Here is a common moment that occurs now and then in doctor’s offices. The physician looks up from their computer screen and tells the patient,
“Your thyroid function tests came back normal, so nothing is wrong with your thyroid.”
That statement reveals the dismal state of medical ignorance about normal-range thyroid lab results.
It’s not entirely the physician’s fault, because thyroid ignorance is built into health care systems.
When I recently tried to write a series of posts about How to analyze an untreated person’s “normal” thyroid lab results, I realized another series was needed first, as a prelude.
Cognitive barriers prevent a person from seeing the value of analysis. It requires a series just to address the barriers.
“Cognitive biases” are a pervasive problem in medical diagnosis, according to the Canadian Medical Protective Association (CMPA). These biases skew a physician’s thinking while analyzing laboratory test results. They can lead to a failure to diagnose and misdiagnosis.
A cognitive bias is like a preference to go through one door rather than another.
A cognitive barrier means certain doors to deeper knowledge are locked or entirely hidden from view.
Any cognitive “bias” can become a cognitive “barrier” when it prevents one from examining the medical evidence that is right before their eyes – normal-range TSH, FT4, and FT3 lab data.
The health consequences of these barriers can be significant. Strong, rigid beliefs about “normal-range” TSH, FT4, and/or FT3 results blind physicians to thyroid hormone health risk, thyroid disorders, pituitary TSH secretion disorders, and most of all, deadly thyroid hormone metabolic disorders that lurk within the reference intervals.
Series summary
- Series introduction [this post]
- “Are normal thyroid reference ranges risk-free zones?“
- “What’s wrong with calling TSH, FT3 and FT4 “thyroid function tests”?“
- “Can a normal TSH rule out thyroid disease?“
In this introductory post I provide a brief comparison across medical fields. I outline how scientists and policymakers in other diseases — kidney, heart, and liver failure — treat “normal range” values with skepticism. I raise the question why thyroid medicine still clings so tightly to the clinical and diagnostic significance of its normal reference ranges, and why it establishes a hormone hierarchy not seen in the diagnosis of other diseases.
The first barrier is the belief that “normal” range is a zone where thyroid hormones and TSH pose no health risk for any non-thyroidal disorders. For a long time, scientists have ignored non-thyroidal disease risk within the FT3, FT4 and TSH ranges because it is quite clear that very abnormal levels are riskier for untreated people than are normal levels, relatively speaking.
But science is now revealing that imbalanced yet normal thyroid hormones and TSH can negatively affect cardiovascular health, kidney health, liver health, and so on.
Secondly, the common phrase “thyroid function test” is a cognitive barrier. It narrows the mind by narrowing the purpose of the test. It focuses on one corner of the HPT axis, the corner that is most accessible to examination and easiest to blame. But analyzing two or three hormones at once enables you to gain perspective, just as using two eyes instead of one enables you to judge depth and distance.
In the hands of an intelligent analyst, the TSH, FT4 and FT3 tests uncover the fine distinction between thyroid gland health and tissue thyroid hormone status, a distinction that is too often collapsed and misunderstood as being synonymous. They also help one evaluate pituitary (and hypothalamus) function as well as peripheral thyroid hormone metabolism.
The third barrier is the belief that a normal TSH has the power to single-handedly rule out almost all thyroid disorders except so-called “rare” pituitary disorders and thyroid cancers. But once you’ve gotten rid of the first and second barriers, this barrier to knowledge is much easier to get out of the way.
Physiology teaches us that a normal TSH is only as effective as the FT3 and FT4 reveal it to be. A normal or abnormal TSH may either fail or succeed at maintaining the untreated individual’s healthy thyroid hormone setpoint.
After the discussion of all these cognitive barriers, we must confront the paradox: Why is it part of evidence-based medicine to discourage physicians from analyzing the rich evidence provided by normal-range thyroid lab data? Some people pride themselves on being “evidence-based” when they are simply promoting or conforming to a programme of institutionalized thyroid ignorance within the normal ranges.
As usual, I provide evidence and reason from scientific journals – the source of all sound medical knowledge, available to all who have full-text access. To that knowledge I add the logical reasoning and analogies of a professor trained in rhetoric and communication. We need to identify fallacies of reasoning so we can move past them.
It’s time to stop making the upper and lower “limits” of the TSH, FT3 and FT4 ranges into the limits of medical understanding.
Not covering thyroid therapy optimization
In this series, I am not addressing the optimization of treated thyroid patients’ hormone levels within the normal range. That’s an incredibly complex topic. Many types of thyroid disorders exist and can overlap. Many treatment approaches exist. Disease and dosing will combine with genetics and nonthyroidal health conditions to alter a person’s optimal thyroid hormone setpoints.
Instead, I’ll be focusing on the lab data of untreated individuals who still rely on a TSH-stimulated thyroid for 100% of their thyroid hormone supply.
However, this topic is still relevant to thyroid therapy. Cognitive barriers to analyzing untreated people’s normal-range thyroid data are at the foundation of many thyroid therapy mistakes. If a doctor believes “normal” is safe and healthy in every untreated person, their cognitive barriers will also become barriers to optimizing thyroid therapy rather than merely normalizing their biochemistry.
