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Cited by 16Thyroid Disorders and TreatmentsThyroid Cancer Diagnosis and TreatmentThyroid and Parathyroid Surgery

Thyroid Hormone Transport into Cellular Tissue

Open access
Holtorf, Kent·2014·Journal of Restorative Medicine
DOI 10.14200/jrm.2014.3.0104
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Abstract

New research is demonstrating that thyroid hormone transport across cellular membranes plays an important role in tissue thyroid levels and is proving to have significant clinical significance. Thus, physicians who evaluate or treat thyroid dysfunction would benefit from an appreciation of this topic. Unfortunately, many physicians are not aware of new developments in the current understanding of thyroid hormone transport, which has resulted in an overreliance on the sole use of standard thyroid blood tests (e.g., thyroid-stimulating hormone (TSH) and T4 levels) to determine the presence or absence of hypothyroidism. This has resulted in the misdiagnosis of many hypothyroid patients as being euthyroid. This overreliance on standard thyroid blood tests and the overconfidence of the diagnostic accuracy of standard thyroid blood tests may be particularly troublesome in the presence of a wide range of common comorbid conditions present in a large percentage of the population.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that thyroid hormone entry into cells is active and energy-dependent, with T4 transport more vulnerable than T3, and that the pituitary has different, resilient transporters. Because pituitary T3 can remain adequate while peripheral tissues become hypothyroid, normal TSH and standard blood tests can miss tissue hypothyroidism, and the author recommends using free T3/reverse T3 ratio, SHBG, and clinical signs/symptoms to guide T3 or T4/T3 therapy.

Key findings

  • Thyroid hormone transport is not simple diffusion but active, energy-dependent transport; the T4 transporter is more energy-dependent than the T3 transporter, so reduced mitochondrial function preferentially impairs T4 uptake. Conditions linked to reduced transport include insulin resistance, diabetes/obesity, chronic dieting, depression, anxiety, bipolar disorder, neurodegenerative diseases, aging, chronic fatigue syndrome, fibromyalgia, migraines, chronic infections, stress, cardiovascular disease, inflammation, and high cholesterol/triglycerides.
  • The pituitary has distinct transporters that are not energy-dependent and are resistant to toxins, stress, and calorie restriction, so it can maintain intracellular T3 while peripheral tissues are hypothyroid; therefore TSH is a poor marker for tissue thyroid status. The paper cites a positive predictive value of TSH of 16% for suppressed TSH indicating over-replacement or hyperthyroidism.
  • Reduced transport can artificially raise serum T4 and T3, especially T4, making standard tests unreliable. A free T3/reverse T3 ratio below 0.2 is described as a marker for tissue hypothyroidism; high or high-normal reverse T3 is a marker for reduced T4 uptake; SHBG above 70 nmol/L in women and above 25 nmol/L in men is suggested as adequate when estrogen is adequate.
  • T4-only therapy is described as often inadequate: in one cited study, normalizing plasma TSH and T4 with T4-only preparations achieved adequate tissue T3 only in brown adipose tissue, cerebellum, and cortex, while almost every other tissue was deficient. Another cited study found T4/T3 combination required to normalize tissue T3, and pituitary T3 was 7 to 60 times other tissues normally and 40 to 650 times other tissues when thyroid levels dropped.

Methods

  • Design: narrative review of thyroid hormone transport, with no systematic review methods described.
  • Data or sample: no new primary data; the paper synthesizes cited cell culture, animal, and human studies, including studies of stress, dieting, T4/T3 replacement, and tissue thyroid levels.
  • Main analysis: narrative synthesis of mechanisms and selected literature, with figures illustrating serum thyroid levels, tissue thyroid levels, and the proposed use of free T3/reverse T3 ratio.

Limitations

  • The paper does not state formal limitations.
  • Evident from the text: it is a narrative review without a described systematic search, inclusion criteria, or primary data collection, and it relies on selected cited studies.
  • The paper states a disclosure of interests: Dr. Holtorf supplies supplements from Holtraceuticals to support thyroid function to his own patients, outside the submitted work.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.14200/jrm.2014.3.0104

Cites

194 of 194 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 14 cited sources checked · 0 supported · 0 flagged

  • Premisenone given
    § INTRODUCTION

    There are a variety of distinct and specific transporters necessary for the transport of T4 and T3 into the cell.

