Why is central hypothyroidism so difficult to diagnose?

Every thyroid patient and doctor should become more informed about the challenges of diagnosing central hypothyroidism.

Did you know that people can even have elevated TSH levels in central hypothyroidism? Wow, really? Yes, the research says so. A graph of research results reveals it clearly, too.

Not only that, but here’s another shocker. As of 2019, it is acknowledged that not only low FT4, but low-normal FT4 can occur with central hypothyroidism. Such amazing things thyroid science can teach.

The news can be so confusing for doctors who are taught a simple idea that Low TSH and Low FT4 need to coexist in central hypothyroidism!

If you have “central hypothyroidism,” it means that not enough TSH hormone is being secreted given your level of thyroid hormones. It can also mean that TSH molecules are not as bioactive. Less bioactive TSH is incapable of functioning in TSH receptors normally.

Here’s the main reasons you, my fellow thyroid patients, can benefit from learning about central hypothyroidism:

If your doctors are trusting the TSH to diagnose you prior to therapy, and you have central hypo but don’t know it, you may remain undiagnosed as a person who suffers a genuine thyroid hormone deficiency.

If you have central hypothyroidism while you’re on thyroid therapy, you may be perpetually underdosed by TSH-only monitoring if doctors mistakenly believe you have a simple case of primary hypothyroidism.

This post, in fact, is an essential introduction to a future post in which I’ll ask the key question “Have you been screened for central hypothyroidism?” — because it can silently coexist with primary hypothyroidism.

In this post, I will do the following:

• Introduce you to the thyroid scientists who are the experts on this condition and whose 2017 and 2019 articles I rely on for a lot of my information (though of course I’ve read far beyond them).
• Provide a summary of the basics and some anatomy diagrams that illustrate normal function, followed by authoritative definitions of central hypothyroidism.
• Discuss an amazing graph showing how diverse the TSH-T4 relationships can be prior to therapy.
• Outline Persani’s updated diagnostic criteria as of 2019, which tweak the 2018 ETA guidelines he co-authored.
• Quote and discuss Beck Peccoz’s 2017 list of 6 diagnostic challenges.
• Suggest 3 potential solutions, and recommend a free diagnostic app.
• Conclude with more general thoughts on the systemic causes of neglected diagnosis of central hypothyroidism.

Meet the scientific experts

Today’s best research is often led by Paolo Beck-Peccoz and/or Luca Persani and coinvestigators. They both hail from the University of Milan in Italy. Some articles on central hypo are co-authored by both of them.

As of writing in late 2019, Beck-Peccoz had no less than 51 scientific articles listed on Scopus database, a scientific citation-aggregation service by Elsevier. The majority of his publications are on advanced topics in central hypothyroidism, such as the 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors and a textbook chapter on TSH hormone.

Persani had 269 scientific documents listed on Scopus. He focuses not only on central hypothyroidism but also problems with cortisol secretion, growth hormone, and sex hormones. One of the many causes of low cortisol is low pituitary secretion of ACTH hormone that stimulates the adrenal glands. He even deals with syndromes of excess secretion of TSH such as resistance to thyroid hormone (RTH). His scope of interdisciplinarity knowledge is utterly jaw-dropping.

In this post I draw mainly on Beck-Peccoz’s 2017 article with supplementary info from Persani’s 2019 article, with support from additional sources. Notice the first title’s claim of neglect:

• Beck-Peccoz, P., Rodari, G., Giavoli, C., & Lania, A. (2017). Central hypothyroidism—A neglected thyroid disorder. Nature Reviews. Endocrinology, 13(10), 588–598. https://doi.org/10.1038/nrendo.2017.47
• Persani, L., Cangiano, B., & Bonomi, M. (2019). The diagnosis and management of central hypothyroidism in 2018. Endocrine Connections. https://doi.org/10.1530/EC-18-0515

How rare is central hypothyroidism, really?

The rates at which Central Hypo is diagnosed are likely lower than they should be.

Persani’s team say this in their 2019 abstract: “Recent data enlarged the list of candidate genes for heritable CeH [Central Hypothyroidism], and a genetic origin may be the underlying cause for CeH discovered in pediatric or even adult patients without apparent pituitary lesions. …

This raises the doubt that the frequency of CeH may be underestimated.”

