I apologize for not having an endocrinology-based entry for quite a while. I do appreciate the many nice comments I have received on past entries. I will try to write something interesting and useful on a more regular basis. Anyway, on to the business at hand. The past few months I have had a number of e-mails from physicians asking my advice about interpreting what seem to be bizarre thyroid test results. The most common situation is a mildly elevated thyroid-stimulating hormone (TSH) level and a high end of normal or even elevated free thyroxine (FT4) level. The second most common scenario is a low TSH level coupled with a low or normal FT4 level. In past entries I have touched on these types of apparently discrepant thyroid test results, but I think it is worth discussing them again and in more detail.
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.
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