The thyroid hormone and Intracellular hypothyroidism

THE SIMPLE TRUTH

THE THYROID GLAND MAKES THYROXINE (T4).
T4 is the raw material from which TRIIODOTHYRONINE (T3) is made. It has no other function.
T3 is essential for efficient function of all cells in the body: without it, all systems would fail.

The thyroid also produces 20% of the body’s T3 and CALCITONIN, which reduces blood calcium.

HOW T4-to-T3 CONVERSION HAPPENS AND WHAT IT DOES
T4 is a protein molecule with 4 Iodine atoms. It is an inactive “prohormone”, from which an Iodine atom can be removed by any one, of 3, “de-iodinase” enzymes (D1, D2, & D3).
D1 and D2 remove a particular Iodine atom, to make T3, which has a special shape.
T3 fits into “T3 receptors”, * designed to accept T3 molecules, which are present in all cells, including those of the Pituitary. When T3 plugs in, it increases the cells’ efficiency.
D3 removes a different Iodine atom, producing “reverse T3” (rT3), which doesn’t work.
Normally, the cells change approximately 60% of available T4 into T3 and 40% into rT3.

CATCH 22: UNDER STRESS, D1 STOPS WORKING INSIDE YOUR CELLS!
All the cells of the body, except the Pituitary, have D1 and D3.
The Pituitary only has D2, for making T3. It does not have D1 or D3.
Under stress, the “stress hormone”, Cortisol, is released from the adrenals.
On entering the cells, cortisol blocks D1 and “promotes” D3.
So the cells make rT3 instead of T3: they become T3 deficient.
I call this intracellular T3 deficiency “intracellular hypothyroidism”.
This doesn’t happen in the Pituitary, because the Pituitary doesn’t have D1 or D3.
Therefore the Pituitary “isn’t in the loop” and doesn’t know what is going on. It keeps on putting out thyroid stimulating hormone (TSH) in accordance with the level of T4 it gets, so the amount of TSH doesn’t tell the doctor what is happening and the doctor is just as ignorant of the situation as the Pituitary is.

THERE’S MORE:
D3 is special stuff! In addition to making rT3 from T4, it also removes an Iodine atom from T3, producing T2, which is garbage!
Also, rT3 can reduce T4 transport into the cells and also, can promote D3’s activity.
So when cortisol blocks D1 and activates D3, T3 production falls and any existing T3 is destroyed by changing into T2. T2 doesn’t work and is excreted.
Thus all the cells in the body lose efficiency, but the Pituitary thinks that all is well and the doctor has no way to diagnose it, because (s)he doesn’t test for T3 or rT3.

Obviously, this is a disaster: inside the cells, there is little or no functioning T3.
I call this INTRACELLULAR HYPOTHYROIDISM: if it stays bad enough for long enough, it can progress to serious illness, which is different from person-to-person depending on which cells and organs are most sensitive to hypothyroidism: as an example, see “Takotsubo cardiomyopathy“, a type of heart failure (“broken heart syndrome”) caused by stress.

THE COMPLICATED DETAILS

The thyroid gland lies in the neck, wrapped around the larynx (the voice-box).
It secretes all the T4 (about 90 to 100mcg daily) and 20% of the T3, in the blood.
The thyroid does not produce enough to T3 supply all the cells: every cell throughout the body, including the Pituitary gland, imports T4 and processes it into T3 for itself, applying the T3 to maximise its efficiency.
Remember: the Pituitary uses Deiodinase #2, but other cells use #1, to convert T4 to T3.

100% of the biological activity of thyroid hormone is due to T3, the body’s “accelerator”.
It increases the metabolic efficiency of all cells.
It controls every cell in the body and brain, promoting optimal growth, development, function and maintenance of all body tissues, including nerve, skeletal and reproductive tissue, cognitive function, skeletal muscle function and heart muscle efficiency.
T3 helps to regulate body temperature, body weight, glucose and cholesterol and everything else from hair and fingernail growth to mood and “well-being”.
T3 is, particularly, essential for the unborn baby’s brain development and if the mother has intracellular hypothyroidism, subtle changes in brain growth may lead to cognitive deficit in the newborn: autism spectrum, schizophrenia, dyslexia and ADD have been found to be related to maternal hypothyroidism.

