As I’ve outlined in a previous post, central hypothyroidism (CeH) is a failure or compromise in the hypothalamus and/or pituitary gland that causes defective TSH or inappropriately low TSH secretion.
There, I echoed the complaints of world-leading experts in the field, Beck-Peccoz and Persani, who point out why it is so difficult to diagnose central hypothyroidism.
If even thyroid scientists complain that it’s difficult to diagnose central hypothyroidism before thyroid therapy, it may be almost impossible for the medical system to begin to see central hypothyroidism for the first time during thyroid therapy.
In this post, I outline the diagnostic problem, then offer diagnostic solutions from scientific publications. Fortunately, published graphs are available to aid in diagnosis of central hypothyroidism in people who have already been diagnosed and treated for primary hypothyroidism.
The problem of blindness
Our medical system has been blinded by gland-centric and mutually-exclusive definitions of hypothyroidism that make it seem impossible to have more than one type of hypothyroidism at the same time.
Central hypo has been defined by exclusion of primary hypo, by the presence of an
“otherwise normal thyroid gland”(Beck-Peccoz et al, 2017)
Another set of scientists define it this way:
“Central hypothyroidism (CeH) is a disorder characterized by defective thyroid hormone production due to insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland.”(Persani et al, 2019)
Why must any reasonable person presume the existence of “an otherwise normal thyroid gland”? Does this mean that in all cases of CeH, the thyroid gland is free of disease or dysfunction? Of course not.
There is no law of nature saying that a thyroid gland and pituitary gland can’t both fail, or that a thyroid can’t fail first, then a hypothalamus or pituitary can fail next.
A skeptic will naturally think “what are the chances of that?” and soon after that, they’ll ask “Where is the research on that?” Yet if the medical field has not permitted a diagnostic overlap to exist, the chance of finding incidence rates and research on this overlap is bound to be more slim than the true rate of patients who have both conditions at the same time. (If you find such publications, please let us know, and congratulate the authors for their scientific powers of observation and insight.)
Once a person is placed on thyroid therapy and the doctor has already categorized them as a “primary hypothyroid” patient whose thyroid gland has failed, how many physicians will even consider Central hypothyroidism (central hypo, CeH) as an additional, overlapping diagnosis later on in the future? Few.
Accusing TSH of being an inappropriate and unfair judge is difficult enough for doctors and scientists. If you are a primary hypothyroid patient or her compassionate doctor, it’s even more difficult.
Hearing a patient accuse their own inappropriately low TSH is like accusing the king of harassment after one has been made his slave and one depends on him to decide the size of one’s daily meal (one’s thyroid hormone dosage). If TSH is truly not trustworthy, the mere slave can’t accuse TSH and win her case, unless she has both TSH and FT4 evidence and can back up an argument with science.
Now let’s look at another case, instead of failure to diagnose CeH, that of misdiagnosis. How likely is it for a person to be mistakenly diagnosed with a thyroid gland problem when one actually has a hypothalamus TRH secretion problem making the TSH untrustworthy?
Misdiagnosis is far more likely. It is easy to fall into the category of primary hypothyroidism while secreting a TSH in the often misleading “subclinical/mildly hypothyroid” zone, where one can find severe hypothyroidism or no signs of hypothyroidism at all. This ambiguous zone exists above reference range but below 10.0 mU/L. In this TSH zone, it is possible to have TSH that is not bioactive enough to stimulate a healthy thyroid, and the result will be a low Free T4. Persani and Beck-Peccoz show graphs (shown below) proving that defective TSH in CeH patients can sometimes be elevated as high as 10 mU/L, which makes a person seem deceptively like a case of primary hypothyroidism.
As of the time of writing, no policy yet exists to urge doctors to exclude CeH in cases of apparent primary hypothyroidism. There is no procedure to determine whether CeH is also (or the only condition) present at the time of the primary hypothyroid diagnosis, or whether CeH has appeared years or decades after a correct diagnosis of primary hypothyroidism. Everyone knows primary hypo. We too easily blame the devil we know rather than the devil we don’t know.
