SHOULD OUR THYROID HORMONAL ASSESSMENT BE REVIEWED?

Currently, our “system” says that to figure out whether a person’s thyroid balance is satisfactory in terms of keeping our cells working at maximum efficiency, all we need to check is the Thyroid Stimulating Hormone. However TSH is a signal sent by the pituitary gland, to tell the thyroid how much T4 to make.
THIS HAS NOTHING TO DO WITH THE REST OF THE BODY:
the pituitary is merely ordering Thyroxine, to satisfy itself.

WHAT OUR MEDICAL SYSTEM IGNORES

Since FT3 is rarely, and rT3 never, measured, family physicians and endocrinologists are unaware of the state of thyroid hormonal balance in the cells and organs: the body has no way of expressing its state of satisfaction, and other than T4/FT3 /rT3 we don’t have a dedicated test for thyroid balance.
We can, however resolve the dilemma with minimum civil disobedience: let’s see FT3 and rT3 results and figure it out!

 METABOLISM OF THYROXINE, THE “T4” HORMONE

T4 is converted preferentially to T3 rather than rT3 under normal circumstances, but when Cortisol output rises due to fasting or any other stress [1,2], FT3 production falls and rT3 increases, while TSH and FT4 are only minimally affected.

If rT3 goes up when T3 goes down, we can estimate the “strength” of the shift by dividing the T3 value by that of rT3; the ratio thus derived is a measure of the severity of the process and the depth of pathological deviation from normal T3/rT3 balance.

It has been observed that when the FT3/rT3 ratio is less than 20.0, hypothyroid symptoms appear; we differentiate this from true Hypothyroidism with a new term: “Intracellular Hypothyroidism”. **

Clinical observation confirms that Hypothyroid symptoms coincide with this logic and that therapy with slow-release Triiodothyronine reliably relieves those symptoms.

** the old names for intracellular hypothyroidism were: low T3 syndrome, nonthyroidal illness syndrome, euthyroid sick syndrome and functional hypothyroidism.

TREATING FUNCTIONAL HYPOTHYROIDISM

Treatment with Sustained Release T3 is safe and side effects (SE) are minimal.

Compounded, slow-release triiodothyronine is prescribed, beginning with 5 µg per day (taken close to 4 AM, so as to mimic the diurnal surge of T3). The dose is increased in 5 µg increments, following a weekly re-estimation of T3, to a target T3 of 5.0 – 6.2 pmmol/L.

As the serum FT3 rises, the rT3 falls and the symptoms subside.

Usually, FT3/rT3 exceeds 20.0 when the serum FT3 rises above 4.5, but a FT3 of 5.0-6.0 and a ratio of >23 are the targets of choice.

The most frequent SE is a feeling of being “high”, with enhanced vision and other sensory abilities, but some subjects have noted a hyper-reactive state, irritability, “antsiness” or increased pulse rate.

If SEs ensue the dose is reduced to the previous level.
TSH, FT4, FT3 and rT3 are repeated at a dose of 25mcg, and then, following each dose increase above 25 µg and the dose is modified, to yield a FT3 between 5.0 and 6.0.

Note that logically, there is no rational need for a “normal range” for reverse T3, since rT3 is not a metabolite. Its only value is as a marker for reduced conversion of T4 to T3.

rT3 “normal”, according to our laboratories, is “5 – 25 nanograms/DL”, but the range is grossly overestimated: for maintenance of a functionally euthyroid state, the serum rT3 should be between 5 and 13 ng/DL.
The level usually falls below 13 Nanograms/Decilitre when T3 exceeds 5.0 pM/Litre.

EFFECT OF THERAPY WITH TRIIODOTHYRONINE

The endpoint of therapy is elimination, or suppression, of hypothyroid symptoms, as judged by the patient.
Successful therapy reduces the perception of stress, whether or not the individual’s stressors are lessened and relapse is unlikely as long as treatment continues.
SRT3 can be discontinued if the stress is eliminated, but hypothyroidism will relapse if it recurs.