THIS IS WHAT THE DEIODINASES DO – the graphic below shows the process clearly: it was taken from “Cardiomyocyte-specific inactivation of thyroid hormone in pathologic ventricular hypertrophy: an adaptative response or part of the problem?”, by Christine J. Pol, Alice Muller, and Warner S. Simonides, in journal “Heart Fail Review, Nov 24, 2008).

D1 (in the Body) and D2 (in the Pituitary) make T3 from T4. 
D3 makes reverse T3 from T4 and T2 from T3, BUT NOT IN THE PITUITARY, where there is no D3.
D1 (in the Body) and D2 (in the Pituitary) make T3 from T4. D3 makes reverse T3 from T4 and T2 from T3, BUT NOT IN THE PITUITARY, where no D3 exists.

Q: SO WHAT IS DEIODINASE #3 USED FOR?
A: D3 SHUTS THE WHOLE BODY DOWN, SAVING ENERGY WHEN LIFE IS THREATENED.
In either physical or psychological high-stress conditions, the cells block type1 deiodinase (D1) and activate D3. This happens in response to increased Cortisol release from the adrenals, but there may be other mechanisms.
With D1 blocked and D3 activated, the normal T4-to-T3 process is crippled, T3 isn’t produced and reverse T3 (rT3) is generated from T4.
In addition, D3 converts any T3 it finds in the cells into T2, which doesn’t work either.
Therefore the whole body loses efficiency, but in the Pituitary, D2 continues to make T3 and with no D3, are T3 is not produced: the pituitary is unaffected.
The Pituitary remains perfectly happy with its Thyroid hormone supply and keeps its output of TSH at the normal level.

WHY DOES THE BODY LOSE EFFICIENCY ?
rT3 is chemically the same as T3, but the three-dimensional arrangement of its atoms is different (see the diagram above) and its shape is wrong, so it doesn’t fit into the receptors: it is nonfunctional.
We used to think that rT3 could hitch itself to the receptors and block the entry of T3, but it’s simpler than that. With T3 formation stopped and available T3 converted to T2, the cells just don’t have enough T3 to keep going.

WHAT HAPPENS NEXT ?
The drastic reduction of available T3 inside the cells results in universal slowdown of all systems in the body.
In some areas (varying from individual to individual), “subtotal” stoppage of function can occur (for example, heart muscle paralysis in Takotsubo Cardiomyopathy).
The unfortunate human feels tired to the point of exhaustion, anxious and depressed. The skeletal muscles don’t work properly and can be painful. There is constipation, because the bowel muscles are hampered too and cognitive loss because of reduced brain function.

If the problem persists the fingernails get brittle, the hair starts to fall out, the voice gets hoarse, the legs swell from retained water, there is a feeling of being called because the brown fat stops burning glucose, the cholesterol may rise, the body weight goes up and diabetes may start.
He or she goes to the doctor, who tests “everything” except T3, T4 and rT3.
So the Doctor can’t “read” the situation and doesn’t recognise the true problem because the only test done for thyroid function is the TSH — and that stays normal because the Pituitary is “happy”.

However the MD is likely to notice that the cholesteerol has gone up, the blood pressure has increased due to the stress and diabetes is on the way (all due to intracellular hypothyroidism).
So the sufferer gets a load of pills to take, instead of a prescription for T3, which would replace the T3 which the cells aren’t making, relieving all the symptoms including cognitive loss and anxiety and reducing the stress which is the cause of the problem.

MESSAGE

An elevation of rT3, confirmed by a reduced T3 level and T3/rT3 ratio, is a “marker”
(a blood test signal) for stress-related intracellular (“subclinical”, or “metabolic”, or “functional”) hypothyroidism, regardless of TSH and T4 levels, which may be normal.