The focus in the past has been on “pituitary lesions,” but people can have genetically-driven central hypothyroidism without explosion of a cyst on the pituitary, and without any concussion or traumatic brain injury.

There are some major obstacles to its diagnosis, mainly the “reflex TSH strategy” now overruling the process of screening of thyroid disease and monitoring thyroid therapy. Additional issues are raised by Beck-Peccoz and team in this 2017 article as well.

Therefore it is likely an underestimate when Beck-Peccoz reports the official incidence rates:

“The global prevalence of central hypothyroidism ranges from 1 in 20,000 to 1 in 80,000 individuals in the general population and it is a rare cause of hypothyroidism (1 in 1,000 patients with hypothyroidism).”

Beck-Peccoz’s article’s title announced that central hypothyroidism is “a neglected thyroid disorder.”

Neglect is a vicious circle.

The insufficient medical education about the thyroid disorder leads to ineffective screening strategies. >> Ineffective screening leads to low rates of diagnosis. >> Low rates of diagnosis mean low statistics on rates of prevalence. >> The low statistics contribute to its continued neglect as a disorder. >> People mistakenly think that only a few patients are falling through the cracks.

Notice what happens when you add one more variable to the screening test at one stage of life: Rates of diagnosis increase, and so do rates of prevalence!

“the prevalence of congenital central hypothyroidism in the Netherlands increases to 1 in 16,000 newborn babies if the screening algorithm is based on the combined measurement of TSH, T4 and T4-binding globulin, which could be effective in diagnosing mild forms of the disease.” (Beck-Peccoz et al, 2017)

What would happen if better screening for central hypothyroidism was offered to adults and newborns everywhere, not just newborn babies in the Netherlands?

The standard TSH-based screening test will not flag central hypothyroidism because it is diagnosed by assessing the inappropriate relationship between Free T4 and TSH.

It can’t be diagnosed by measuring TSH alone, or FT4 alone.

Even if both TSH and FT4 are measured in the same blood test, their interrelationship will often be overlooked. Central hypo can’t be diagnosed by the usual way doctors diagnose things nowadays — by looking at these two numbers in isolation from each other and only in relationship to reference range boundaries. Often a history of many lab tests is necessary to see a general pattern.

Anatomy and function

To see the pattern of the pathology, we should start by understanding the basic theory underlying normal function.

In the center of your head, the pituitary gland dangles down below the hypothalamus from the middle of your brain.

In this visual model below, the hypothalamus and its TRH is colored red, and the pituitary and its TSH in green. (As a side note, the pituitary looks rather like a teeny weeny pair of testicles, and I wonder how that imagery has played into the impression of TSH’s dominance over thyroid hormones.)

The hypothalamus secretes TRH to the anterior pituitary, where the TSH-secreting “thyrotrope” cells are located.

TRH stimulates TSH secretion, which stimulates thyroidal T4 and T3 secretion.

Multiple hormones, multiple functions

The term “central” has arisen because the gland that has failed to secrete enough hormone is located in the place that endocrinology has declared the “center” of hormone control.

These two “central” glands secrete many hormones that regulate other glands like the thyroid, adrenals, and gonads.

I’ve highlighted in yellow the two hormones involved in the HPT axis in this image, the TRH and the TSH:

You can see how important these glands are.

It’s sometimes imagined that these central glands are part of the “brain,” but they are not.

Despite their close proximity to the brain, most of the hypothalamus and all of the pituitary gland is not protected by the blood-brain-barrier (BBB) so that they can receive input from factors both inside and outside the BBB. Some of these factors can interfere with T4 and T3 co-regulation of TRH secretion.

Definitions of hypothyroidism

Hypothyroidism has tended to be defined by which gland has failed:

1. Primary hypothyroidism is failure of the thyroid gland to secrete enough T3 and T4 hormone in response to TSH.
2. Secondary hypothyroidism is failure of the pituitary gland to secrete enough TSH from pituitary “thyrotropes” (That’s why TSH is sometimes called “thyrotropin”), and
3. Tertiary hypothyroidism is the failure of the hypothalamus to secrete enough TRH (thyrotropin releasing hormone) to stimulate the pituitary gland to secrete enough TSH, or enough bioactive TSH.

