IH (INTRACELLULAR HYPOTHYROIDISM)

Intracellular T3 deficiency

Intracellular T3 deficiency, referred to in this article as Intracellular Hypothyroidism (IH), has been given many names, but has not been recognized as a bona fide metabolic abnormality deserving of a formal title.
Thus although the condition was definitively described in 2014, it has been ignored by mainstream medicine and its diagnostic panel has yet to be added to the medical armamentarium.
It is time to accept this ubiquitous metabolic abnormality as the pervasive, important syndrome which it is.
This article therefore is intended to educate the public, and not least, my colleagues, on the subject of intracellular thyroid 3 hormone starvation.

History

Dr. Denis Wilson, a family physician unrelated to Dennis Wilson of the Beach Boys, suggested the idea of T3 deficiency in 1986. He accurately described the symptoms, correctly attributed the condition to failure of conversion of T4 to T3, erroneously named it “Wilson’s temperature syndrome” and perspicaciously treated it with sustained-release, rather than rapid-release, triiodothyronine.

Unfortunately, Dr. Wilson did not discuss his ideas with his peers and did not, as he could have, reach out to an academic colleague with whose assistance he could have presented his excellent idea to his profession.

Again unfortunately, although many of his treatments were successful, one of his patients took too much triiodothyronine and developed a cardiac arrhythmia, to which she succumbed. After that happened, Dr. Wilson was accused of “fleecing patients with a phony diagnosis” and excoriated by the medical profession, including the American Thyroid Association, the Florida Board of Medicine, the Mayo Clinic and many others.
He was disciplined by the Florida Board of Medicine, fined $10,000 and struck from the roster of physicians until he had submitted to psychological testing and undergone 100 hours of continuing medical education.
His medical license was not reinstated until he agreed not to prescribe Triiodothyronine.

The metabolism of thyroid hormones within individual cells has been explained more recently by Dr. Kent Holtorf, who in 2014, first described the effects of intracellular T3 starvation, ascribing it to failure of thyroid hormone transport into cellular tissue [1].
In a subsequent collaboration with Erika Schwartz, as the metabolic process became clearer, he briefly considered the descriptive title, “Reverse T3 Dominance”, in which rT3 was credited with an active role in blocking access of T3 to thyroid receptors [2]. Finally, in a paper on the subject, in 2014, [3] Dr. Holtorf succinctly explained the true situation:
Deiodinase 1 converts T4 into active T3 throughout the body.
Deiodinase 2 converts T4 into active T3 in the pituitary gland.
Deiodinase 3 converts T4 into rT3 and T3 into T2, but there is no D3 in the pituitary.
D1 is blocked, preventing conversion of T4 to T3, when cortisol rises in response to stress.
D2 is not affected by cortisol.
D3 is activated by cortisol. as an energy-saving measure, it converts T4 to rT3 and any pre-existing T3, to T2.

Therefore under stress, no T3 is produced intracellularly and pre-existing, or imported, T3 is destroyed.
By this means, intracellular T3 starvation ensues; but the pituitary gland and its output of TSH are unaffected.

Definition

Serendipitously discovered and named “Wilson’s temperature syndrome” by Dr. Denis Wilson in 1988 and later termed “Reverse T3 dominance” by Dr. Kent Holtorf in 2014, intracellular deficiency of T3 is termed “Functional Hypothyroidism” by the Metabolic Medicine community. It is also known as “Low T3 Syndrome”, “Subclinical Hypothyroidism”, “Euthyroid Sick Syndrome” and “Nonthyroidal Illness Syndrome”, in allopathic medicine.
However “Intracellular Hypothyroidism” (IH), succinctly describes an insufficiency of T3 in the cells [4].

Etiology

IH is due to two intracellular effects of cortisol, to which the pituitary gland is exempt:
(1) Blockade of Deiodinase 1, with failure of conversion of T4 to metabolically active T3.
(2) Activation of Deiodinase 3, which converts T4 to metabolically inactive reverse T3 and T3 to inactive T2.

As defined, IH (intracellular T3 deficiency) follows the release of cortisol by the adrenals, in response to stress.

Incidence

Intracellular Hypothyroidism is ubiquitous.

