This post continues our opening series on “Developing Infographics for thyroid testing.”
In this post I discuss the scientific basis and potential usefulness of an infographic meme on “Screening for hypo, before therapy begins.”
Q: Why doesn’t this meme mention antibodies? A: This one is not about diagnosing autoimmune etiology. First we need to know if they are hypothyroid or not if they are presenting with signs and symptoms of hypothyroidism. Then the next step is to figure out what is causing it.
Q: Why doesn’t this meme question the “TSH <10 vs. >10” arbitrary upper boundary of the “subclinical” hypothyroidism category? A. We could have questioned it, but it’s not worth fighting over in this meme. It would be just as arbitrary for us to choose a TSH of 12 or 9 to spite tradition. Higher TSH may be found people with TSH-secreting pituitary adenomas and resistance to thyroid hormone (RTH), but their conditions usually present with signs of hyperthyroidism or euthyroidism.
The most important aspect of this meme is to be rigorous about discovering true hypothyroidism below a TSH of 10, where hypothyroidism does indeed exist for some people who are unable to secrete enough TSH.
Q: Why doesn’t this meme say that TSH needs to be “high,” at least above reference range, for hypothyroidism to exist? Because hypothyroidism also exists within the normal TSH reference range and below it.
Dr. Luca Persani and Dr. Paolo Beck-Peccoz, leading European endocrinologists in the field of central hypothyroidism, would stand with us on this point.
The “TSH Reflex method” is one in which Free T4 is only tested when TSH falls outside of the normal range.
This policy cannot identify central hypothyroidism because the diagnosis requires both TSH and Free T4 measurement.
We draw the lower boundary for hypothyroidism no higher than the lowest the TSH can fall, 0.001 mU/L, because some patients have a genetic condition that causes them to synthesize an undetectable yet bioactive form of TSH (Rahimkhani et al, 2020).
Some patients have an isolated TSH deficiency. Their other pituitary hormones are all normal, but they can have genuine hypothyroidism, with a Free T4 below reference (Cho et al, 2012) or a Free T4 that is within the lower part of reference that is not capable of being raised by their TSH.
If a patient’s Free T4 falls lower within reference range while their TSH is low or undetectable, such patients may indeed be hypothyroid, for all we know, but because of their inability to secrete measurable TSH in the reference range, they may be misclassified as the very opposite of hypothyroid — “subclinically hyperthyroid.”
We must stand in solidarity with all patients whose hypothyroidism will be overlooked and misunderstood because of their inability to secrete TSH above the reference range. Their health is at stake within our TSH-only testing policies.
Q: How do we justify performing the FT3 test? It is often dismissed because it is likely to be within reference before therapy, even in central hypothyroidism. A. This is a meme whose goal is to screen for hypothyroidism of all kinds.
People who deserve screening for hypothyroidism are suffering from its symptoms and signs. We should do what we can to either discover, or thoroughly rule out, even “tissue hypothyroidism” which is present when T3 concentrations are low, such as in nonthyroidal illness (NTIS).
In some cases, the low T3 could be a sign of an undiagnosed chronic illness, such as a cancer, and this might be the first clue that something is wrong.
In nonthyroidal illness, the TSH and FT4, both independently and in relationship, are unable to identify tissue hypothyroidism. T3 concentrations, whether Total T3 or Free T3, within reference range are independently capable of predicting poor health outcomes in the context of many known chronic and critical health conditions.
T3’s predictive value increases when T3 is analyzed in relationship to Free T4 concentrations.
The health significance of low Free T3 concentrations within reference remains strong even after excluding people deemed hypothyroid by traditional TSH-T4 definitions.
If TSH or T4 could truly detect this form of hypothyroidism, T3 concentrations would not so boldly disagree with them.
To provide one example among many, a retrospective study on heart failure in 2017 by Kang and colleagues excluded all patients with diagnoses or treatment for thyroid conditions, and nevertheless found the average Total T3 of 30 patients with heart failure was 84.32 ± 21.04 and of 735 patients without heart failure was 101.20 ± 20.30. Both values were within the laboratory reference range of (80 to 200 ng/dL).
Even though their T3 was not “low,” not below reference range, it was low enough to identify their tissue hypothyroidism.
Further, the ROC curve analysis showed that the cut-off values of total T3 for predicting the 1-year HF was ≤ 85 ng/dL. Again, the cutoff is within reference range.
In addition, the sensitivity, specificity and negative / positive predictive value of Total T3 “were slightly augmented by using a composite marker, T3/fT4, compared to a single marker, total T3 level.”
Therefore, T3:T4 ratios within reference are just as significant as absolute values of T3 within reference, when discovering tissue hypothyroidism.