METABOLIC, OR “FUNCTIONAL” HYPOTHYROIDISM, ALSO CALLED “SUBCLINICAL” HYPOTHYROIDISM, PERHAPS BEST NAMED INTRACELLULAR HYPOTHYROIDISM

Stress-related T3 deficiency, previously termed “Reverse T3 dominance”, is called “Functional Hypothyroidism” by the Metabolic Medicine community. It is also called “Subclinical Hypothyroidism”, Euthyroid sick syndrome and nonthyroidal illness syndrome, by mainstream medicine, but
THE MOST APPROPRIATE TERM IS, PERHAPS, INTRACELLULAR HYPOTHYROIDISM.

It is characterised by reduction of serum T3 from the individual’s usual level, down to the low end of the “normal” T3 range, plus an elevated reverse T3 *.
TSH and T4 levels are normal, excepting when the patient also has true hypothyroidism.
The diagnosis is made when a reduction of the T3/rT3 ratio, to less than 20.0, is found on testing, in a person who has hypothyroid symptoms.

INTRACELLULAR HYPOTHYROIDISM is part of the pattern in all life-threatening illnesses, in the vast majority of chronic debilitating conditions and in prolonged depression.
It may be the result of the illness, or the cause.
It is associated with heart failure, PTSD, Chronic Fatigue Syndrome, ME, Fibromyalgia, infertility with recurrent abortion, major depression, schizophrenia and any condition severe enough for admission to an ICU.

Intracellular Hypothyroidism is pervasive and is very easily missed.
A “thyroid profile”, including TSH, T4, T3 and rT3 should be included in every “checkup” test series and should be ordered in the prediagnostic “workup” whenever a patient presents with a new complaint.
Upon receipt of the test results, the doctor should calculate the T3/rT3 ratio** and if it is less than 20, the patient’s thyroid balance should be restored to >20 (>23 is better), in addition to appropriate therapy for whatever disease is diagnosed.

* Please go to my blog on “NORMAL” and scroll down to the section re. the Thyroid.
** See below: /media/drive_D/A User/Documents/A WORK AIDS/Cameron Sutherland’ s T3 – rT3 Worksheet

CALCULATING THYROID TEST RESULTS

In the bloodstream, a “binding protein” captures a lot of the T3, holding it as a backup supply.
That portion of total T3 is inactive, so WE DON’T CHECK TOTAL T3.
We check the “FREE”, UNBOUND T3 and references to “T3” in this website always mean “Free T3” (FT3).

Calculating the FT3/rT3 ratio is simple in principle, but mystifying for those who aren’t mathematically inclined.
The FT3 value must first be converted from Picomoles/Litre, to Nanograms/Decilitre, so as view both values in Ng/DL, the scale in which rT3 is reported.
To convert FT3 to Ng/DL, divide its value by 0.0154 (eg, 4.0 Pm/L /0.0154 = 259.74 Ng/DL).

Then divide FT3 (Ng/DL) value by the rT3. eg, if T3 is 259.74 and rT3 is 15, the ratio = 259.74/15, = 17.3.
A T3/rT3 ratio of > 20 is normal, >24 is excellent (my opinion) and < 20 indicates preferential conversion of T4 to rT3, severe enough to cause intracellular hypothyroidism (FH).

CAVEAT !
FH is easily and safely corrected by taking Triiodothyronine
(T3), but:
(1) Best results are seen when T3 is taken fasting, close to 4AM, to fit our diurnal rhythm.
(2) Triiodothyronine should be supplied in a slow-release capsule, not a rapid-release tablet such as “Cytomel”, because quick-release tablets dump their T3 into the intestine soon after they are swallowed, causing a “spike” of T3 in the blood.
The spike can cause “hyperthyroid” side-effects in the morning.
Further, the half-life of T3 is 2 hours. So after spiking from the rapid-release pills, the serum T3 falls quickly, causing hypothyroid symptoms in the afternoon.
(4) If T4 is prescribed for people with IH, most of it is converted into rT3. The higher rT3 encourages even more T3-to-T2 conversion by type 3 deiodinase, with further reduction of T3 availability, so the patient’s condition gets worse.
(5) rT3 also slows down absorption of T4 into the cells, so there is little, if any, T4-T3 conversion.