Conjecturally, it is the most pervasive metabolic aberration.
It may result from, or may complicate, any illness. Demonstrably, it complicates all life-threatening illnesses.
IH is found in the vast majority of chronic debilitating conditions; it is present in PTSD, in prolonged depression, in morbid obesity, in anorexia nervosa and in starvation.
It complicates severe physical injury, major surgery, significant psychoshock and any acute illness severe enough for admission to an intensive care unit.
It is associated with heart failure, cardiomyopathy [6,7], Long Covid [8], PTSD, Chronic Fatigue Syndrome [9], ME, Fibromyalgia, the Post-Finasteride Syndrome [9a], infertility with recurrent abortion, major depression, schizophrenia, chronic true hypothyroidism and a host of other conditions, including neurological and neuromuscular diseases such as Multiple Sclerosis, Parkinson’s disease, Alzheimer’s disease, Hoffman’s syndrome [10] and Stiff Person syndrome [11].
When it occurs in the first 20 weeks of pregnancy, it may cause all of the foetal cognitive and psychological defects previously ascribed to true hypothyroidism.

It is reasonable to conclude that IH accompanies each and every severe disease, but “the message has been lost in translation”. For example, an extremely thorough, erudite and otherwise admirable report on ALS [12], written in 2021, purports to consider all possible aetiologies of Amyotrophic Lateral Sclerosis; but the reported battery of tests, including a thyroid panel with TSH, FT4 and FT3, does not mention reverse T3.
IH cannot be diagnosed without reverse T3: thus IH, which is most likely either a background cause of ALS or a result of it, was excluded from the deliberations.

Duration

IH may be short-lived, existing only as long as brief stress persists, or may be a long-term partner to chronic stress [13].
It tends to self-perpetuate, because mental confusion, psychological uncertainty and anxiety produced by the hypothyroid condition keeps the affected person’s “subconsciously perceived” stress high, long after the Initiating stressful situation has passed.

Impostors/doppelgängers

IH is indistinguishable, in terms of its symptomatology, from true hypothyroidism, chronic fatigue syndrome, “long Covid”, PTSD and other conditions whose symptoms approximate those of hypothyroidism.
Thus chronic IH is probably the real cause of chronic fatigue syndrome (CFS) and is probably implicated in “Long Covid” [8]. it is likely, the baseline factor in “burnout” and a major underlying factor in “ennui”.

Diagnosis

Some individuals are able to hide, or ignore, low-thyroid symptoms. Therefore IH may seem asymptomatic, especially in confident people with high self-esteem, who can endure mild symptoms without complaint [13].
However it is very easily diagnosed Via laboratory testing of TSH, FT4, FT3 and reverse T3 (rT3).

The diagnosis of intracellular hypothyroidism is usually missed by doctors, because the T3/rT3 ratio, which is the only accurate indicator of IH, is not recognized as a valid parameter by the medical profession.

Reverse T3 is a sensitive marker of intracellular failure to convert T4 into normal T3 and its elevation is usually accompanied by suppression of serum Free T3. The combination, a normal TSH, normal FT4, low FT3 and high rT3, with calculation of the T3/rT3 ratio, is a sensitive marker of intracellular failure to convert T4 into normal T3. Therefore asymptomatic IH can be diagnosed confidently when the T3/rT3 ratio Is less than 20.

Caveat:
the cardinal test for diagnosis of IH is the T3/rT3 ratio: in IH, TSH and FT4 are usually normal; but if a previously hypothyroid individual develops IH, test results may show high TSH, low FT4, vanishingly low FT3 and only minimally elevated rT3.

Opinion

In view of the high incidence of unrecognized intracellular hypothyroidism, a “thyroid panel“, including the FT3/rT3 ratio, should be included in every diagnostic test series in addition to TSH and free T4 (FT4), whether or not a clinical diagnosis of hypothyroidism (“low thyroid syndrome”, “nonthyroidal illness”, etc.) seems likely.

Caveat
(1) Logically, the idea of “age-adjusted normal TSH and T4 levels” tries to negate an undeniable fact: the natural, age-related decrease of thyroxine production eventually delivers unsuspecting humans willy-nilly, into low-grade hypothyroidism.

(2) The “age-adjusted” paradigm fosters acceptance of hypothyroid effects as “normal” in most of the population: in fact, the “normal” ranges for TSH, FT3 and rT3, accepted by medical practitioners, are all suspect [15, 15b].
Wartofsky and Dickey, considering this problem in 2005 [14], were correct: the upper limit of normal for TSH should be 2.5 mIU/L, regardless of age. By their calculations, the TSH is elevated to >2.5 in uncomplicated true hypothyroidism, [14] and serum FT4 and FT3 are low.