In central hypothyroidism, your hypothalamus or your pituitary gland (or both) has been compromised, and their co-regulation of TSH secretion from the anterior pituitary cannot be trusted.

The end result is “defective TSH secretion,” which means TSH can be defective in both quality and quantity.

Let’s look at what Beck-Peccoz and colleagues have to say about the definitions and language:

• “Central hypothyroidism is characterized by a defect in thyroid hormone secretion, resulting from the insufficient stimulation of a healthy thyroid gland by TSH. This condition can be a consequence of an anatomic or a functional disorder of the pituitary gland and/or the hypothalamus.

• Central hypothyroidism was formerly termed [1] secondary hypothyroidism of pituitary origin or [2] tertiary hypothyroidism of hypothalamic origin, resulting from insufficient TSH stimulation by TSH-releasing hormone (TRH).

• These terms [secondary and tertiary], however, are no longer in common use because the disorders frequently affect both the hypothalamus and the pituitary gland and the common result is defective TSH secretion.”

Persani et al, 2019 further breaks down the pathology of central hypo into 3 sub-factors:

1. a) “impaired [pituitary] thyrotrope stimulation” by TRH — either due to hypothalamus organ damage/defects causing less TRH secretion, or “TSH resistance” in pituitary thyrotrope cells due to genetic mutations.
3. b) “reduced pituitary TSH reserve” — anything causing a loss in the number of cells or sensitivity of TSH-producing thyrotrope cells.
5. c) reduced “bioactivity” of TSH molecules secreted by the pituitary.

The additional component often forgotten is item C, which maps onto the lesser known phenomenon of defective TSH molecules.

Look at how falsely elevated the TSH can be when non-bioactive TSH is detected by the TSH assay!

Each dot in the graph above represents a single patient prior to thyroid therapy.

You can see how diverse the condition is in its biochemistry. All of these dots are evidence of dysfunctional TSH secretion. Persani’s 2012 article, which also uses a version of this graph, explains that the higher TSH levels in this graph are from persons with a hypothalamic dysfunction officially diagnosed by TRH-TSH testing. It is largely non-bioactive TSH incapable of stimulating T4 secretion from the thyroid. The lower FT4 results are mostly people who have dysfunction centered more in the pituitary than the hypothalamus.

Because of this, in central hypothyroidism, misdiagnosis is easy:

• You can have lab results that look like subclinical hypothyroidism (moderately elevated TSH with low-normal FT4) when you are actually extremely hypothyroid.
• You can have lab results that look like normal thyroid hormone health because TSH is “in reference range,” if FT4 is not tested.

Diagnostic criteria

Beck-Peccoz has said this in 2017:

“The diagnosis of central hypothyroidism is based on low circulating levels of free T4 in the presence of low to normal TSH concentrations.”

But wait! It’s not that easy! You see the graph above!

Persani edits the Free T4 generalization in 2019.

Persani’s article mentioned that the new 2018 European Thyroid Association guildelines say this:

“experts agreed that diagnosis of overt CeH should be considered in every subject with low serum concentrations of FT4, measured by reliable immunoassay and low or normal immunoreactive TSH concentration, confirmed on two independent determinations.”

However, Persani’s Figure 1, supposedly a representation of the ETA guidelines, silently appears to amend the guidelines by saying not just “Low T4” but “Low or low-normal FT4,” both in the figure notes and in the figure itself.

Persani is the lead author of the 2018 ETA guidelines. Persani’s 2019 article is also coauthored. One cannot assume they collectively made this edit as a mistake.

As of 2019, therefore, Persani’s edited version of the ETA guidelines state a broader set of biochemical criteria prior to thyroid therapy:

“low, or even low–normal, free T4 with inappropriately low/normal TSH.”

This is the starting place, and additional investigations are recommended to confirm it.

The bottom line is the word “inappropriately” — the TSH level does not constitute an appropriate response to the Free T4 level.