CAVEATS:

Weight loss may occur, but SRT3 MUST NOT BE PRESCRIBED FOR WEIGHT CONTROL.
The endpoint of therapy is elimination, or suppression, of hypothyroid symptoms, as judged by the patient.
Successful therapy reduces the perception of stress, whether or not the individual’s stressors are lessened. However relapse is unlikely as long as treatment continues.
SRT3 can be stopped if stress is eliminated, but hypothyroidism will relapse if it recurs.
If the serum T3 exceeds 6.2, the T3 dose should be reduced, to avoid hyperthyroidism.
If the serum T3 is less than 4.5, stress-related recurrence of intracellular hypothyroidism becomes more likely.

ANCILLARY PRESCRIPTIONS

DHEA, progesterone are often necessary because they decline after age 25.
Iodine and Selenium supplements may help if the patient has true hypothyroidism. Successful prescription of Triiodothyronine does not affect the patient’s requirement for other supportive hormone replacements or prescribed medications.
However the body’s Glucose and Cholesterol control will improve, rendering antidiabetic and anti-cholesterol medications unnecessary.
Further, antihypertensives, cognitive support, soporifics and psychoactive drugs can often be stopped or reduced as the patient’s condition and symptoms improve.

REGARDING THE “NORMAL” RANGES OF T3, REVERSE T3 AND TSH

TSH: the upper limit of “normal” (4) is much too high: it should be 2.5 .

T3: the lower limit of “normal” is low: it should be 4.0, to avoid intracellular hypothyroidism.

rT3: the range of normal should be 5 – 13, not 5 – 25: to achieve a T3/rT 3 ratio of <20, the patient will need a TSH of >5 if the rT3 is >14.

The normal level of Reverse T3, nominally 5 to 25, is difficult to assess.
Similarly to T3 and TSH “normals”, it has been subject to error.
Functionally hypothyroid subjects have been included in the group of “normal” people whose thyroid profiles have been used to calculate the reference ranges.

I have seen approximately 300 cases: my opinion is that the rT3 level is only significant because it gives laboratory evidence of excessive conversion of T4 to rT3.
We don’t need a “normal” for rT3: such a value is unnesessary, perhaps confusing. Having said which, I would suggest a nominal “Normal” of 5-13 Ng/DL.

NOTES

• Patients given Eltroxin or Synthroid during an episode of functional hypothyroidism, while T4 is being preferentially converted to rT3, experience worse hypothyroid symptoms.
  This is because the T4 is converted to rT3, which forces Deiodinase 3 to convert any normal T3 remaining in the cell, into T2, which is “garbage”.
  Therefore the T3 level goes even lower and the hypothyroid symptoms get worse.

• Patients who experience a stressful episode while on treatment for intracellular hypothyroidism, may have the same problem If their T3 dose is too low.
• Dessicated Thyroid should not be used to treat stress-related intracellular hypothyroidism, because desiccated thyroid is 70% T4 and 30% T3.
  The T4 in it may increase symptoms, just like Eltroxin.
• Patients taking T3 (slow-release) often reduce rT3 production to < 9 Ng/DL.
• Since T3 usually penetrates the Pituitary and since the Pituitary actually uses its level of T3, not T4, to gauge its TSH output, TSH can go as low as <<1.0.
• Reduced TSH results in minimum T4 production by the thyroid, so sometimes we see a T4 of 8 or less during SRT3 treatment. THIS IS NOT A CAUSE FOR CONCERN.

Most often, T3 taken by mouth enters the pituitary easily and TSH falls to a minimum. However in a few people, the T3 can’t get into the pituitary: so the pituitary calls for more T4 by increasing its TSH production.
When this happens, the tests show a high-normal T3 and very low rT3.
In these cases, the test results look weird; but the situation is actually very simple.
A prescription of a low-dose of T4 (Eltroxin or Synthroid), is all that is needed to keep the pituitary gland happy: a small amount of it may be converted to reverse T3, but not enough to cause a problem.

