaplowitz, MD, PhD discloses that he does not have any financial relationships with any manufacturer in this area of medicine.
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