Truly, even a low-normal FT4 ought to be diagnostic if it is mainly the “inappropriateness” of TSH secretion and its non-bioactivity that is at issue.

Aren’t you left wondering why Persani didn’t edit the criteria to include an elevated TSH, given the graph above? You should be.

Six barriers to diagnosis of central hypo

Will it be easy to notice central hypo if the TSH has the largest voice in diagnosis? No.

Will adding FT4 testing help enough to diagnose or adjust therapy? Not if technology or expertise are lacking, based on the barriers Beck-Peccoz has outlined.

Let’s look at the short list of misunderstandings summarized in Beck-Peccoz’s abstract:

“Obtaining a positive diagnosis for central hypothyroidism can be difficult from both a clinical and a biochemical perspective. “

Beck-Peccoz outlined 6 reasons for the neglect of a central hypothyroidism diagnosis:

1) methodological interference in free T4 [measurements] or

2) [methodological interference in] TSH measurements;

3) routine utilization of total T4 or T3 [rather than Free T4 or T3] measurements;

4) concurrent systemic illness that is characterized by low levels of free T4 and normal TSH concentrations;

5) the use of the sole TSH-reflex strategy, which is the measurement of the sole level of TSH, without free T4, if levels of TSH are in the normal range; and

6) the diagnosis of congenital hypothyroidism based on TSH analysis without the concomitant measurement of serum levels of T4.”

False outcomes of inappropriate testing

Item #6 above is the major barrier.

But there’s a 7th barrier even if both TSH and FT4 are tested.

• 7) Incorrect or outdated medical knowledge of the clinical and biochemical presentation and diagnostic criteria. If FT4 is not analyzed with knowledge of an “appropriate” TSH in mind, the diagnosis of “inappropriate” TSH secretion will be missed.

TSH-reflex testing will often hide central hypo (CeH) in three ways:

• If TSH is normal, the CeH patient can be misclassified as normal, euthyroid, and FT4 won’t even be tested to confirm it. False.
• If TSH is mildly high, even if FT4 is tested by “reflex,” if it is just above the FT4 boundary the CeH patient can be misclassified as subclinical hypo and not yet deserving of thyroid therapy. False.
• If TSH is low, if the reflex testing of FT4 or FT3 reveals them as also low-normal, the CeH patient can be misclassified as subclinical hyper because of a mistaken belief that TSH always trumps thyroid hormone levels. False.

In comparison to the barriers caused by TSH monotesting policy (which they call a “reflex”), the methodological interferences they list first are relatively minor.

That’s because you have to get past the barriers of lack of expertise and TSH-only reflex testing before you even get to the level of noticing that test interferences exist:

• Because FT4 tests are subject to interference, they can yield falsely amplified T4 results that make it seem like the TSH level is not inappropriate. Do you know all the causes of FT4 test interference? Probably not.
• Because TSH results can also be subject to interference, it can’t show how abnormal the TSH truly is in relation to FT4. Do you know all the causes of TSH test interference as well? There are more than most people know and more than are listed by Beck-Peccoz et al, 2017.
• If TT4 is measured instead of FT4, changing ratios of bound versus free hormone can falsely inflate the results. Diagnosis should focus on the “free” fraction that can enter cells, including hypothalamus and pituitary cells.
• If TSH and FT4 are interfered with by concurrent critical illnesses, it is difficult to separate permanent/preexisting central hypo from temporary, illness-induced central hypo. (NOTE: If central hypo is preexisting or permanent, you may have a harder time recovering from the low T3 levels in critical illness because recovery requires elevated bioactive TSH secretion to stimulate a healthy thyroid. But this is a fact Beck-Peccoz does not mention.)

Solution #1

Educate. Diagnosis requires correct knowledge.

I’m sure Persani and Beck-Peccoz would agree that we need to spread medical education about all causes of hypothyroidism, including central, primary, and peripheral thyroid dysfunctions.

Educate doctors about the vulnerability of the HPT axis!

Stop teaching them to mindlessly mumble the mantra that “the TSH is the most exquisitely sensitive test of thyroid function” as if saying it over and over gives TSH the power to trump contradictory thyroid hormone test results.