(3) In IH, TSH and FT4 are usually normal, and FT3 at, or below, the low end of the FT3 range, while reverse T3 is sufficiently increased to reduce the FT3/rT3 ratio to less than 20.0 [15].

(4) Currently, a “normal range” for rT3, (10-25 MUI/L) has been postulated. in the opinion of metabolic medicine practitioners, there is no need for a “normal range” for rT3: the diagnostic “number” is the T3/rT3 ratio. If a range for rT3 must be specified, it should be a “preferred range”, of 7–13 (this is from “response to treatment” observations, between 2014 and 2021).

IH, combined with true hypothyroidism

True hypothyroidism (TH) may predate IH. When it does, investigation usually suggests TH, because
(1) TSH is elevated to > 2.5
(2) FT4 is low normal, or below the normal range,
(3) FT3 is low-normal, or below the normal range,
(4) rT3 production is restricted by the low T4, so it is only minimally elevated and the T/rT3 ratio is borderline.

Thus in combined true and intracellular hypothyroidism, IH is often masked until T4 is prescribed and a follow-up thyroid profile is done.
The situation then becomes obvious, because:
(1) TSH has returned to normal,
(2) FT4 has increased,
(3) FT3 remains low,
(4) rT3 has increased, due to preferential conversion of prescribed T4 to rT3, so the T3/rT3 ratio is less than 20.

Calculation of the T3/rT3 ratio, from test results

FT3 is reported in Picomoles per litre (Pm/L) and rT3 is reported in Nanograms per decilitre (ng/DL).
To obtain the ratio, first convert the FT3 value to ng/DL, by dividing FT3 by 0.0154.
Then divide the FT3 (ng/DL) by the rT3 value: this presents the “FT3/rT3 ratio”*.
The accepted normal ratio is >20 and the preferred optimum is >24.
Intracellular hypothyroidism is diagnosed if the ratio is <20.

Table, for calculation of T3/rT3 ratio in IH

By permission, from Cameron Sutherland:
T3 (picomoles/L) is in the light blue column.
T3 (nanograms/DL) occupies the yellow column.
Light blue horizontal numbers are reverse T3 values.
Normal T3/rT3 values are located in the pink area.
Subnormal T3/rT3 values are in the white area.

 T3/rT3 ratios: the numbers in light blue are rT3 values.

Rating the severity of IH:

It is reasonable to rate the severity of intracellular hypothyroidism thus:
7-10 = Severe, 11-15 = Moderate, 16-20 = Mild.
However the degree of IH varies with the individual’s stress level and it is in the patient’s interest that the clinician assume the worst.

Treatment protocol – choice of therapy

When IH, or combined TH and IH, is diagnosed, Triiodothyronine should be prescribed rather than Thyroxine [3, 4] or T3/T4 combinations, because exogenous thyroxine will be preferentially converted into reverse T3.
Thus desiccated thyroid, for example, may improve the intracellular T3 concentration, but the T3/rT3 ratio may not increase and any improvement in IH may be masked [4].
Appropriate therapy for any associated disease, if available, should be prescribed concomitantly.
The choice of triiodothyronine (T3) format is important: a Lyothyronine tablet is available, but its active content is rapidly released and absorbed [16], producing a “spike” of serum FT3, about two-and-one half hours post-dose, with resumption of the patient’s symptoms in the afternoon.
Compounded T3, in a slow-release format, is preferred [4]: it does not produce a “spike and crash” phenomenon and symptom relief persists throughout the day.
In hypersensitive or apprehensive subjects, therapy may begin with tiny (less than 5 µg) of triiodothyronine, provided in aqueous solution.

Treatment protocol – Titrating the dose of T3

(T3) is taken by mouth at, or close to, 4 AM, so as to mimic the diurnal rhythm of thyroid hormone release.
The prescription commonly begins with 5-10 µg of Triiodothyronine (Liothyronine) .
Serum T3 is estimated weekly*, increasing the T3 dose by 5 µg each week until an FT3 of 4.5-6.2 pmol/L is attained [4].
If a T3 test result >6.2 pmol/L is reported, the dose is reduced.
When a serum FT3 level of 5 pmol /L – 6.2 pmol/L has been reached, the prescription is renewed without change.