Solutions: Ways to obtain a correct diagnosis
What can we do if one is a patient, or a doctor of a patient, who possibly has both central and primary hypothyroidism, or has been misdiagnosed with primary hypothyroidism when one has only central hypothyroidism?
Don’t give up.
That’s what too many people do when they get a glimpse of the real complexity of thyroid hormone disorders and the TSH.
A truly good doctor or a well-informed patient can see the patterns and the logic that can guide accurate diagnosis and effective therapy. The patterns enable one to seek further testing — or they can rule out the likelihood of CeH before wasting a lot of time and anxiety on the issue.
When to suspect CeH:
The TSH is abnormally low per unit of Free T4 during thyroid therapy, while FT3 levels are also incapable of lowering the TSH.
Rule out a TSH that is only temporarily abnormally low or is biased low by medications. The inappropriately normal or low TSH may be partly or entirely explainable by:
- Euthyroid levels of Free T3 hormone in the upper half of reference range or mildly above range during thyroid therapy while dosing more than 15 mcg of T3 per day (porcine desiccated thyroid provides 8-9 mcg of T3 per 60-65 mg dose).
- When FT4 is concurrently within reference range while dosing T3 or desiccated thyroid, if the lower FT4 counterbalances the higher FT3, this biochemistry likely to be metabolically euthyroid despite the low TSH. It is neither a case of central hypothyroidism nor subclinical hyperthyroidism.
- Dosing corticosteroids or prednisolone or other known “Drugs that suppress TSH or cause Central Hypothyroidism” (Haugen, 2010),
- Other well-studied TSH-lowering health conditions like calorie restriction or chronic exhausting exercise (See Table 2 in Chatzitomaris et al).
- The condition of nonthyroidal illness (NTIS, Low T3 syndrome). In this state, people often “have thyroid function values that considerably overlap with those of patients who have central hypothyroidism. […] A clue to distinguish central hypothyroidism from non-thyroidal illness syndrome is the evaluation of serum levels of free T3, which are reduced in non-thyroidal illness syndrome but which are normal in mild to moderate forms of central hypothyroidism” (Beck Peccoz et al, 2017).
- A more conclusive test is the measurement of Reverse T3 to discover both an abnormally high RT3:T4 ratio and a concurrently abnormally low T3:T4 ratio (Ingbar & Braverman, 1982). RT3 and FT3 hormones tend to have normal relationships to Free T4 levels in a state of health.
- The presence of TSH-receptor stimulating antibodies (TSAb) in a patient with Graves’ hypothyroidism during anti-thyroid therapy or after a thyroidectomy or radioiodine ablation of the thyroid. TSH can be independently oversuppressed by TSAb antibodies. The antibodies overstimulate the pituitary’s TSH receptors and interfere with its ultrashort feedback loop (the Brokken – Prummel – Wiersinga feedback loop) that co-regulates TSH secretion.
- Instead of having CeH, if a patient’s hormones are low or low-normal, such patients are underdosed because of a deceptively low TSH during a TSAb antibody flare. Thyroid researchers openly state that TSH cannot be trusted as a guide to therapy when TSAb interfere (Paragoglia et al, 2019).
If any of these cases cause TSH to be biased low or abnormally suppressed by factors other than thyroid hormone negative feedback, one must diligently rule out true hypothyroidism, hyperthyroidism, overdose or underdose. The FT4 and FT3 ought to be monitored alongside symptoms and laboratory biomarkers other than TSH.
Experts in central hypothyroidism recommend also testing known biomarkers of thyroid hormone action in tissues, such as sex-hormone binding globulin / SHBG (Beck-Peccoz et al, 2017) which is high if T3 signaling is higher than normal in liver.
Other common biomarkers of local tissue response besides the pituitary’s local response of TSH, include total cholesterol (often high when T3 is insufficient in liver, due to reduced clearance rates; see M), norepinephrine — also called noradrenaline (often elevated in hypothyroidism, mildly low in hyperthyroidism), and creatine kinase (elevated when myalgias are caused by hypothyroidism).
