Every week I give lectures to the medical students and resident physicians rotating through the Division of Pediatric Endocrinology. I try to keep things pretty informal and I usually do the talks using a case history format. I suggest a number of topics, such as growth, sexual development, calcium metabolism, fluids and electrolytes, thyroid disorders, and various diabetes mellitus topics. It is rare that the group picks thyroid disorders as the discussion topic. My theory is that the students and resident docs think they know enough about thyroid disorders, and that I should focus on something they are not so confident about. I have to “bite my tongue” to keep from telling them that they actually don’t know as much as they need to know about diagnosis and treatment of thyroid disorders, particularly, hypothyroidism.
The principal thyroid hormones, tetraiodothyronine (T4) and triiodothyronine (T3) play critical roles in many aspects of cellular metabolism. Under normal circumstances, their secretion from the thyroid gland is tightly regulated by a classic negative feedback mechanism. The thyroid gland sits in the neck, just below the cricoid cartilage. It consists of an isthmus that bridges the trachea and two lateral lobes. The gland is a busy factory for the production of T 4 and T3, although most T3 is formed in the liver from T4 by a process called monodeiodination. Both hormones circulate tightly bound to serum proteins: albumin; thyroid-binding prealbumin (only T4); and thyroid-binding globulin, which has the most affinity for both T4 and T3. T4 is much more tightly bound than T3- 99.99% vs. 99.90%. Only the unbound or “free” hormones are biologically active and bind to specific intracellular receptors. T4 and T3 are metabolized to inactive products by successive monodeiodinations. It is also important to know that T4 can be monodeiodinated in the liver to T3 or to reverse T3 (rT3), which is not biologically active. It is rather amazing that the body somehow knows to convert more T4 to rT3 than to T3 when the serum T4 level is elevated.
The final piece to this engineering marvel resides in the brain. The hypothalamus secretes a hormone called thyrotropin-releasing hormone or TRH. TRH travels through the pituitary portal vascular system to the anterior pituitary, where it stimulates secretion and release of thyrotropin (also called thyroid-stimulating hormone or TSH). TSH in turn finds its way to the thyroid gland, where it binds to specific receptors on the plasma membrane of the thyroid follicular cells. Then, through a cyclic adenosine monophosphate (cAMP)-mediated process, TSH stimulates secretion and release of T4 and T3. Are you still with me? I bet you already know all of this stuff. The beauty of this system is that circulating T4 and T3 “feed back” to the hypothalamus and anterior pituitary gland, regulating their secretion. So, if the circulating T4 and T3 levels drop even a little bit below normal, they let the brain know that it had better step up secretion of TRH and TSH. Assuming that the thyroid gland is normal, the increased TSH secretion brings the circulating levels of T4 and T3 back to normal. If the circulating levels of T4 and T3 are elevated, the opposite thing happens: the brain gets the message that it had better decrease the secretion of TRH and TSH. That’s all there is to it. It only becomes a problem if part of this wonderful system is not working properly.
Laboratory Testing: Historical Perspective
Now days it is pretty easy to determine if a patient is hypothyroid. Except in rare situations, measurement of serum free T4 and serum TSH is all that it takes. If both test results are in the normal range, the patient should be considered to have normal thyroid gland status, or to be euthyroid. If the free T4 is low, the patient should be considered hypothyroid. If in this instance the TSH is elevated, the patient has primary hypothyroidism. If the TSH is normal or low, the patient has secondary or tertiary hypothyroidism, the result of hypothalamic or anterior pituitary dysfunction, respectively. Finally, if the TSH is elevated, but the free T4 is in the normal range, the patient’s hypothyroidism is considered “compensated.” That is all there is to it. We endocrinologists often deal with the very small percentage of cases that don’t “follow the rules.” For example, a condition called thyroid resistance syndrome can make it tricky to figure out what’s going on. But, remember, these types of situations are the exception to the rule.