* The half-life of T4 is 6 or 7 days, so when Eltroxin or Synthroid are prescribed, the thyroid profile is repeated 6 weeks after the prescription is made, to ensure testing at a “steady-state” of T4 serum concentration. However T3’s half-life is 22 hours [16], so the blood tests can be done 7 days post-Rx.
* The half-life of oral Liothyronine varies with the individual’s thyroid function status and with the method of calculation, so it is variously reported by different investigators: perhaps the best estimate to date is that by Jacqueline Jonklaas et al [16] in 2015.

Caveat
– The T3/rT3 ratio shows whether an abnormality of thyroid hormone metabolism needs to be corrected and is valuable in follow-up. However T3/rT3 is not a “target”, in terms of calculating the dosage of slow-release T3: the serum FT3 level is better.
Therefore Serum rT3, to confirm a normal T3/rT3 ratio, is not checked until after the optimum dose has been selected.
– The patient’s symptoms are more important than the serum FT3 and for “perfect” physical and psychological function, some individuals need to maintain FT3 at, or slightly over, the accepted upper limit of normal.

Successful therapy

Oral triiodothyronine is absorbed into the cells.
Remission of IH is achieved when the daily dose of triiodothyronine is sufficient to overcome the effects of D3, increasing the intracellular T3 concentration.and thereby normalising cellular efficiency.
Hypothyroid symptoms, including cognitive and psychological effects, regress as control of IH develops, .
Relief from psycho-cognitive aberration banishes perceived stress, so the “call” for cortisol production is reduced.
By this means, the metabolic response to stress is eliminated and the patient returns to normal.
Therapy with triiodothyronine should be continued until the individual’s stressors cease: if the cause of stress cannot be avoided, continuing therapy, possibly at a reduced dose, may be necessary.

Follow-up

So as to avoid recurrence of IH, it is best to maintain serum FT3 of 4.5 – 6.2 pmol/L.
Fluctuating stress may render cortisol production, and  its effects on intracellular T3 concentration, variable. Therefore the patient’s symptomatology and FT3/rT3 ratio are reviewed every 3 months for a year and thereafter, yearly.

Caveat: as suggested by the gradual increase of TSH, T4 secretion by the thyroid falls with age and the older person may not naturally produce sufficient T4 to ensure adequate intracellular T3 levels [14].
The elder population is therefore more susceptible to IH, since their baseline intracellular T3 concentration is reduced.
Therefore the aged are more likely to need ongoing triiodothyronine replacement therapy, with more frequent surveillance of the T3/rT3 ratio as a guide.

Discontinuation of therapy

Occasionally (more often in younger subjects), stress can be completely eliminated, in which case IH remission occurs. When this happens, it may be reasonable to reduce, or discontinue, T3 treatment.
However a relapse to IH is likely, if stress recurs.

Takotsubo cardiomyopathy, which remits with stress relief and recurs with subsequent stress, is the best example of this phenomenon.

A special problem

Intracellular hypothyroidism is a particular danger in pregnancy.

In terms of the mother’s serum FT3 level, IH is no different than true hypothyroidism, but it is not recognized and not treated.
This is to the detriment of the foetus, who is liable to all the effects of maternal hypothyroidism, including cognitive deficits, ADD, ADHD, dyslexia, autism, schizophrenia and gender dysphoria [17].
With this in mind, a “thyroid panel”, including T3 and rT3, should be checked prior to conception, or at the latest, immediately upon the diagnosis of pregnancy and the T3/rT3 ratio should be reviewed immediately, by a functional medicine professional.
Mothers with IH should be treated with triiodothyronine, utilizing the protocol outlined above and therapy should be continued until the 20th week of pregnancy, so as to provide the fetus with the benefit of normal availability of T3. After the 20th week, therapy should be continued for the mother’s benefit, or at the least, the supervising practitioner should ensure that she has an adequate intake of iodine, selenium etc., so as to provide the developing baby with the necessary nutrients for thyroid gland function.

