…article continued:
Laboratory Examination
Our history and physical examination having identified patients who may have thyroid trouble, we trust the laboratory for confirmation. Quoth the Expert: “In the majority of patients, thyroid disease symptoms are subtle… so only biochemical testing or cytopathologic evaluation can detect the disorder.”49
We are very fortunate to have an excellent variety of tests from which to select—more options than most providers understand how to use! The information they offer affords us a medical version of “measure twice and cut once” and helps to avoid therapeutic surprises. I prefer to order thorough testing, not a “bare-bones” work-up, although minimalism is officially encouraged.50
Physicians are concerned about the cost of laboratory tests. Lab bills to insurance look expensive but insurance pays a small fraction. Uninsured patients can get tests affordably from direct-to-consumer labs online. These results give accurate diagnosis (priceless) and prepare us to anticipate complications as we initiate treatment, and prevent disappointments—ultimately a great savings.
Before You Test
Even the best laboratory tests are vulnerable. “Pre-analytical errors” are largely avoidable.51 Ask patients to stop biotin supplements 48 hours before the tests: Doses of 5 mg/ day can interfere with most immunoassays and may produce wholly misleading results.52 We should enquire about other potentially interfering agents: Steroids, OCP and HRT; amiodarone; “hormone-free glandulars” (which legally can contain T3); large lithium doses and iodine supplements greater than 1.1mg/ day.53 Remember that patients may be unaware of taking even large doses of iodine – or may, for their own reasons, withhold information about taking thyroid hormone.
“Analytical errors” occur, producing misleading assays. Immunoassays are vulnerable not only to biotin but to “heterophile” antibodies—immunoglobulins produced by the patient’s immune system that cross-react with the assay components.54,55 When needed, liquid chromatography/tandem mass spectroscopy is a better method.56 Blood spot assays are for screening newborns…I don’t trust them for this work.
Perhaps the most important issue is post-analytical error, which could be paraphrased: The ordering Doc doesn’t know what the results mean.57 Even the most basic test, TSH should not be taken simply at face-value.
Thyroid Stimulating Hormone
An accurate TSH assay shows how much of that hormone was recently released from the pituitary gland (its half-life is six hours). When the thyroid gland is diseased, TSH becomes abnormal before freeT4 does; therefore, it is considered the “gold-standard” diagnostic test of hypothyroidism.49 However, a thyroid-stimulating hormone assay doesn’t prove normal or abnormal thyroid hormone function.
Researchers state TSH is “neither normatively fixed nor a precise marker of euthyroidism.”58 At best, it reflects the freeT4 concentration that acts on the hypothalamus and influences the pituitary.49
There are other issues with the TSH test. Clinical laboratories do not use a truly scientific “normal range” of TSH values.59 Analysis by the statistical method shows the median TSH value is 1.5 µIU/L and the reference interval (-2SD to +2SD) should be 0.40 to 2.90.49 However, the upper limit of “normal” has been extended to bring the reference-interval into line with expectations based on treatment results. In the last twenty years, the upper limit has been reduced from “10” to “4.5” in most national labs…but statistically, TSH = 3.0 is a high value.
TSH results can be misleading in other ways: Major issues include heterophile antibody interference and importantly, the abnormal amplitude of pulsatile TSH-secretion when the gland is damaged (“spikiness”). This was demonstrated in the laboratory60,61 and can be observed in mildly hypothyroid patients.62 Other complex issues have been raised that are beyond our present scope.63,64
The error of depending on TSH alone was demonstrated in a medical malpractice case: A woman was declared hyperthyroid because her TSH was low and her gland was ablated with radioiodine-131. She did badly on replacement therapy, so she was referred to an “Ivory Tower” endocrinologist. He also relied on TSH to regulate her T4 dose with similarly poor results. A few years—and a few doctors—later, an Emergency Department CT scan identified the adenoma crushing her pituitary and impairing her ability to make TSH.