What CeH looks like during therapy
Once you’ve ruled out these and other suspects that can temporarily and artificially over-suppress the TSH, it is time to screen for a more permanent form of hypothalamic and pituitary dysfunction.
Our medical systems still have buttons we can push and levers we can pull to get the right things happening. Knowledge and advocacy can bring hope.
Here is a pattern you can look for in thyroid lab tests.
TSH and Free T4 are necessary as a bare minimum, and Free T3 can aid diagnosis.
If the laboratory routinely cancels Free T4 when TSH is normal, ask your doctor to write in the explanation box “suspected central hypothyroidism. Do not cancel FT4″
In the graph above, the patients all had been diagnosed with pituitary failure prior to being put on thyroid therapy. None of them had hypothalamic failure — that will be a significant factor you’ll see in later graphs below.
You might wonder what their Free T3 was doing, but here it’s not an issue. Why? Nobody was taking T3 therapy or desiccated thyroid therapy.
Here in LT4 monotherapy, what we call the “T3 dosing effect” is NOT happening — I’m referring to the TSH suppression that is inevitable when FT3 has significant peaks and valleys in blood. We know from studies that Free T3 levels do not fluctuate much in T4 monotherapy, since we lose even our natural FT3 and FT4 circadian rhythm.
If you look carefully, there are a few outliers. There’s a couple of circles close to the triangles, and a couple of triangles up by the circles, but those were probably just one test among many over time in the same patient.
Keep in mind that the article says some of these patients were also concurrently being treated with glucocorticoids for adreneal hyposecretion due to ACTH hyposecretion. Glucocorticoids can lower TSH secretion, but by how much per dose and for how long? The Synthroid monograph by Mylan pharmaceuticals, Canada says “hydrocortisone greater than or equal to 100 mg/day or equivalent” can depress TSH (p. 12), but Mylan claims that it’s a transient effect: “the reduction is not sustained; therefore, hypothyroidism does not occur” (they are also bold to prophesy that the patient won’t be hypothyroid from underdose or poor T4-T3 conversion). The researchers who made the graph above don’t say how long these patients were dosing glucocorticoids, but we can assume since their CeH diagnosis when thyroid therapy began.
Therefore, if you have enough lab history, you can plot a graph with data. You should be able to see a pattern, as long as you also know what the “normal” TSH-FT4 relationship looks like.
The normal TSH-FT4 relationship
Do you have any TSH-FT4 pairs in your medical history before you were treated with thyroid disease?
How about TSH during T4-only therapy?
The “inappropriate” TSH per unit of FT4 can be seen against this background.
CAUTION: The graph can be misread if you don’t look closely at the labeling of the axes.
Notice the X axis for Free T4 is linear, adding +5 each time: 5, 10, 15, 20, 25 pmol/L.But the TSH Y axis tickmarks are at multiples of x10 : 0.1, 1, 10, 100, 1000. Without doing this distortion, the graph would be extremely tall.
The following two graphs that zoom in to a narrower TSH range do not have this distortion.
The basis of the graph
The graph above represents data from 120,403 people, which is a huge number.
They EXCLUDED patients with central hypothyroidism, as well as other categories of people who could have had abnormal TSH secretion for various reasons:
“We excluded 79 719 records (15.2%)” who were from “hospitalized patients, pregnant women, patients aged younger than 1 year, patients receiving specialist endocrine, surgical, or medical care . . . treated Graves disease or thyrotoxicosis, multinodular goiter, thyroid cancer, partial or total thyroidectomy, and hypopituitarism” and “and those with a history of treatment with radioiodine, antithyroid drugs, lithium, antiepileptic drugs, amiodarone, or liothyronine [T3].” (Hadlow et al, 2013)
Next, are you male or female?
You can see that the sex difference matters if you are in the normal range for FT4 and TSH during thyroid therapy.
Next, how old are you?
You can see that if you are under 39 years old, your TSH-FT4 relationship is very different.
You have to factor in these subtleties if you are judging the TSH-FT4 relationship during therapy when both are within the normal reference ranges.