NOTES:

In 2014, two of my patients stopped their T3 and subsequently presented to an ER with FT3 of 1.7: both had myxoedema and heart failure.

Check TSH, as an indicator of the Pituitary’s need for T4, but not for T3 balance.

The Normal for T3/rT3 being > 20, the optimal level should arguably, be 24-50.

The T3 range, currently skewed because a large, unrecognised percentage of our population is functionally hypothyroid, should be reviewed and a new “normal” scale should be proposed.

THIS TABLE WAS DEVISED FOR A PREVIOUS ITERATION:
I INCLUDE IT HERE, “JUST FOR FUN”

T3 (in Pm/L)	T3,Ng/DL	rT3,Ng/DL	T3/rT3	DIAGNOSIS	COMMENT
2.8 (Lo N)	181.8	10	18.2	Mild IH	Includes endemic hypothyroidism
3.2 (old LowN)	207.8	11	18.9	Mild IH	Need rT3 <11, to be Euthyroid
5.0 (Opt. LoN)	324.7	25 (Lab High N)	13.0	Severe IH	Need rT3 < 16 to be Euthyroid
5.0	324.7	20 (Lab High Mid)	16.2	Moderate IH	Need rT3 < 16 to be Euthyroid
5.0	324.7	17 (Lab Low Mid)	19.1	Mild IH	Need rT3 < 16 to be Euthyroid
5.8(New HiN	376.6	19	19.8	Mild IH	Need RT3 <19 to be Euthyroid
6.2 (Opt Hi N	402.6	21 (Lab Mid-High)	19.2	Borderline IH	Need rT3 < 20 to be Euthyroid
6.2 (Opt Hi N)	402.6	25 (Lab High N)	16.1	Moderate IH	Need rT3 < 20 to be Euthyroid
7.6 (Hi++)	493.5	25	19.7	Still has IH	If rT3 = 25, Need T3 > 7.6 to be Euthyroid

REGARDING TSH

In 2005 Leonard Wartofsky and Richard A Dickey wrote, (paraphrased, for brevity):
“It has become clear that our reference ranges are no longer valid.”
We have more sensitive TSH tests and also, we now realise that
previous reference populations included people with (low) thyroid dysfunction, whose high TSH levels led to a spuriously high reference range for TSH in the group.
Recent laboratory guidelines from the National Academy of Clinical Biochemistry indicate that more than 95% of normal individuals have TSH levels below 2.5 mU/liter.”

In 2007 Martin I. Surks and Joseph G. Hollowell said as follows (paraphrased, for brevity)……
“The TSH median, 97.5 centile and prevalence of subclinical hypothyroidism (SCH) increase progressively with age.
Age-adjusted reference ranges would include many people with TSH greater than 4.5 mIU/liter.” *
They continued: (”Without thyroid disease”), 10.6% of 20- to 29-yr-olds had TSH greater than 2.5 mIU/liter. *
In 80+ year-olds, “without thyroid disease”, 14.5% had TSH greater than 4.5 mIU/liter. *
TSH frequency distribution curves of the 80+ year-old group showed higher TSH.

The 97.5 centiles for the 20–29 and 80+ year-olds were 3.56 and 7.49 mIU/litre, respectively.

70% of older patients with TSH greater than 4.5 mIU/liter were within their age-specific range (up to 7.49)**. In spite of these findings (almost 100% of) our medical doctors preferred to think like Surks and Hollowell and the reference range for TSH has remained unchanged. ***

However to me, the implications are clear:
· Wartofsky and Dickey were correct: the upper limit of normal TSH should be 2.5.
· Surks and Hollowell would have done better to label the older folks hypothyroid, rather than concluding that “high TSH is normal for the older population”.
What their findings mean is that a large percentage of the 80+-year-olds were hypothyroid and should have been excluded from calculations of normal.
In addition,they should have realised that 10.6% of their 20-29-year-olds were also hypothyroid and should have excluded them. ****

* AGE-SPECIFIC NORMAL, or “NATURAL NORMAL”, makes no sense.