How “normal” ranges are regarded in kidney, heart, and liver failure
Consider how medical scientists think of normal-range data in kidney, heart, and liver failure. In those diseases, being in the normal range for the population does not rule out organ disease or health risk.
So, why do people still think this way about “normal” thyroid biochemistry?
Nephrologists have acknowledged that chronic kidney failure begins within the normal ranges of kidney biomarkers. Stage 1 kidney damage may exist despite a normal estimated glomerular filtration rate (eGFR) and normal-range creatinine (Benjamin & Lappin, 2022). In addition, kidney biomarkers can be used to predict the risk of heart failure (HF).
When looking at HF risk in kidney biomarkers like the albumin-creatinine ratio and GFR, Nowak and Ärnlöv (2020) found that standard reference ranges are not as significant as “interquartile ranges” – a narrower distance from the population median (25th percentile to 75th percentile). In contrast, the standard reference range width is approximately two standard deviations wide, from the 2.5th percentile to the 97.5th percentile.
Cardiologists have distinguished between heart failure with “preserved” ejection fraction (HFpEF) and with “reduced” ejection fraction (HFrEF) usually <50%. They don’t use the term “subclinical.” Instead, their words emphasize physiological mechanisms. The underlying chronic disease exists whether or not a person has preserved or reduced ejection fraction.
Intelligent cardiologists debate the LVEF and treat it like a continuum. They say
“heightened risks for heart failure specific major adverse events occur across the broad range of ejection fraction, including normal.”
(Pfeffer et al, 2019)
A new diagnostic category has arisen for mid-range LVEF between 41%-49%, which acknowledges that 50% is too rigid a cutoff. But they haven’t made this into a “subclinical” zone. They continually speak of a “spectrum” and “continuum” as the most correct way to think about heart failure diagnosis, as opposed to cutoffs and categories. Specialists acknowledge that despite the ejection fraction level, sex differences and a wide range of cardiac and non-cardiac health factors are significant to health outcomes (Boulet et al, 2021).
To move past categories of LVEF, they recommend creating “phenotypes” with multiple biomarkers:
“distinct HF phenotypes, in which LVEF is one criteria, that may otherwise overlap within the conventional classification. … Such a phenotype-based HF classification would then inform clinical trial design to match new and established therapies more effectively to patients’ needs.”
(Boulet et al, 2021)
In short, cardiologists do not take for granted everyone with an LVEF percentage below a threshold is equally in danger and everyone above that threshold is safe. They don’t use percentages as diagnoses and say that people with preserved ejection fraction don’t have a disease. They use LVEF to grade just one aspect of cardiovascular function. They know that disease, and health risk, exists across the entire spectrum.
Hepatologists know that in chronic liver diseases, liver damage exists within the normal reference ranges for liver enzymes. There is “compensated cirrhosis” and “decompensated cirrhosis.” The threshold between these entities is not set at the reference range limit of a biomarker. A recent scientific article emphasizes the importance of educating physicians to see liver disease within the normal ranges:
“The health care burden from chronic liver disease (CLD) will likely continue to rise, unless clinicians are made aware that normal or near normal laboratory findings may be seen in asymptomatic patients.
(Ahmed et al, 2018)
Earlier identification of asymptomatic patients will allow for treatment with new promising modalities and decrease morbidity and mortality from CLD.”
“Often times, patients with advanced liver disease and cirrhosis have subtle changes in laboratory values, typically falling within the normal ranges.
As such, routine laboratory studies should not be used as a sole screening tool to identify or exclude individuals suspected of having CLD. History and physical examination remain the cornerstone of the diagnostic workup.”
Of course, thyroid diseases are not the same as kidney, liver, or heart diseases. Each disease has its own diagnostic criteria.
But one thing is clear from this comparison. Thyroid diagnosis is in the dark ages of biomarker analysis because it aligns population reference range cutoffs with disease diagnosis and does not question this alignment.
While specialists in other diseases have moved past the dismissal of “normal” values as healthy and disease-free, we still see naïve people claim that a TSH value within a laboratory reference range has the power to singlehandedly “rule out” not only chronic thyroid disease but also non-thyroidal health risk.
The abnormal hierarchy of “normal vs. abnormal TSH” over FT3 and FT4
Combined with an obsession over reference limits, thyroid diagnosis is plagued with a particularly unusual hierarchy of biomarkers that does not prevail in other disease diagnoses.
In 2020, Fitzgerald and team performed a meta-analysis of the clinical significance of Total/Free T3, FT4 and TSH measurements to clinical parameters in many non-thyroidal diseases. They discovered 58 scientific articles discussing the relevance of these hormones to a long list of conditions:
“atrial fibrillation, other cardiac parameters, osteoporosis and fracture, cancer, dementia, frailty, mortality, features of the metabolic syndrome, and pregnancy outcomes.”