Physiology 102: Thyroid Hormones
Most authorities state tests for thyroid hormones are unnecessary, unless the TSH value lies between 5 and 10 (when low fT4 distinguishes “true” from subclinical hypothyroidism) …but I disagree. The TSH assay gives incomplete information and is prone to unreliable values. For these and other reasons, I also test thyroid hormones: freeT4, freeT3, totalT3 and reverse T3 (RT3). Reviewing more physiology will help readers to understand why. Let’s get to know the players.
The “fully-loaded” thyroid hormone carries four iodine atoms. It is called 3,5,3’,5’-tetraiodothyronine (T4) and it is the most abundant (90%) of the three main hormone-products released by the thyroid gland.65-67 The other two have three iodine atoms, lacking one on the outer (T3) or inner rings (reverseT3). Like the teeth on a key, the positions of the iodine atoms determine the functions of these variants.
We’ve seen that after release from the thyroid gland, the great majority of thyroid hormones are carried on proteins.68 This permits their passage in the aqueous (watery) bloodstream,69 and protects them from spilling out through the urine and from being broken down in the liver. Importantly, it also maintains a large, inactive but ready-reserve of hormone.
Modern assays are so sensitive they can accurately report the tiny amounts of free T4 and T3 (down to 2 pg/mL—that’s 10-12 of a gram!). Most practitioners, knowing that only free hormones can enter cells,70 order “free” hormone tests, not “total.” Besides, “total” measures are significantly distorted by anything altering the liver’s production of these binding proteins, including oral contraceptives, pregnancy or women’s hormone replacement therapy; liver or kidney disease; insulin resistance, and severe illness.
T4 is a pre-hormone and T3 is active.
Most importantly, as you provide and monitor patient care, remember: T4 is a pre-hormone with little genomic effect. The 19th-and-20th-century focus on the thyroid gland only—its ability to produce T4—is no longer adequate. We must know how the pre-hormone is being “processed.”
To activate T4, cytoplasmic deiodinase enzymes within the cells of many tissues71 remove one iodine atom from the outer, “prime” ring, making T317 (See Figure 1).Why does the gland release a pre-hormone instead of making all active T3? For the same reason Campbell’s puts soup in cans instead of steaming hot bowls: It is safer to transport; it has a long shelf-life; and you should be able to open it anytime you want.
As stated, T3 “sets the thermostat of the metabolism.” Its genomic effect stimulates every DNA program that increases cell metabolism and activity—and impedes the DNA programs that slow them.
Conversely, removing one iodine atom from the inner ring of T4 makes reverseT3 (RT3), which everyone agrees has absolutely no stimulatory effect and cannot be retro-converted to T3 (Figure 1). Increased RT3 has long been noted to indicate an adaptive down-regulation of thyroid hormone effect during stress (injury, illness, starvation, or psychological distress).72-74
Remember this paragraph Thus, the deiodination of T4 to either T3 or RT3 determines thyroid hormone function at the cellular level.71 This “processing” of T4 is tightly controlled75,76 and it is the primary means of regulating the biological activity of thyroid hormone.20 The best indicator of this is the ratio of T3 to RT3, both in clinical use and in research.77,78 Blood tests of these hormones are reliable too, accurately reflecting their values in tissue samples.79
Calculate the Ratio of T3 to RT3
Even using the best assay (LC/MS-MS), there is too little free reverseT3 in the blood to be measured; thus, “totalRT3” is reported. Because the amounts of binding proteins are so variable, the critical T3:RT3 ratio must be calculated comparing RT3 to totalT3—apples-to-apples, total-to-total. Efforts to compare freeT3 to RT3 are ultimately doomed to fail—as I learned years ago, when a congenitally athyreotic patient became pregnant.
The relative amounts of T4 and T3 within their “normal” ranges and the totalT3/totalRT3 ratio show how the body is processing its hormones. The value of analyzing these multiple parameters has been supported.80 Patient 2will show their clinical significance (Table 1): If T4 is a “can of Campbell’s soup,” does the body have a can-opener?
Examine the values for all five tests I’ve recommended in the same critical way a basketball coach watches his five players on the court: Is each one where he should be and doing his job? Are all five coordinated and running the same play—or is someone out of synch and hurting the team?
