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INTRACELLULAR HYPOTHYROIDISM
== 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. ==

History
== Dr. Denis Wilson, a family physician unrelated to Dennis Wilson of Beach Boys fame, developed the concept of T3 deficiency in 1986. He accurately described the symptoms, correctly attributed the condition to failure of conversion of T4 to T3, inaccurately 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 at large. ==

Again unfortunately, although most of his treatments were successful, one of his patients overdosed Triiodothyronine and presented with a cardiac arrhythmia, to which she succumbed.
== 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. However over the years he steadily gained a stellar reputation and has trained many physicians in the diagnosis and management of "Wilson's temperature syndrome". ==

== The disturbed metabolism of thyroid hormones within individual cells, which leads to a syndrome in which reduced body temperature is one of many effects, has been explained more recently by Dr. Kent Holtorf, who in 2014, first described the effects of intracellular T3 ablation, ascribing it to failure of thyroid hormone transport into cellular tissue [1]. ==

== In a subsequent collaboration with Dr. Erika Schwartz, when 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]. ==

Definition
Stress-related, cortisol-mediated intracellular T3 starvation, originally serendipitously discovered and named “Wilson’s Temperature Syndrome” by Dr. Denis Wilson and later termed “Reverse T3 dominance” by Dr. Kent Holtorf, is called “Functional Hypothyroidism” by the Metabolic Medicine community.

It is also known as “Low T3 Syndrome”, “Subclinical Hypothyroidism”, “Euthyroid Sick Syndrome” and “Nonthyroidal Illness Syndrome”, by allopathic medicine.

However a new term, “Intracellular Hypothyroidism” (IH), succinctly describes an insufficiency of T3 within 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 into metabolically active T3 and

(2) Activation of Deiodinase 3, which converts T4 to metabolically inactive reverse T3 and T3 to inactive T2.

(3) As defined, IH (intracellular T3 deficiency) follows the release of cortisol by the adrenal glands, 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 and demonstrably, it accompanies all life-threatening illnesses.

IH is found in the vast majority of chronic debilitating conditions; it is present in prolonged depression and in morbid obesity, in anorexia nervosa and 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 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, in an extremely thorough, erudite and otherwise admirable report on ALS [12], published in 2021, which purports to consider all possible aetiologies of ALS, the reported battery of tests includes a thyroid panel consisting of TSH, FT4 and FT3. There is no mention of reverse T3, without which IH cannot be diagnosed, and thus IH, possibly 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 stressful situation has passed.

Thus chronic IH is often confused with chronic fatigue syndrome (CFS) and is probably implicated in “Long Covid” [8].

Diagnosis
Some individuals are able to hide, or ignore, low-thyroid symptoms.

So IH may be asymptomatic, especially in confident people with high self-esteem, who tend to endure mild symptoms without complaint [13].

However rT3, though nonfunctional, is a sensitive marker of intracellular failure to convert T4 into T3 and asymptomatic IH can be diagnosed confidently when the T3/rT3 ratio exceeds 20.

The diagnosis of IH is usually missed by doctors, because in IH, the pituitary gland is unaffected and TSH production is normal, but the medical establishment believes TSH to be the only true diagnostic parameter for thyroid function.

Therefore a “thyroid panel“, including the free T3 (FT3)/reverse T3 (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 has been made.

Caveat

- Logically, the idea of “age-adjusted normal TSH and T4 levels” denies an undeniable fact: the natural age-related reduction of thyroxine production eventually delivers unsuspecting humans willy-nilly, into low-grade hypothyroidism.

- The “age-adjusted” paradigm fosters acceptance of hypothyroid effects as “normal” in most of the population: thus the “normal” ranges for TSH, FT3 and rT3, accepted by medical practitioners, are all suspect [15, 15b].

- Wartofsky and Dickey [14], reporting in 2005, expressed the opinion that the upper limit of normal for TSH should be 2.5 mIU/L, regardless of age. They were were correct:

- In uncomplicated true hypothyroidism, the TSH is elevated to >2.5 [14] and serum FT4 and FT3 are low.

- In IH, TSH and FT4 may be normal, and FT3 at, or below, the low end of the “normal” FT3 range, but reverse T3 is sufficiently increased to reduce the FT3/rT3 ratio to less than 20.0 [15].

- In fact, diagnostic errors occur even when rT3 is tested, because the “normal” (10-25 MUI/L) range for rT3 is also incorrect (If rT3 were 25, FT3 would have to be > 8, to render the FT3/rT3 ratio > 20).

Comparison with true hypothyroidism
True hypothyroidism (TH) may coexist with IH and 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, the 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 exogenous T4 to reverse T3 and the T3/rT3 ratio is less than 20.

Calculation of the T3/rT3 ratio, from the thyroid profile 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

T3/rT3 ratio table, by permission from Cameron Sutherland: the light blue horizontal numbers are reverse T3 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 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.

Treatment protocol - Titrating the dose of T3
(T3) is taken at, or close to, 4 AM, so as to mimic the diurnal rhythm of thyroid hormone release.

The prescription begins with 5 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 the thyroid profile is not repeated until 6 weeks after prescribing thyroxine, to ensure testing at a “steady-state” of T4 serum concentration, but T3’s half-life is 22 hours [16], so the T3 can be checked at 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 provided by Jacqueline Jonklaas et al [16] in 2015.

Caveat

- Serum rT3, to confirm a normal T3/rT3 ratio, is not checked until 2 weeks after the optimum dose has been selected.

- 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 for the individual: the serum FT3 level is better.

- 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, thus

reinstituting cellular efficiency by increasing the intracellular T3 concentration.

As control of IH develops, hypothyroid symptoms, including cognitive and psychological effects, regress.

Relief from psycho-cognitive aberration banishes perceived stress and 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 discontinue: 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 between 4.5 and 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.

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.

Special situation: Intracellular hypothyroidism is a particular danger in pregnancy.
IH is no different than true hypothyroidism, excepting that 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, 19].