“Normal” should be understood to mean the status of healthy humans aged 20-25 with no abnormal results for any test: any abnormal finding should disqualify the candidate for all estimates of “normal”.

** Any result >2.5 suggests hypothyroidism, so this implies that more than 14.5% of the 80+ year olds were hypothyroid.
Including them in the “normal” group means that 15+% of 80-yr-olds won’t get the treatment they need.

*** I dare suggest that one should apply fair logic to every scientific paper, so as to exclude glaring errors and prejudices like these from your belief systems.

**** Think about it – if I am right, since the thyroid hormone dictates the efficiency level of every cell and system in the body, and if 10.6% (or more) of the thyroid test study population should have been excluded from the calculation of “normal” thyroid hormone levels, then
The parameters for our other tests could be wrong: maybe a lot of tests are invalid!

MESSAGE

· Many other hormones suffer the same fate as DHEA: Melatonin, Progesterone, Allopregnanolone, Testosterone and Thyroid hormone all go down over time, mostly by slow, gradual loss of production.

· In some people several hormone levels can “crash” suddenly, causing various symptoms of deficiency depending on which hormones are involved.
This can happen with Melatonin in the “teens”, Progesterone and Allopregnanolone in the twenties, Testosterone in the thirties or earlier and particularly Oestrogen, which disappears naturally in the early fifties but can fall to almost zero in the late thirties or early forties and to absolute zero . If the ovaries are surgically removed .

· Thus assesssment of “normal” in the presence of “natural age related hormonal change” is very difficult.

· To give medical investigators their due, an effort is always made to include only the fittest individuls in the group evaluated. However there are instances in which unknown or ignored factors lead to a “curve ball” situation and consequent unreliability of an accepted “normal” range.

· IN SUMMARY, aberrations of hormonal production are pervasive and there is a delicate interdependence of hormonal systems.
Test subjects should be BETWEEN AGE 20 AND 25 YEARS and
ALL THEIR OTHER RESULTS SHOULD BE 100% NORMAL
If not, they should be excluded from studies to calculate a “normal” reference range.
This should apply for whatever test is to be evaluated.

  REFERENCES

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[2] Diversion of peripheral thyroxine metabolism from activating to inactivating pathways during complete fasting, A G Vagenakis, A Burger, G I Portnary, M Rudolph, J R O’Brian, F Azizi, R A Arky, P Nicod, S H Ingbar, L E Braverman, PMID: 1150863, DOI: 10.1210/jcem-41-1-191 J Clin Endocrinol Metab, 1975 Jul;41(1):191-4. doi: 10.1210/jcem-41-1-191. https://pubmed.ncbi.nlm.nih.gov/1150863/

(3) The evidence for a narrower thyrotropin reference range is compelling
Leonard Wartofsky ¹ , Richard A Dickey, J Clin Endocrinol Metab, 2005 Sep; 90(9):5483-8 PMID: 16148345 DOI: 10.1210/jc.2005-0455 .https://pubmed.ncbi.nlm.nih.gov/16148345/

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Martin I. Surks, Joseph G. Hollowell, The Journal of Clinical Endocrinology & Metabolism, Volume 92, Issue 12, 1 December 2007, 4575–4582, https://doi.org/10.1210/jc.2007-1499 01 Dec. 2007.
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PM ID: 124-2390, DOI: 10.121 0/jcem–41–5–911 the(11) https://pubmed.ncbi.nlm.nih.gov/1242390/

(12) Diversion of peripheral thyroxine metabolism from activating to inactivating pathways during complete fasting, A G Vagenakis, A Burger, G I Portnary, M Rudolph, J R O’Brian, F Azizi, R A Arky, P Nicod, S H Ingbar, L E Braverman, PMID: 1150863, DOI: 10.1210/jcem-41-1-191 J Clin Endocrinol Metab, 1975 Jul;41(1):191-4. doi: 10.1210/jcem-41-1-191. https://pubmed.ncbi.nlm.nih.gov/1150863/

G. A. Harry, MB, BS (London), LMCC, FRCSC (urology), ABAARM (A4M, 2014).