Rationale: Reference ranges

Updated 2018-07-09

Reference ranges vs. set-points

In medical practice, the laboratory reference range is the measure used to define the hypothyroid state, and it aids clinical decision-making.

With any blood test reference range, is easy for a doctor to forget that “normal” is based on a statistical calculation of 95% of the norm, but the average could be anywhere within that range, and the average may differ based on sub-populations.

A Free T3 near the bottom of reference range may be seen in less than 5% of healthy humans, but many a doctor will deem it “normal” for a patient to remain with borderline low T3 for decades, unaware that in a normal-thyroid patient, such lows would be temporary (only during illness).

During health, the average Free T3 level is in the mid to upper half of reference, as seen in the levels of 3,875 healthy, untreated euthyroid controls in Gullo et al’s 2011 article on levothyroxine monotherapy. [60]

Likewise, TSH values above the reference range are rare, seen in less than 5% of healthy humans, but in many cases, patients are declared “subclinically” hypothyroid (doctors are told to refrain from a diagnosis and withhold therapy) until their TSH exceeds 10 miU/L.

Today, thyroid therapy is held hostage to the tyranny of statistical reference ranges and patients are suffering from doctors who are unaware of the controversies.

Individual set-points

From the perspective of the biological organism, a state of thyroid hormone deficiency or excess is NOT relative to a population-wide statistically determined reference range, but is rather relative to that individual’s “set-point” for euthyroidism.

Thyroid hormone references are very unlike most other blood test reference ranges.[52] Most reference ranges are the same for individuals as well as the population, but for T3, T4 and TSH, the healthy “set point,” the healthy range of variation, for any single individual covers a range that is approximately 50% narrower than the statistical reference range. [64, 61, 51]

A 50% narrower individual set point means that if a patient’s thyroid hormones fall in the lower quarter of “normal” range, or their TSH is in the upper quarter of normal range, there is a much greater chance that they could be suffering biochemical hypothyroidism.

Hypothyroid patients on therapy may be forced to spend years or decades outside of their healthy set point. In their body, the TSH cannot sensitively adjust their damaged or missing gland’s secretion. They are dependent on a static dose from day to day. They cannot as easily change their hormone levels when they are stressed, exercising, or cold. Their dose has to be precisely adjusted so that it is not putting them on the edge of hypo- or hyperthyroidism, but as much as possible in the center of a narrower range of euthyroid levels.

Upper limit of “normal” TSH

Researchers have also argued that the TSH upper reference limit is biased against the detection of hypothyroidism in patients and is more sensitive to detect hyperthyroidism. [68]

It is well known that the upper limit of the normal adult TSH reference range is both arbitrary and controversial. In the early 2000s the upper boundary was 10 mIU/L, whereas now, it is usually set between 4.0 and 5.0 depending on the country and laboratory. The reference interval even depends on the population’s consumption of iodine.

While the upper limit is controversial, the average TSH level is not. There is a huge peak in the population curve between 0.4 and 2.5. The vast majority of the healthy population has TSH levels below 2.5 mIU/L, and the average is approximately 1.5 to 1.6. Accordingly, “In 2005, the National Academy of Clinical Biochemistry (NACB) … suggested that the upper limit of the TSH reference range be lowered to 2.5 mIU/L.” [69] In 2006, a study concluded that “a target TSH level of less than 2 might be advisable to lower CRP levels and homocysteine levels, and possibly lipid parameters.”[70]

Such recommendations to lower the upper TSH boundary have not been adopted because, given the current dominance of TSH alone in screening, scientists know that it would result in too many false positives. “About 20–26% of the population would be hypothyroid if the upper limit of the normal range is lowered to 2.5–3.0 mIU/L,” [69] and indeed, in a healthy person, a temporarily high TSH will effectively stimulate an increase in thyroid hormone secretion, rather than indicate a deficiency.

Few stop to consider whether the TSH debate has continued for so long because it is not an invariable indicator of hypothyroidism, for if it were, the debate would have been settled long ago.

In our current state in which TSH is the only indicator measured in screening, women with autoimmune hypothyroidism are at higher risk of suffering from a delayed diagnosis. TSH is a far more sensitive indicator of subclinical hyperthyroidism than it is of subclinical hypothyroidism, and is less sensitive in indicating hypothyroidism in women and the elderly.

Because TSH is normally higher for men than women, male TSH will more easily rise past the upper boundary of normal reference range. One study found that women with higher TSH were more likely to shift from subclinical to overt hypothyroidism. [71] The higher risk for women’s diagnosis to be delayed is compounded by the fact that autoimmune hypothyroidism is far more prevalent among women than men.

If the TSH reference range is biased against the detection of hypothyroidism, one may predict that the Free T3 and Free T4 reference ranges are also skewed to include values that are inappropriately low.

Altered HPT axis

The standard belief about the HPT axis (Hypothalamus – Pituitary – Thyroid axis) is that the TSH is capable of telling us where exactly within the “normal” range an individual should be when they are euthyroid in their T4 and T3 levels.

However, to start with, the set point even in healthy human beings is not a univariate (single-variable), linear index based on TSH alone, but is well known to be a relationship between TSH and T4, and more precisely, between TSH, T4 and T3.