THE EASY WAY TO CHECK T3/rT3 BALANCE:
A table renders T3/rT3 calculation quick and easy: you need only read the number at the intersection of the (horizontal) T3 row and the (vertical) rT3 column.
Please see a link to Cameron Sutherland’s “worksheet”, below.

Cameron Sutherland’s T3/rT3 worksheet
/media/drive_D/A User/Documents/A WORK AIDS/Cameron Sutherland’ s T3 – rT3 Worksheet 24Jan2019 working copy.xlsxDownload .
Open with excel or compatible app.
Column 1 shows FT3 in Pm/L.
Column 2 is FT3 in Ng/DL.
First row shows rT3.
The FT3/rT3 ratio appears at the row/column intersections:
The PINK area = normal range, the WHITE area = Intracellular Hypothyroidism range.

TREATMENT OF INTRACELLULAR HYPOTHYROIDISM

IH is easily and safely treated with slow-release T3, but most doctors do not believe in, accept or even recognise the diagnosis and doctors are specifically taught not to prescribe T3.
They call the illness “low T3 syndrome” and prescribe T4, expecting reliable conversion to T3.
This is disastrous: the T4 is preferentially metabolised to rT3, making the situation worse.
Most doctors are unfamiliar with Deiodiinase 3 and don’t believe patients who say that they get worse when they take T4: if the patient complains, they prescribe more Eltroxin.

HOW MUCH T3 does a person need?

Everyone has an individual requirement for T3, so we begin with a low dose and increase it sequentially, using weekly or two-weekly blood tests to determine when the correct dose has been reached.
Most people’s “blood – brain barrier” (BBB) allows T3 to enter the brain and the pituitary easily and when prescribed T3 comes into the pituitary, it reduces TSH production to almost zero, and the thyroid responds by making less T4.
The thyroid is also sensitive to T3 level to some extent and quite often, it reduces T4 output.
So in most cases, on-treatment tests show a higher T3, low-normal T4 and very low TSH.

Interestingly, some people’s BBB blocks entry of T3 and in those cases, since the Pituitary’s T4 supply is down because the thyroid isn’t making enough, the pituitary puts the TSH up, to call for more T4.
When this happens, tests show high TSH, low T4 and upper-normal T3.
This situation is easily solved by adding a little T4 to the prescription or by changing the prescription to desiccated thyroid, which contains 70% T3 and 30% T4.

REMISSION:

Spontaneous remission of functional hypothyroidism may follow stress relief, because preferential activation of Deiodinase #3 ceases when the stress level and Cortisol output return to normal.
However most subjects promptly increase rT3 production and relapse into IH when a stressful situation arises.
The most spectacular example of remission and relapse of an intracellular hypothyroidism-based condition is found in cases of Takotsubo Cardiomyopathy.

ADRENAL FATIGUE”
Transient stress causes short-term increase of cortisol output by the adrenal glands.
Cortisol inhibits type 2, 5-deiodinase enzyme and promotes D3, reducing conversion of T4 into T3, increasing rT3 production and increasing conversion of T3 into (inactive) T2.
By these mechanisms stress, whether physical, as in terminal illness, catastrophic infection, severe injury, major surgery, burns etc., or psychological, produces Intracellular Hypothyroidism.
After a while under prolonged stress, the adrenals no longer respond with high cortisol production and often, cortisol tests show low production.*
Practitioners unfamiliar with deiodinase metabolism and intracellular hypothyroidism are at a loss to explain the low cortisol levels and the patient’s continuing complaints. They assume that the symptoms are due to low cortisol production, so they call the condition “Adrenal Fatigue”.
Therefore many ill effects caused by Functional Hypothyroidsm are blamed on “Adrenal Fatigue”, a fanciful label which is inappropriate, as far as I am concerned.