How to use the graphs above
- First, correct the X and Y axis labels so that the “normal range” square in the middle lines line up with YOUR lab reference ranges. (Each lab will have a slightly different range that fits their lab test manufacturer and population.) Here, the TSH reference range is (0.4–4.0 mU/L) and free T4 reference range is (10–20 pmol/L). For example, if your Free T4 reference range is 10 to 25, cross out their “20” and replace it with “25.” You can do the math to fix the other tickmarks so that the same number of units is between every two tickmarks.
- Find your Free T4 level on the corrected X axis. Then follow a line with your eyes to see where the average (triangle) and range (dotted lines) of expected TSH values would be at the given FT4 level.
Or use SPINA-Thyr
Alternatively, use the free endocrinologist-developed SPINA-Thyr program to give a more careful mathematical analysis of your pituitary gland health given your TSH and Free T4 levels.
The current version, however, does not ask age or gender, so some subtleties in reference range may be overlooked.
Keep in mind that its assessment of TSH Index is not accurate during T3 dosing or desiccated thyroid dosing, so only enter data from T4 monotherapy or prior to therapy.
Consider non-bioactive TSH
This graph tells you how different pituitary vs. hypothalamic central hypothyroidism can look, prior to thyroid therapy, when there is a healthy thyroid gland.
Keep in mind that because it’s before thyroid therapy, ALL of these dots are with a Free T4 below or just below reference range.
You are not going to see TSH rise in CeH on thyroid therapy unless a person is underdosed.
Why does the TSH sometimes rise above reference in tertiary (hypothalamic) CeH?
1. Because the pituitary is not as injured or compromised as the hypothalamus
These patients’ pituitary gland can still independently sense the low T4. The pituitary is doing everything it can to secrete TSH. It’s even secreting more than it should at that level of TSH given their Free T4 is almost in reference range. It looks like abnormal TSH in another way, too much TSH.
But here’s the difference — the high TSH is not going to be very bioactive if TRH from the hypothalamus is low, so it can’t stimulate a thyroid enough, if the thyroid gland is healthy.
2. Because of the ultrashort feedback loop.
Non-bioactive is not only incapable of stimulating TSH receptors on the thyroid, but it also can’t stimulate TSH receptors on the pituitary gland that it uses to adjust TSH levels. This was discovered in the early 2000s. It is called the TSH ultrashort feedback loop. Most people see this feedback loop as TSH-suppressive, but it can also inflate TSH by the same logic and mechanism.
This happens because the pituitary can’t sense enough bioactive TSH floating around. Therefore, it is secreting more TSH than it normally would.
How can one discern tertiary hypo?
Test again when FT4 is significantly higher and see whether TSH is abnormally low or if the TSH-FT4 relationship has significantly changed.
It is very likely that once the hypothalamic CeH patient is placed on thyroid therapy and Free T4 rises with dosing, the pituitary will not oversecrete excess non-bioactive TSH anymore.
The tertiary CeH patient may only have an elevated TSH when FT4 is low-normal (when underdosed), but when FT4 is high, it’s likely that the TSH will suppress too far too soon, when the pituitary is getting enough T4 but not enough TRH. The lack of TRH may then be a bigger factor that lowers TSH.
This is why it may be necessary to have several lab tests at different times and different doses of T4 to discern a pattern of CeH in the treated patient with hypothalamic failure.
Consider the context of medical history
If you see any patterns in your TSH-Free T4 test relationship, now is the time to consider other telltale signs of central hypothyroidism.
If you can’t zoom in, see the original article online.
The only difference is that during thyroid therapy you may not be able to qualify for the initial state at the top of the flowchart, which presumes a person with low T4 who is NOT on thyroid therapy.
To go through the flowchart, you will need to know more about the potential causes and whether they line up with anything in your medical history.
Consider acquired CeH causes
Have you ever had a concussion or hit your head very hard? Traumatic brain injury is a major cause of CeH.
Consider the following in light of your health history:
The table on “congenital” and genetic causes is too large to duplicate here and would have to be viewed at the source: see the original article online.