They noticed that within thyroid diagnosis there was an anomaly in the use of biomarkers in diagnosis — something unusual was going on that wasn’t seen in other disease diagnosis processes.
The “controlling hormone” (TSH) is permitted to dominate over thyroid diagnosis.
By “controlling hormone” they meant that the TSH hormone acts in an indirect regulatory role, as a physiological lever, which permits it to adjust or control the target biomarkers that actually provide evidence of a disorder.
In other diseases, their respective “controlling hormones” did not play a key role in diagnosis of whether a syndrome or disorder was present or absent:
“any [diagnostic] model whereby judgment of the thyroid status includes consideration of the TSH level is anomalous, in that the levels of other [non-thyroidal] physiological parameters are not judged by the levels of their controlling hormones.
For example, whether or not an individual has hypoglycemia or hypercalcemia is not determined by reference to insulin or parathyroid hormone levels, respectively.Adrenocorticotropic hormone (ACTH) levels, though helpful in diagnosing adrenal autonomy, are not considered diagnostic for Cushing’s syndrome.
In general, the level of a controlling hormone is used to determine the cause of a disturbance rather than identifying whether or not there is a disturbance.
(Fitzgerald et al, 2020)
If the same method were to be applied to thyroid hormone diagnosis, the TSH controlling hormone’s level would merely aids in the identification of the cause or etiology of a “disturbance,” such as Graves’ disease or Hashimoto’s thyroiditis or nodular thyroid disease. But the thyroid hormone levels would be treated as the most direct evidence that a person is actually in a hypothyroid or hyperthyroid state.
Hypothyroidism is a syndrome of thyroid hormone deficiency, not TSH (thyrotropin) hormone excess. If TSH excess was the actual syndrome that caused harm, the disease would have be called something like hyperthyrotropinemia.
Something unusual is going on within thyroid diagnosis that is skewing medical judgment. Not only is there an unusual obsession with normal vs. abnormal levels in general, but there is an illogical hierarchy of hormones. The hormone that helps to discern disease etiology is being used as a judge of the biochemistry that signifies disease.
It’s as if people imagine the human body has to ask the TSH level’s permission first before it’s allowed to be in a hypothyroid state.
People are permitting a “normal vs abnormal TSH” to cloud their judgment about whether a particular normal-range FT3 and FT4 is healthy or not, and whether a thyroid disease, pituitary disease, or metabolic disorder is present or not.
People have become so familiar with this way of thinking about TSH and thyroid hormones that it seems like the only way a person can or should think about it. Cognitive barriers direct us toward narrow ways of thinking, like cattle being directed into their pen.
Continue to later posts in this series to investigate the cognitive barriers that prevent critical analysis of normal-range TSH, FT4 and FT3 levels:
Barrier 1: Are normal thyroid reference ranges risk-free zones? (coming soon!)
Barrier 2: Can a normal TSH rule out thyroid disease?
Barrier 3: What’s wrong with calling TSH, FT3 and FT4 “thyroid function tests”?
References
References for all articles in the series are in a separate post: “Reference list for analyzing normal thyroid lab results”
- Tania S. Smith, Ph.D., President, Thyroid Patients Canada
Thyroid patient and thyroid science analyst
Even doctors who have an inkling something is going on meet barriers.
In the UK (as many other countries/systems) the system allows GPs to request Thyroid Function Test. But, in reality, that means TSH only in most cases, with reflex to FT4 only in some circumstances. And FT3 pretty much only with very low TSH, and high FT4 – suspecting hyperthyroidism.
We can blame a generation of endocrinologists for acquiescing in this becoming standard. Rather less can we blame individual GPs who find test requests refused. (Within computerised systems, they might struggle to find any way of specifically requesting ~FT4 and/or FT3.)
We can blame laboratories for imposing restrictions which are beyond their competence. They have never seen these patients (beyond the technicality of sometimes doing the phlebotomy). They do not have access to full patient records. They are not thyroid specialists and cannot be expected to fully appreciate the clinical interpretation of results. Especially as keeping up to date with the science is hard even for those who are well-versed.
(At the same time, I think labs doing more tests if earlier results indicate they are appropriate can have benefits.)
We can blame the whole medical system for allowing the testing regime to not do tests which have been requested.
All test requests should be treated transactionally. Someone orders a test. The lab does the test and reports the result or, if they can’t or won’t, they report back with an explanation. There should be no test requests with blanks in patient records. Every request made has to have some form of result.
It is abundantly clear that, as thyroidology has turned its attention to T3 again, the lack of historic T3 data is crippling understanding. There are many research papers which might make a lot more sense had T3 also been tested. There many retrospective researches using patient records which would also benefit from having T3 results – even were they not justified for the individuals.
From a laboratory point of view, just how much extra would it cost to actually do TSH, FT4 and FT3 on all samples? They perhaps could negotiate a better deal with the test supplier by doing all three on every sample. Simplifying reagent supplies, etc., into a 1:1:1 ratio.
Finally, if doctors start to see complete sets of results, they might start to realise that almost any pattern of results is possible.