* BY WHAT MECHANISM DOES “ADRENAL FATIGUE” COME TO BE ?
We don’t know the mechanism of cortisol output reduction – certainly, there is nothing wrong with the adrenal glands.
Certainly, the symptoms of Adrenal Fatigue are indistinguishable from those of IH.
SO, perhaps the cause is simple: we know that metabolic slowdown due to IH affects the whole body except the Pituitary.
The adrenals are part of the body. So if, as we would expect, the adrenals respond to inadequate intracellular T3 in the same way as all our other cells, a reduction of efficiency and reduced cortisol production is inevitable and unsurprising.
Therefore the failure of cortisol production, referred to as “Adrenal Fatigue”, observed in IH is simply a previously unrecognised manifestation of Intracellular Hypothyroidism an has nothing to do with the abilities of the Adrenal glands.

NOTES AND DEFINITIONS:
(1) Low T3, from true hypothyroidism or from IH, in women can cause infertility or abortion.
If a pregnancy persists, T3 deficiency during the first trimester may cause maldevelopment of the baby’s brain, causing learning disability, gender dysphoria, ADD/ADHD, Autism, Schizophrenia and other neurocognitive conditions (? dyslexia, etc).
The foetus begins T4-to-T3 conversion for itself at approximately 12 weeks gestation.
Thereafter, it is independent of the mother’s T4 supply, as long as there is sufficient iodine and selenium in the mother’s blood.

(2) Stress: “Perceived stress” is stress subconsciously perceived by the brain, even if the individual claims to be stress-free.
Reasons for “perceived stress” include psychoshock (including abuse) and PTSD, life-threatening infections, severe injury and surgery. However it can be due to any disturbance of body or mind.
Even dieting, vitamin or mineral deficiencies, toxins or diseases like heart failure can be the cause.
Basically, whatever “stresses you out”, physically or emotionally, can start the problem.
Perceived stress, with or without subjective or objective stress, is present in close to 100% of ICU patients and can be proven by checking theT3/ rT3 ratio.
“Subjective stress”
is consciously “felt” and can be described by the individual.  
“Objective stress”
is stress to, or on, the individual, as observed by others.

(3) Intracellular (“Functional”) hypothyroidism is a condition presenting with recognised, or unrecognised, hypothyroid symptoms and signs in which T3 is reduced and reverse T3 rises. FH can coexist with true hypothyroidism.
IH cannot be diagnosed with a TSH test: it is necessary to calculate the T3/rT3 ratio.
IH must not be treated with T4, because these folks will convert the T4 into rT3.

(4) “Desiccated Thyroid” pills are made from dried porcine or bovine thyroids and contains 30% T3 and 70% T4.
Both the T3 and the T4 are bioidentical with the human hormone. Human thyroid tissue contains 20% T3 and 80% T4, but the disparity is insignificant.
A person with IH, treated with Dessicated thyroid, is getting a lot of T4 and may get worse symptoms by overproducing rT3 from it (see (3), above).

(5) The TSH value is not related to the body’s satisfaction with intracellular T3, which to date can only be assessed by estimating FT3/rT3.
The TSH test is only relevant to the Pituitary’s degree of satisfaction with its T4 supply.
TSH diagnoses true hypothyroid disease, but cannot be used to diagnose IH.

(6) As thyroid function deteriorates and slows, so does the rest of the body.
Thus no system is exempt from the effects of Hypothyroidism: it can make you fat, cause hair loss (especially the outer 1/3 of the eyebrows) and dry skin. It can make your skin coarse and your voice hoarse.
Hypothyroidism can weaken bowel muscles, which results in constipation.
It can affect the eyes, tear glands (“dry eye”), long nerves (peripheral neuropathy), skeletal muscle (weakness and muscle aches) (6) and heart muscle (7, 8 – below).
It can cause leg swelling and puffy eyes and face from fluid retention, numbness with tingling fingers and brittle fingernails.
In the worst cases, atrial fibrillation, heart failure or dilated cardiomyopathy (7,8) may result from intracellular hypothyroidism.
Briefly put, Intracellular Hyothyroidism can cause almost any symptom you can name, because it can affect any organ.