Consider autoimmune etiologies of CeH
The vast majority of causes of pituitary and hypothalamus failure are not autoimmune. However, a few articles on autoimmune central hypothyroidism acknowledge the overlap with autoimmune thyroid disease.
One of the causes of central hypothyroidism not mentioned in the table is “Empty Sella” (ES), which some theorize to be an outcome of “lymphocytic hypophysitis.”
The word “hypophysis” is a medical synonym with “pituitary,” and of course, “-itis” is an inflammation. When someone is hypothyroid, the excess TSH secretion often causes the pituitary gland to expand, just like the thyroid gland can swell when overstimulated. Those who know about thyroid disease might find that “lymphocytic” rings a bell – Hashimoto’s used to be called “chronic lymphocytic thyroiditis.”
Research has been building up since 2005 associating cases of Primary Empty Sella, Lymphocytic hypophysitis, and primary autoimmune thyroid disease.
See the reference list.
Certain syndromes can mimic the biochemistry of central hypo when TSH and FT4 are viewed in isolation.
The list above does not mean that CeH cannot exist when they are present. It means that CeH may be “transient” or that CeH may not be the only condition that requires diagnosis.
A major condition not listed above is T3 therapy or desiccated thyroid therapy, which can suppress or lower TSH at euthyroid doses even when FT4 and FT3 are both in reference range. There are many reasons for this that I cannot go into here, but it has long been known that even metabolically euthyroid oral T3 dosing can be a TSH suppressant. It is largely due to the benign fluctuations in Free T3 during dosing.
If you suspect that you were misdiagnosed with primary hypothyroidism and your thyroid gland is actually functional, you could try assessing your thyroid gland health:
- Antibody testing to rule out autoimmune thyroid disease. Consider also testing for Graves’ disease antibodies because those can be present even in patients with Hashimoto’s thyroiditis. Graves antibodies can artificially reduce TSH at the pituitary ultrashort feedback loop even when the thyroid is disabled and thyroid hormones are too low.
- If Graves’ disease family history exists or thyroid nodules are suspected and you have thyroid tissue, examine your lab test history to see whether FT4 has increased significantly (more than 2-3 pmol/L) without an increase or decrease in LT4 dosage. Graves’ disease acting on a thyroid fragment can inflate FT4 even when TSH is fully suppressed, complicating diagnosis of any concurrent CeH.
- Thyroid ultrasound to look for normal dimensions (lack of thyroid atrophy) and normal ecogenicity to rule out fibrosis of tissue.
What can go wrong?
What are the medical consequences of undiagnosed CeH in thyroid therapy?
Sometimes you have to spell out the consequences before people are motivated to do anything about a potential problem.
First of all, if you have central hypothyroidism, your thyroid therapy can’t be guided by TSH. A person with CeH will be perpetually underdosed on thyroid medication if it’s adjusted by the current shortcut, by faith in TSH alone.
Since thyroid therapy lasts the rest of your life, that’s a long time to be underdosed.
Other hormone deficiencies
Secondly, if CeH has been overlooked, nobody will screen for deficiencies in other pituitary or hypothalamic hormones that often coexist with CeH.
Other hormones secreted by the pituitary and hypothalamus control adrenal glands, kidneys, sex organs, pregnancy and childbirth, obesity, and mental health. A multitude of mysterious symptoms can be misattributed to other causes and impact quality of life … until a major health crisis occurs.
And that’s the third problem. Health crises down the line. CeH may first present itself in a subtle manner, but it can worsen over time and increasingly interfere with overall health. You can also have an accident that injures already vulnerable organs.
Near impossibility of diagnosis during a health crisis
Once you’re in a health crisis in a hospital setting, you’re in the worst possible state for an accurate diagnosis of CeH.
In hospitals, doctors are taught to see central hypothyroidism as a temporary syndrome. CeH can be caused by critical illness itself. In “nonthyroidal illness syndrome,” TSH won’t rise as the body dumps thryoid hormones to lower metabolic rate. It can happen during the acute phase of any extreme illness. If they see CeH while you’re in the intensive care unit, they’ll shrug it off as a routine biochemical blip.