Many other traditional biomarkers were used in the study, including TSH and T4 and cardiovascular measures, but T3 and the T3/FT4 ratio were the most significant values correlated with “1-year major adverse cardiovascular and cerebrovascular events” in their population.
Kang and colleagues called this type of lower-T3 hypothyroidism “tissue hypothyroidism,” explaining in their discussion section that
Paradoxically, studies like Kang’s occasionally show that patients have higher risk when T4 is higher in reference at the same time that T3 is relatively lower in reference compared to healthy controls.
They explain that after a myocardial infarction (heart attack), Free T4 levels often rise while T3 falls. The higher the Free T4, the lower the T3/T4 ratio will be, and the lower ratio is predictive of greater health risk.
In the context of their cardiovascular health risk, patients with “normal” levels below 85 ng/dL were were hypothyroid enough to die, but they were not hypothyroid enough to fit standard definitions focused on a thyroid gland’s capability to secrete T4 when commanded by TSH.
Studies like these, by excluding classically hypothyroid individuals, fail to inform us of the degree to which their diagnosis was more or less significant to their mortality than their T3 levels and T3/T4 ratio. Nevertheless, by excluding those with the classic diagnosis, they are capable of seeing a hypothyroid T3 level within reference range. The T3-based “tissue hypothyroidism” produced and maintained by a post-heart attack metabolic failure is indeed hypothyroidism.
Gland-based hypothyroidism (hyposecretion)
Even when one attempts to narrowly assess thyroid-gland-based and pituitary-gland-based hypothyroidism as syndromes of hormone hyposecretion rather than dysfunctional metabolism, it’s clear that FT3 supplies useful analytical data for diagnostic outcomes in steps 3 and 4.
When a doctor faces the diagnosis of a patient who is fortunate enough not to experience a nonthyroidal illness, the hypersecretion of T3 and increased T4-T3 conversion is often a telltale sign of a particular causes of thyroidal hyposecretion, most commonly Hashimoto’s thyroiditis.
Q: Why only list central hypothyroidism and nonthyroidal illness? A. In a “subclinical hypothyroidism” diagnosis, these are two high-priority thyroid conditions that can be blurred with the more common third condition of early primary autoimmune thyroid gland failure.
Q: Why feature SPINA-Thyr analysis? A. SPINA-Thyr (as explained in the Dietrich, 2016 citation on the meme) provides a more refined analysis of the mathematical TSH-FT4 relationship and the FT3:FT4 ratio, in light of clearance rates and population characteristics.
Employing SPINA makes better use of laboratory test results, enabling careful distinctions between these three conditions and even their overlap.
The T3:T4 ratio and TSH-FT4 relationship are diagnostic tools that can aid in distinguishing primary, secondary, tertiary, and tissue hypothyroidism and potentially even discerning when two or more forms coexist within a patient.
Usually TSH and FT4 are broadly categorized as merely by being “in range” in FT4 and “out of range” with TSH. This is not very informative. As with the T3 hormone, the human body does not look at population ranges and decide whether to step over an invisible line in the sand to inform us of a crisis in thyroid hormone supply.
Thyroid hormones and TSH interact with each other and express meaningful patterns by their ratios. For example, if TSH is largely non-bioactive as it is in hypothalamic hypothyroidism, the reduced TSH signalling in the thyroid will produce a lower FT3:FT4 ratio, as revealed in the GD. This ratio will be significantly lower than in primary hypothyroidism caused by Hashimoto’s thyroiditis. In turn, the FT3:FT4 ratio in Hashimoto’s will be significantly higher than in persons with a healthy thyroid who have a nonthyroidal illness. NTIS in a healthy-thyroid population can invert their FT3:FT4 ratio, reducing T3 while maintaining relatively higher concentrations of T4 at all times. Even after Total T4 falls below reference in some cases of severe NTIS, Total T3 will be relatively lower.
If you combine primary hypothyroidism with NTIS, you may see the conflict between the high T3:T4 ratio of Hashimoto’s and the low T3:T4 ratio of NTIS result in a hormone ratio that falls in between the two extremes. The absolute values and ratios of TSH, FT4, and FT3 would aid in further interpretation of thyroid gland function and metabolic dysfunction.
Learning how to use SPINA is exciting and mind-expanding for doctors and curious thyroid patients. They let you see your hormones an entirely new way, and they inspire us to ask new, important questions about what most powerfully defines hypothyroidism — the thyroid’s T4 hormone secretion rate, the body’s T4 hormone conversion rate and pathway, and/or T3 and T4 signalling and TSH synthesis in the hypothalamus and pituitary?