Educate doctors to be humble and open minded to information from clinical data, new research and from scientifically educated patients.

However, we can’t wait forever until all doctors become better educated, better critical thinkers, and more humble.

Once beliefs become dogmas and presumptions, they can blind doctors and entire medical associations’ stances and guidelines for decades.

Therefore, we must educate patients themselves and the public so that they can be armed with the science to dispel medical ignorance and advocate for themselves and their loved ones who suffer.

Solution #2

Stop the mass institutionalization and enforcement of TSH reflex testing systems. They hijack clinical decision making, subvert ethical doctor-patient partnerships, keep sick people sick, and can lead to further costly testing and treatments for the supposed “nonthyroidal” causes of hypothyroid symptoms.

I’m sure Beck-Peccoz and Persani would agree with this too.

What about the loophole that “you can get around the TSH-reflex strategy if you write a valid reason for requesting a Free T4 test on the requisition, if you say you suspect central hypothyroidism”? (That’s what patients and doctors are being told in some Canadian provinces where this policy is enacted.)

Well, that’s just not fair.

The suspicion of a central hypothyroid diagnosis may not even enter a doctor’s or patient’s mind until full thyroid results are provided and end up being puzzling in the light of knowledge!

Nobody should put thyroid hormone test prohibition powers in the hands of health care organizations and laboratories for the sake of saving $10-13 CDN per test.

Let educated doctors and patients decide together on which collection of thyroid hormone and TSH tests are needed on a case by case basis, without interfering coercion from health administrators who declare FT4 knowledge “unnecessary” before anybody knows it.

Solution #3

Provide calculations based on hormone relationships to improve diagnosis.

This solution is something overlooked by both Persani and Beck-Peccoz’s articles.

Not everyone is going to be an expert capable of looking at TSH and FT4 to immediately discern an “inappropriate” relationship between them, especially in the stress and multiple distractions of medical professional life.

For some of our lab results, the physician is already provided calculations or ratios to aid diagnosis.

Consider the way LDL / HDL cholesterol ratios are analyzed now. We even have liver test calculators and kidney failure calculations.

Where are our thyroid hormone ratio calculations?

Use the free SPINA-Thyr app

Until laboratory test results give doctors an accurate FT4-TSH relationship calculation, consider downloading SPINA-Thyr.

SPINA-Thyr has been developed and clinically tested by researching endocrinologists over the past 20 years to account for T4 hormone binding, normal T4 clearance rates, the normal statistical range of sensitivity of TSH secretion to T4, and the logarithmic nature of TSH measurement. See our SPINA-Thyr post for references and more information.

Here is a screenshot of a sample SPINA-Thyr analysis of lab test results in a person before thyroid therapy.

Signs of TSH secretion inappropriateness are the lower TSHI and the lower TTSI, both with asterisks showing they are borderline or low.

• Its “TSH-index” can show how abnormally low the TSH is in relation to FT4 cases of central hypothyroidism.
• The “TTSI” calculation can also show how abnormally high the TSH is in relation to the FT4 — it is mainly useful to diagnose cases of resistance to thyroid hormone or pituitary TSH-secreting adenomas.

Signs of thyroid gland health are in the GT and GD structural parameters. Keep in mind these parameters can only be calculated for adults on no thyroid therapy (GT & GD) and/or LT4 monotherapy (GD).

• The GT (thyroid gland secretion) normal reference range is 1.4 to 8.57, and a result of 2.7 is on the lower end of normal. TSH is not stimulating this gland to put out as much T4 as the average person, but it’s still in normal range.
• The GD is the global deiodinase efficiency of T4-T3 conversion, range 20.0 to 40.0, showing a very high-normal efficiency, more FT3 is being converted from T4 than the average.

Use lab test analysis tools even while keeping in mind that any test results may be subject to technical or biological interference.

A neglect caused by disease invisibility and complexity

To conclude, I’d like to suggest that the “neglect” of central hypothyroidism is larger than just a failure of diagnostic technology and screening guidelines that show up in Beck-Peccoz’s list.

Diagnostic failure rests in human perception and psychology.