REFERENCES

[1] Thyroid Hormone Transport into Cellular Tissue. By Kent Holtorf,  Journal of Restorative Medicine 3(1):53-68,
April 2014, DOI:10.14200/jrm.2014.3.0104

[2] Hormones in Wellness and Disease Prevention: Common Practices, Current State of the Evidence, and Questions for the Future. By Erika T. Schwartz, MD, Kent Holtorf, MD, Prim Care Clin Office Pract 35 (2008) 669–705
https://custommedicine.com.au/health-articles/reverse-t3-dominance/

[3] Peripheral Thyroid Hormone Conversion and Its Impact on TSH and Metabolic Activity, Kent Holtorf, MD, Journal of Restorative Medicine 2014; 3: page 30, 2014, DOI 10.14200/jrm.2014.3.0103

[4] T3 and intracellular Hypothyroidism. By Gervais A. Harry, cbhrt.ca, 2022. Https://cbhrt.ca/intracellular-hypothyroidism/

[5] “Cortisol”, by G. A. Harry, at cbhrt.ca, 2022 https://cbhrt.ca/cortisol/

[6] Myocardial Induction of Type 3 Deiodinase in Dilated Cardiomyopathy (experimental, Mice). By Ari J. Wassner,¹Rebecca H. Jugo,¹David M. Dorfman,²Robert F. Padera,²Michelle A. Maynard,¹Ann M. Zavacki,³Patrick Y. Jay,⁴ and Stephen A. Huang¹ . Thyroid. 2017 May 1; 27(5): 732–737. Published online 2017 May 1. DOI: 10.1089/thy.2016.0570PMCID: PMC5421592PMID: 28314380. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421592/

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[8] Euthyroid Sick Syndrome in Patients With Covid-19. By Runmei Zou,^1,† Chenfang Wu,^2,† Siye Zhang,² Guyi Wang,² Quan Zhang,³ Bo Yu,² Ying Wu,² Haiyun Dong,² Guobao Wu,² Shangjie Wu,⁴ and Yanjun Zhong^2,*. Front Endocrinol (Lausanne). 2020; 11: 566439. Published online 2020 Oct 7. DOI: 10.3389/fendo.2020.566439

[9] Higher Prevalence of Low T3 Syndrome in Patients With Chronic Fatigue Syndrome: A Case–Control Study.
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[9a] The Post-Finasteride Syndrome, a direct effect of five-alpha reductase blockade, by G. A. Harry, in Research Gate, November 2022, DOI: 10.13140/RG.2.2.33404.82561

[10] Hoffman’s syndrome – A rare facet of hypothyroid myopathy, by Swayamsidha Mangaraj and Ganeswar Sethy, Neurosci Rural Pract. 2014 Oct-Dec; 5(4): 447–448. PMCID: PMC4173264PMID: 25288869
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[11] “Stiff person syndrome” – https://my.clevelandclinic.org/health/articles/6076-stiff-person-syndrome

[12] Amyotrophic lateral sclerosis (ALS) and the endocrine system: Are there any further ties to be explored? , By Alexios-Fotos A Mentis, Anastasia M Boujea and George P Chrousos, in “Aging Brain”, Volume 1, 2021, 100024

[13] Biography of a Doctor (a case report). By G. A. Harry. cbhrt.ca. April 2023.
Https://cbhrt.ca/2023/04/25/biography-of-a-doctor/

[14] The evidence for a narrower thyrotropin reference range is compelling.
By Leonard Wartofsky ¹ , Richard A Dickey, J Clin Endocrinol Metab, 2005 Sep; 90(9):5483-8PMID: 16148345.https://pubmed.ncbi.nlm.nih.gov/16148345/
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[15] Thinking about normal. Cbhrt.ca 2021. By G. A. Harry. https://cbhrt.ca/2021/10/23/thinking-about-normal/.
[15b] THYROID TESTS: SHOULD OUR THYROID HORMONAL ASSESSMENT BE REVIEWED? by G. A. Harry. Cbhrt.ca, 2021. https://cbhrt.ca/2021/11/05/thyroid-tests/

[16] Single-dose T3 administration: kinetics and effects on biochemical and physiological parameters. By Jonklaas J, Burman KD, Wang H, Latham KR. Ther Drug Monit. 2015 Feb;37(1):110-8. PMID: 24977379; PMCID: PMC5167556.
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 (17) Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study, by S L Andersen  ¹ , P Laurberg, C S Wu, J Olsen, PMID: 24605987,
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[18] Defending plasma T3 is a biological priority. Sherine M. Abdalla, Antonio C. Bianco. Clinical Endocrin., Volume81, Issue5, Review, November 2014, Pages 633-641: 05 July 2014 https://doi.org/10.1111/cen.12538