It was not always so easy to assess a patient’s thyroid status. In 1965, when I first started seeing patients, measurement of serum TSH was not widely available nor was it well standardized, and was subject to interferences. The only way to estimate serum T4 was by measuring serum protein-bound iodine (PBI). This test worked by ashing a serum sample and measuring the iodine content. It measured T4 and T3, but also iodotyrosines, thyroglobulin, iodine bound to non-specific proteins, and some dyes or drugs that contained iodine. A useful variation of the PBI was the butanol-extracted iodine test BEI), which eliminated all of these iodine compounds except for thyroglobulin and some iodinated dyes. Under normal circumstances, the PBI was about 1 microgram/dl higher than the BEI. If the difference between the PBI and BEI was greater than 2 micrograms/dl, this meant that the PBI was not accurately estimating the T4. This situation occurred often in patients with chronic lymphocytic thyroiditis (CLT), and with a consistent physical examination of the thyroid gland, was considered more or less diagnostic of CLT. We did have thyroid antibody tests then, but many patients with biopsy proven CLT had negative thyroid antibody test results.
I have not yet mentioned the problem back then with alterations in the serum proteins to which T4 and T3 were tightly bound. For example, if a woman was pregnant or taking estrogens, the TBG concentration would be elevated. In such a situation, if a woman were euthyroid, the PBI would be elevated, but the TSH would be normal. Or, if a patient had a genetic disorder with low TBG, the PBI would be low, but the TSH would be normal. Fortunately, we did have a test that measured the thyroxine-binding capacity of the plasma. The degree of saturation of the thyroxine- binding proteins could be assessed by addition of radioactive T3 to the plasma, and then adding a resin or red blood cells. Measurement of the amount of radioactive T3 taken up by the resin or the red blood cells was a useful estimate of the degree of saturation of the plasma proteins with T4 and T3. So. in a patient taking estrogens whose PBI was elevated and whose TSH was normal, a low radioactive T3 uptake by the resin or red blood cells, meant the patient was euthyroid, not hyperthyroid. Did I confuse you? If so, don’t worry about it, because now days, measurement of free T4 eliminates the need for the T3 radioactive uptake test.
Treatment of Hypothyroidism
Back in the 1965, the only way to treat hypothyrodism was with dessicated thyroid. This was ground-up animal thyroid, which contained all sorts of stuff, including T4 and some T3. Now days, the standard treatment for hypothyroidism is to use synthetic T4 (L-thyroxine). I am not aware of any compelling data in the prevailing medical literature to show that the brand name T4, Synthroid, is any more efficacious or safe than generic L-thyroxine. As you would expect, the goal is for the patient to have a serum free T4 and serum TSH in the normal range. A typical dose for an adult is 100-125 micrograms daily. Some argue that we should treat patients with either ground-up animal thyroid, which contains T4 and some T3 or a mixture of T4 and T3. This argument makes no sense since the body will make all the T3 it needs, which is basically how things work in people who are euthyroid and take no thyroid medication. Others argue that if a patient still has signs and/or symptoms suggesting hypothyroidism, despite normal free T4 and TSH levels, the patient’s thyroid dosage should be increased. Does that make any sense to you?
Diagnosis and treatment of hypothyroidism is pretty simple these days. I just wish all health professionals knew that. We still need to talk about the various causes of hypothyroidism, how they present and how to diagnose them, but that can wait for another entry which I will post in the near future. You may want to look through the my blog archives, since I have already written quite a bit about thyroid disorders. One other thing. In the unlikely event that a patient’s thyroid test results make no sense at all, such as a very, very high TSH and a normal free T4 or a very, very low TSH with a normal free T4, it may be time to call in an endocrinologist, as we tend to deal with weird things all the time.
- Hemoglobin A1c: Is Lower Always Better?
- Diagnosis and Treatment of Hypothyroidism in Children and Adolescents: Part 2