Re. muscles and the heart, see Hoffmann’s syndrome (effect on skeletal muscle) and cardiomyopathy (effect on heart muscle).
Also see:
a case history, entitled “Hypothyroidism-induced reversible dilated cardiomyopathy” (note that this patient recovered when treated with T4, which in my opinion was lucky: she would have done better with T3) and
My own history of Intracellular Hypothyroidism.

GENERAL SYMPTOMS OF HYPOTHYROIDISM:

T3 hormone is the efficiency factor for all body parts and the problems resulting from lowered T3 depend on which part of the individual’s body is most sensitive to lack of T3, so symptoms are many and varied. Virtually any symptom may present, including those from Adrenal slowdown.
Many people with Hypothyroidism, either “true” hypothyroidism from underproduction of T4, or “functional” (intracellular) hypothyroidism, with metabolic loss of T3 inside the cells, report sluggishness, anxiety, “brain fog”, cognitive loss and a feeling of low energy, in addition to the classical hypothyroid complaints (see below).

A SHORT LIST of SYMPTOMS, SIGNS, DIAGNOSIS & TREATMENT OF HYPOTHYROIDISM 

SYMPTOMS short list
Fatigue
Low motivation
Depressed mood
Impaired memory
Poor sleep quality
Weight Gain
Depression
anxiety
Reduced sex drive, male or female
Heavy or irregular “periods”
PMS
Infertility
Recurrent abortion
Subtle inconsistency of a baby’s brain development
Chronic yeast infections
Muscle weakness, including Myocardial weakness (see Ref # 6,7,8).
Muscle aches
Joint Pain, stiffness, swelling
Constipation
Difficulty staying warm
Hoarseness
Difficulty breathing
Slower heart rate
Puffy face, Dry skin, Acne
Brittle hair and nails
Calloused heels
Headaches
Premature gray hair  
Brittle fingernails
SIGNS OF HYPOTHYROIDISM
Slow pulse, Irregular pulse, Low BP,
Temperature < 36°C
Dry skin + Dry hair / grey hair
Heel calluses
Hair loss from the head, legs or eyebrows (outer 1/3)
Swelling below lower eyelids
Skin swelling over the shins
Hoarse, “thick” speech,
Dry cough
Slow thinking, confusion
Memory loss,
Untidyness
Home in endemic area
Economic disadvantage
History suggesting FH
High-stress job
High-stress job partner
High-stress life partner
Separation, divorce
(Parents): difficult children
(Children): difficult parents
Childhood abuse of whatever type
Chronic illness, eg.
Celiac Disease or gluten intolerance
Severe illness, with ongoing anxiety
Difficult life circumstances
Poverty
Dependent relatives
Anxious personality disorder
Other psychopathy, schizophrenia and “bipolar disease”
Family history of hypothyroidism
Retirement, social isolation
Alcohol / tobacco / THC /drug habit
TYPES/CAUSES of HYPOTHYROIDISM
1:   Iodine deficiency
2:   Selenium deficiency
3:   Hashimoto’s thyroiditis
4:   Ionising radiation
5:   Therapeutic radiation
6:   Thyroid / Pituitary Surgery
7: Unknown cause
8:   Prescribed medication
9:   Stress (IH)
10: Worse IH with Eltroxin *
11: Hypopituitarism 
TEST RESULTS ASSOCIATED WITH HYPOTHYROIDISM
Elevated blood cholesterol level
Borderline blood sugar/A1C
High TSH, with or without low T4
Low T3, High reverse T3, Low FT3/rT3 ratio, with or without high TSH
“Adrenal Fatigue”
Low DHEA, Testosterone, Oestrogen, Progesterone, Allopregnanolone
Fluid retention, with or without heart failure  
Iodine &/or Selenium deficiency
HEAVY METAL OVERLOAD CAN CAUSE SIMILAR SYMPTOMS: the Urine should be checked for Heavy Metal “burden”
TREATMENT
Eltroxin*, plus iodine and/or selenium, for # 1 – 8.
Compounded, slow-release T3, for # 9, 10 & 11.
Selenium (2 Brazil nuts per day will provide enough).
Iodine (2 drops of Lugol’s iodine per day).
Iron: serum iron (“Ferritin”) should be kept >100.
DHEA, 50mg/day (men) and 25-50mg/day (women) reduces symptoms.
* Eltroxin makes #9 MUCH worse.
CONDITIONS ASSOCIATED WITH Intracellular Hypothroidism
Long-COVID syndrome,
POST-FINASTERIDE syndrome,
CFS/FM, Gulf war syndrome, PTSD (CHILDHOOD or ADULT)
Lyme Disease,
Goitre,
Menopause, Psychiatric conditions, autism, Type I or II Diabetes, obesity, peripheral neuropathy, Alzheimer’s, Autoimmune diseases (rheum. arthritis, lupus, sarcoidosis, Sjogren’s, etc.),
Fibrillation, heart failure, Takotsubo Cardiomyopathy,
Adrenal Fatigue,
Crohn’s disease, Ulcerative colitis, Diverticulitis,
Heavy-metal overload,
Multiple sclerosis (MS), Hypercholesterolaemia, Heart failure,
Chronic anxiety/depression, Schizophrenia
ALL TYPES OF SEVERE ILLNESS, or admission to an ICU.