They’ll also shrug it off because it’s something they’re not permitted to treat the same way they would treat kidney or lung failure in the ICU. Why not? Because it’s not categorized as real hypothyroidism, because TSH is not high and they are told the pituitary knows best even in illness, and because it’s not caused by thyroid gland failure but by a thyroid hormone metabolism failure.
Despite all the literature showing high rates of death predicted by the low T3 hormone in critical illness, and even worse rates of death when T4 is high and T3 is low, doctors have a mistaken hope.
They are taught that if you, a thyroid patient, are destined to survive, it will have to happen naturally in spite of your thyroid disease. A sudden rise in TSH secretion will stimulate your healthy thyroid fragment, which will will dig you out of the low T3 hole. Alternatively, your T4 therapy that is converting more to RT3 than to T3 during illness will magically start converting to enough T3 again in time to save your life.
Have they studied thyroidless patients or CeH patients to test these hopeful assumptions? Nope. We’re routinely excluded from studies of “nonthyroidal” illness if they know we have a “thyroidal” illness.
The harms of a missed diagnosis are entirely plausible given the way the human body works (and fails) and the way our medical systems work (and fail).
The challenges of diagnosis mostly have to do with the way medical deference for TSH has blinded people from considering abnormal thyroid hormone – TSH relationships.
Medical systems don’t change just because individuals fall through the cracks.
They only change when large groups of people fall through the cracks and cost the health care system money, or when the identification of such groups provides a new opportunity for pharmaceutical profit.
Until that time comes (and it can only come after thyroid patients and/or researchers provide large scale data), individual self-education and self-advocacy is the only route to accurate diagnosis in complex cases of thyroid disease.
The diagnosis of central hypo during thyroid therapy is challenging, but it is possible with enough scientific knowledge and relevant health data.
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
Chatzitomaris, A., Hoermann, R., Midgley, J. E., Hering, S., Urban, A., Dietrich, B., Abood, A., Klein, H. H., & Dietrich, J. W. (2017). Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00163
Haugen, B. R. (2009). Drugs that suppress TSH or cause central hypothyroidism. Best Practice & Research. Clinical Endocrinology & Metabolism, 23(6), 793–800. https://doi.org/10.1016/j.beem.2009.08.003
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
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
Shimon, I., Cohen, O., Lubetsky, A., & Olchovsky, D. (2002). Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism. Thyroid: Official Journal of the American Thyroid Association, 12(9), 823–827. https://doi.org/10.1089/105072502760339406
Empty sella CeH — possibly autoimmune
García-Centeno, R., Suárez-Llanos, J. P., Fernández-Fernández, E., Andía-Melero, V., Sánchez, P., & Jara-Albarrán, A. (2010). Empty sella and primary autoimmune hypothyroidism. Clinical and Experimental Medicine, 10(2), 129–134. https://doi.org/10.1007/s10238-009-0071-z
Guitelman, M., Garcia Basavilbaso, N., Vitale, M., Chervin, A., Katz, D., Miragaya, K., Herrera, J., Cornalo, D., Servidio, M., Boero, L., Manavela, M., Danilowicz, K., Alfieri, A., Stalldecker, G., Glerean, M., Fainstein Day, P., Ballarino, C., Mallea Gil, M. S., & Rogozinski, A. (2013). Primary empty sella (PES): A review of 175 cases. Pituitary, 16(2), 270–274. https://doi.org/10.1007/s11102-012-0416-6
Lupi, I., Manetti, L., Raffaelli, V., Grasso, L., Sardella, C., Cosottini, M., Iannelli, A., Gasperi, M., Bogazzi, F., Caturegli, P., & Martino, E. (2011). Pituitary autoimmunity is associated with hypopituitarism in patients with primary empty sella. Journal of Endocrinological Investigation, 34(8), e240-244. https://doi.org/10.3275/7758
Molitch, M. E., & Gillam, M. P. (2007). Lymphocytic hypophysitis. Hormone Research, 68 Suppl 5, 145–150. https://doi.org/10.1159/000110611
Categories: Central hypo