TSH and Free T4 cannot be used to estimate T3 levels because TSH and T4 are not the only drivers of T3 levels in serum. [72] Three deiodinases are in control T4 conversion to T3 in bloodstream and within tissues; their activity is influenced by each other’s activity, and these enzymes respond directly to the availability of T4 as well as other hormones and substances. [73

Therefore, at the heart of the problem for symptomatic hypothyroid patients is the well established fact that the standard L-T4 monotherapy therapy causes a TSH-T3 disjoint in patients, and that disjoint increases in those who have little or no thyroid tissue. [74, 75, 60] Because of this disjoint, free T3 levels can drop below an individual’s normal set point as well as below reference range, and paradoxically, T3 can become lower as T4 rises in the normal range. [60, 62, 76]

Mild TSH suppression may be an unexplored a side-effect of the artificial nature of oral dosing. The hypothalamus and pituitary are designed to adapt to natural thyroidal secretion and conversion which occurs in a gentle circadian rhythm. However, L-T4 doses cause an artificial rise in Free T4 levels in serum which peak at 2-3 hours. This peak parallels the much greater artificial rise of Free T3 levels in patients who are dosing L-T3. The difference between thyroid hormone dosing and natural T4 and T3 thyroidal secretion may indeed be responsible for this different TSH-T3 relationship researchers have described in treated patients vs. controls.

When T3 is low but T4 is normal, TSH will not rise appropriately to indicate the deficiency of T3. This TSH-T3 disconnect is seen not only in heart failure and critical illness, but also in supposedly healthy patients on L-T4 hormone therapy. [51, 65, 60]

Another reason TSH does not respond well to low T3 is that the pituitary gland is designed to survive low T3 due to its high expression of Deiodinase type 2. In the low-T3 state, “T3 levels in the pituitary are normal because of enhanced local deiodination. Thus the pituitary is actually euthyroid, while the rest of the body is hypothyroid.” 81 (p59) Thus the pituitary gland can be protected from and blinded to a T3 deficiency that exists outside of its own tissues. Therefore, neither TSH nor T4 levels are capable of assessing the chronic T3 deficiency commonly seen in thyroid disease and treatment.[62, 59, 50, 75]

Due to the shifts in the HPT axis in disease and therapy, “the same TSH value could be normal for one individual but pathological for another.” [36 (p178)] In fact, TSH is such a variable indicator that “differences in thyroid function within the euthyroid TSH reference range are associated with negative health outcomes.” [69]

If doctors applied a mathematical guideline or chart to determine the abnormal “gap” or “contradiction” between TSH, FT4 and FT3 in relationship (for example, a very low-normal Free T3 appearing with mid- or low-range TSH while on therapy), they would be more able to discern whether an individual is suffering hypothyroidism despite a “normal TSH.” If they took into account that thyroid hormone dosing can artificially suppress TSH and that TSH can be blind to low or suboptimal T3, their diagnostic discernment would be much more accurate.

Subclinical hypothyroidism

“Subclinical” hypothyroidism is a very controversial category that is of questionable utility in clinical practice.

The “normal” response between TSH pituitary hormone and T4 thyroid hormone expresses what is known as the hypothalamus-pituitary-thyroid (HPT) axis.

The HPT axis was once believed to be perfectly linear, but more recent research has shown that it is not, even among healthy subjects. There are variations.

Sex and age significantly affect the HPT axis, as well as other factors such as smoking and TPO antibody status.[78] For women and elderly patients, TSH is lower on average when the T4 concentration is identical to the T4 level in a healthy male or young adult.

There are clinically important points of physiological stress at the upper and lower edges of the “normal” TSH range where TSH response is dampened or exaggerated.

As T4 depletion occurs and TSH is in the upper-normal reference range, the TSH is markedly slower to rise along with each equal drop in T4 concentration. Conversely, as T4 excess increases in hyperthyroidism, TSH is far more suppressed for each decrease in T4. [79, 80]

This dampened effect on TSH secretion in the state of subtle hypothyroidism is thought to be due to temporary compensatory mechanisms that attempt to increase T3 levels (the upregulation of Deiodinase type 2, stimulating more conversion to T3). This occurs in early autoimmune hypothyroidism in persons with a still-functional thyroid gland. [75] However, at a certain point in T4 deficiency, which is different for each person and different for each sex and age group, compensatory mechanisms break down and TSH once again begins to rise in response to loss of T4.

As a result of these distortions, controversy exists. Current definitions vary widely among researchers and regions, but they usually begin with an “abnormal” TSH level defined by the “normal” reference range. Next, the classification of “subclinical” is applied if either, or both, T4 or T3 are anywhere within their “normal” reference ranges. [81, 64]

The term “subclinical” once used to mean a patient was without symptoms as well as clear laboratory test results, but now patients’ symptoms, T3 levels, and individual set points are ignored, and TSH, and secondarily T4, and the population-wide reference ranges have taken over the definition entirely.

Because of the problematic definition of “subclinical” thyroid disease, we have arrived at a system that can place hypothyroid, hyperthyroid and euthyroid patients within this category: “subclinically hypothyroid patients … comprise a heterogeneous population of truly dysfunctional and truly euthyroid subjects.” [52]

Some doctors have even misapplied the term “subclinical” to patients on thyroid therapy. This is a category meant only for diagnosis prior to the initiation of therapy, and it is not meant to be applied after thyroid hormone therapy artificially manipulates the HPT axis.

Subclinical hypothyroidism is therefore a clinically dubious category and harmful for the truly hypothyroid patients left to languish within it. Testing Free T3, testing for thyroid antibodies, and listening to patient symptoms can help to discover the patients who are trapped in this gray zone, suffering without a diagnosis or therapy.

 

References

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