MY OWN PROBLEM WITH FUNCTIONAL HYPOTHYROIDISM

If you think the above list is fanciful, please read my own history of FH in the blog post, ON THE SUBJECT OF FIBROMYALGIA“, for the whole story.

REFERENCES:

(1) Trans Am Clin Climatol, 2013;124:26-35, Cracking the code for thyroid hormone signaling: Antonio C Bianco 1 PMID: 23874007, PMCID: PMC3715916
(2) Endocrinology, 2021 Aug 1;162(8):bqab059. doi: 10.1210/endocr/bqab059.Deiodinases and the Metabolic Code for Thyroid Hormone Action, Samuel C Russo 1 Federico Salas-Lucia 1 Antonio C Bianco 1 PMID: 33720335, PMCID: PMC8237994 (available on 2022-03-15),
DOI: 10.1210/endocr/bqab059
(3) Endocr Rev. 2019 Aug 1; 40(4):1000-1047. doi: 10.1210/er.2018-00275. Paradigms of Dynamic Control of Thyroid Hormone Signaling, Antonio C Bianco 1 Alexandra Dumitrescu 1 Balázs Gereben 2 Miriam O Ribeiro 3 Tatiana L Fonseca 1 Gustavo W Fernandes 1 Barbara M L C Bocco 1 , PMID: 31033998, PMCID: PMC6596318, DOI: 10.1210/er.2018-00275
(5) Clinical Endocrin., Volume81, Issue5, Review, November 2014, Pages 633-641: Defending plasma T3 is a biological priority Sherine M. Abdalla, Antonio C. Bianco: 05 July 2014 https://doi.org/10.1111/cen.12538
(5) https://cbhrt.ca/2021/10/23/thinking-about-normal/
(6) Hoffman’s syndrome – A rare facet of hypothyroid myopathy, Swayamsidha Mangaraj and Ganeswar Sethy, Neurosci Rural Pract. 2014 Oct-Dec; 5(4): 447–448. doi: 10.4103/0976-3147.140025PMCID: PMC4173264PMID: 25288869 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173264/
(7) Hypothyroidism-induced reversible dilated cardiomyopathy, by P Rastogi, A Dua, S Attri, and H Sharma, J Postgrad Med. 2018 Jul-Sep; 64(3): 177–179. doi: 10.4103/jpgm.JPGM_154_17
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066629/
(8) Myocardial Induction of Type 3 Deiodinase in Dilated Cardiomyopathy (experimental, Mice), 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/
(9) Thyroid Hormone Transport into Cellular Tissue, Journal of Restorative Medicine 3(1):53-68, April 2014, DOI:10.14200/jrm.2014.3.0104, by Kent Holtorf, Holtorf Medical Group (HMG),I can supply further references, on request.

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