If even the experts complain that it’s difficult to diagnose central hypothyroidism before thyroid therapy, it can be almost impossible for the medical system to begin to see your central hypothyroidism during thyroid therapy.
Once you are on thyroid therapy and your doctor has already categorized you as a Primary hypothyroid patient, how many will even consider Central hypo as an additional, overlapping diagnosis?
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.
In a medical climate in which people have put TSH in charge over everything to do with a thyroid even after the thyroid is dead or gone, hardly anyone ever suspects defective TSH secretion could be a problem.
Accusing TSH as a primary hypothyroid patient is like accusing the king of harassment after you’ve been made his slave and you depend on him for your daily meal of scraps. If your TSH is truly not trustworthy, you can’t accuse him and win your case unless you have evidence.
Our medical system has been blinded by gland-centric and mutually-exclusive definitions of central hypothyroidism, claiming that “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)
Wait a minute! Why do they say “an otherwise normal thyroid gland”? Does this mean that in all cases of CeH, the thyroid gland is normal? Of course not. But gland-centrism blinds people, even the experts.
Let’s be reasonable. Is there any law of nature saying that your thyroid gland and pituitary gland can’t both fail, or that your thyroid can’t fail first, then your hypothalamus? Of course not. But a skeptic will naturally think “what are the chances of that?” and they’ll ask “Where is the research on that?”
CeH is rare, according to statistics. But even the experts say its incidence is under-reported. It’s rarely diagnosed because it’s rarely screened for, because TSH alone can’t screen for it. If that’s the situation we’re in, how many research articles are likely to be written about finding CeH during thyroid therapy when guidelines say thyroid therapy is supposed to be monitored by TSH alone?
Now let’s look at the opposite likelihood. How likely are you to be mistakenly diagnosed with a thyroid gland problem when you actually have a hypothalamus TRH secretion problem making your TSH untrustworthy?
Now that’s actually more likely.
You could have been diagnosed when you were oversecreting a TSH of 10.0 mU/L that was not bioactive enough to stimulate any thyroid. Really? Yeah. Persani and Beck-Peccoz show graphs (shown below) proving that defective TSH can sometimes be elevated as high as 10 mU/L, which makes you look deceptively like a case of primary hypothyroidism.
Everyone knows primary hypo. We too easily blame the devil we know before the devil we don’t know.
What can you do?
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.
I’ll show you what patterns to look for in your thyroid lab tests and your health history so you can consider further testing — or you can rule out the likelihood of CeH before wasting a lot of time and anxiety on the issue.
If you suspect your TSH is abnormally low per unit of Free T4 during thyroid therapy, and if you’ve ruled out the usual suspects —
- if it’s not entirely explainable by higher-normal levels of Free T3 hormone during thyroid therapy when dosing T3,
- if it’s not entirely explainable by dosing corticosteroids or prednisolone or other known “Drugs that suppress TSH or cause Central Hypothyroidism” (Haugen, 2010),
- if it’s not entirely explainable by other well-studied TSH-lowering conditions like calorie restriction or chronic exhausting exercise (See Table 2 in Chatzitomaris et al),
Once you’ve ruled out these and other usual suspects that oversuppress the TSH, it is time to learn and screen for permanent underlying 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.
What CeH looks like during therapy
Here is a pattern you can look for in your thyroid lab tests.
You need TSH and Free T4 as a bare minimum.
If your 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.
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 so happy 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 on their glucocorticoids, but we can assume since their CeH diagnosis when thyroid therapy began.
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.
Therefore, if you have enough lab history, you can plot a graph with your 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)
Now, 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.
Now, 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 rise in tertiary hypothyroidism?
- 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.
Because the pituitary can’t sense enough bioactive TSH floating around, it is secreting more TSH than it normally would.
How do you 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.
Autoimmune central hypo
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, “-it is” 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
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Categories: Central hypo