Human strengths and weaknesses in reasoning are at the basis of scientific observation and institutional decision-making.

In all aspects of medicine, our collective strengths and humility move us forward, but our weaknesses and arrogance hold us back.

Arrogance regarding one’s present state of thyroid education and clinical experience can affect the most brilliant of doctors and scientists, and it can infect entire medical associations.

The hypothalamus and pituitary and thyroid are as just as crucial as the heart and brain, and they are not disconnected from the rest of the body. The heart and the brain, and every other organ, require enough thyroid hormone to function.

Even if the thyroid is healthy, inappropriately low TRH and TSH secretion can put T4 and T3 supply to heart and brain at risk. Whether it is temporary or permanent central hypothyroidism, a distinction made by Beck-Peccoz, does not make much of a difference to the glands and tissues that suffer and the patients at higher risk of death in Low T3 Syndrome / Nonthyroidal Illness (NTIS).

Our society focuses on heart and brain diseases more than hypothyroidism largely because we have attributed to heart and brain diseases the manifest causes of death and crippling disease.

We tend to focus on the manifest diseases and their final display before one’s demise, and we have invested a lot in the technologies of monitoring these pathologies once they get to the point of manifestation and especially hospitalization.

The invisibility of hypothalamus / pituitary compromise is largely due to these glands’ tiny size, their unseen location in the middle of our skull, and their incredibly high level of sensitivity and complexity.

But most of all, pathologies of inappropriate TSH secretion are bound to remain invisible in the medical culture’s standard view of thyroid hormone health and disease.

Blinded by TSH worship, this culture fails to attend to abnormal TSH-thyroid-hormone relationships that can undermine overall human health and subvert recovery.

Who that is steeped in TSH-T4 paradigm wants to admit that the TSH demigod is fallible and that the certainty built on belief in its omniscience is false?

The short-term and superficial cost-saving nature of the TSH-only or TSH-reflex diagnostic strategy is seductive yet harmful. Boasts about reduced costs too often overwhelm the ethical and scientific arguments on behalf of the patients who suffer from misdiagnosis and non-diagnosis.

Nobody can hold systems accountable for causing misdiagnosis or a missed diagnosis if doing so would require the evidence from test results that were discouraged or outlawed, right? They’ve forbidden the existence of incriminating test results.

These anti-thyroid-testing campaigns and their oversimplified view of lab results are an insult to experts like Beck-Peccoz and Persani and all those who understand the crisis of central hypothyroidism in critical illness and early childhood development.

Central hypothyroidism is truly more complex, diverse, widespread, and may I even suggest, more deadly and crippling than we realize.

• Tania S. Smith

References

Beck-Peccoz, P., Lania, A., Beckers, A., Chatterjee, K., & Wemeau, J.-L. (2013). 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. European Thyroid Journal, 2(2), 76–82. https://doi.org/10.1159/000351007

Beck-Peccoz, P., Bonomi, M., & Persani, L. (2014). Thyroid-Stimulating Hormone (TSH). In Reference Module in Biomedical Sciences. https://doi.org/10.1016/B978-0-12-801238-3.00102-1

Beck-Peccoz, P., Rodari, G., Giavoli, C., & Lania, A. (2017). Central hypothyroidism—A neglected thyroid disorder. Nature Reviews. Endocrinology, 13(10), 588–598. https://doi.org/10.1038/nrendo.2017.47

Persani, L. (2012). Central Hypothyroidism: Pathogenic, Diagnostic, and Therapeutic Challenges. The Journal of Clinical Endocrinology & Metabolism, 97(9), 3068–3078. https://doi.org/10.1210/jc.2012-1616

Persani, L., Cangiano, B., & Bonomi, M. (2019). The diagnosis and management of central hypothyroidism in 2018. Endocrine Connections. https://doi.org/10.1530/EC-18-0515

Persani, L., Brabant, G., Dattani, M., Bonomi, M., Feldt-Rasmussen, U., Fliers, E., Gruters, A., Maiter, D., Schoenmakers, N., & van Trotsenburg, A. S. P. (2018). 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism. European Thyroid Journal, 7(5), 225–237. https://doi.org/10.1159/000491388