    “It has also been demonstrated that there are a variety of distinct and specific transporters that are necessary for the transport of T4 and T3 into the cell.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning
    § INTRODUCTION

    TSH levels become an even worse indicator for an optimal replacement dose in the presence of comorbidities including insulin resistance or obesity, chronic calorie reduction, depression, bipolar depression, neurodegenerative diseases, advanced age, chronic fatigue syndrome, fibromyalgia, migraines, chronic infections, stress or anxiety, heart failure or cardiovascular disease, inflammation or慢性ill

    “Additionally, TSH levels become an even worse indicator for an optimal replacement dose in the presence of the following comorbidities: insulin resistance or obesity; chronic calorie reduction; depression; bipolar depression; neurodegenerative diseases; advanced in age; chronic fatigue syndrome; fibromyalgia; migraines; chronic infections; stress or anxiety; heart failure or cardiovascular disease”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning
    § INTRODUCTION

    Since thyroid hormone transport into the cell is largely energy dependent, any condition associated with reduced production of cellular energy (mitochondrial dysfunction) could also be associated with reduced transport of thyroid hormone into the cell.

    “Since the transport of thyroid hormones into the cell is largely energy dependent, any condition associated with reduced production of the cellular energy (i.e., mitochondrial dysfunction) could also be associated with reduced transport of thyroid hormone into the cell.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning
    § INTRODUCTION

    Cellular hypothyroidism is not routinely detected by standard serum T4 or T3 levels.

    “This is one of the primary reasons that cellular hypothyroidism is not routinely detected by standard serum T4 or T3 levels.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning
    § INTRODUCTION

    The pituitary is unique in its ability to concentrate T3 in the presence of diminished serum thyroid levels.

    “Thus, the pituitary is unique in its ability to concentrate T3 in the presence of diminished serum thyroid levels.”
    Quote in the paperSubstantial claim
  • May combine two claims. 51
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    A standard TSH level will not detect cellular hypothyroidism because the pituitary has completely different transporters that are not energy dependent.

    “A standard TSH level will also not detect such cellular hypothyroidism because the pituitary has completely different transporters that are not energy dependent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § CONCLUSION

    The intracellular T3 deficiency seen with these conditions often results in a vicious cycle of worsening symptoms that usually goes untreated because standard thyroid tests look normal.

    “The intracellular T3 deficiency seen with these conditions often results in a vicious cycle of worsening symptoms that usually goes untreated because standard thyroid tests look normal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § Abstract

    The thyroid transporters in the body are very energy dependent and are affected by numerous conditions, including low energy states, toxins and mitochondrial dysfunction, while the pituitary remains unaffected.

    “The thyroid transporters in the body are very energy dependent and are affected by numerous conditions, including low energy states, toxins and mitochondrial dysfunction, while the pituitary remains unaffected.”
    • Also stated in: § CONCLUSION · plain
      “The pituitary has different transporters than every other tissue in the body; the thyroid transporters in the body are very energy dependent and are affected by numerous conditions while the pituitary is minimally affected.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    Because the rT3 and T4 transporters are equally energy dependent, a high serum rT3 is a marker for reduced uptake of T4 into the cell.

    “Because the rT3 and T4 transporters are equally energy dependent, a high serum rT3 is shown to be a marker for reduced uptake of T4 into the cell.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § INTRODUCTION

    Fraser et al. found that a suppressed or undetectable TSH was not an indication or a reliable marker of over replacement or hyperthyroidism.

    “They found a suppressed or undetectable TSH was not an indication or a reliable marker of over replacement or hyperthyroidism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fraser et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    Consequently, pituitary levels of T3 and the subsequent TSH level are poor measures of tissue hypothyroidism, as almost the entire body can be severely hypothyroid despite having a normal TSH level.

    “Consequently, the pituitary levels of T3 and the subsequent TSH level are poor measures of tissue hypothyroidism, as almost the entire body can be severely hypothyroid despite having a normal TSH level.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § INTRODUCTION

    Among patients with thyroid hormone transport dysfunction resulting in intracellular hypothyroidism, a free T3/reverse T3 ratio of less than 0.2 is a marker for tissue hypothyroidism (when free T3 is expressed in pg/mL (2.3-4.2 pg/mL) and reverse T3 is expressed in ng/dL (8-25 ng/dL)).

    “Among patients with this type of thyroid hormone transport dysfunction (resulting in intracellular hypothyroidism) assessing the free T3/reverse T3 ratio can aid in a proper diagnosis, with a free T3/reverse T3 ratio of less than 0.2 being a marker for tissue hypothyroidism (when the free T3 is expressed in pg/mL (2.3–4.2 pg/mL) and the reverse T3 is expressed in ng/dL (8–25 ng/dL)) (see Figure 2)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § INTRODUCTION

    The positive predictive value of TSH (the likelihood that a suppressed TSH indicates over-replacement or hyperthyroidism) has been determined to be 16%.

    “In fact, the positive predictive value of TSH (the likelihood that a suppressed TSH indicates over-replacement or hyperthyroidism) has been determined to be 16%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Hennemann et al. stated that even a small decrease in cellular ATP concentration results in a major reduction in the transport of T4 (and rT3) but only slightly affects T3 uptake.

    “As stated by Hennemann et al. in Endocrine Reviews: “Even a small decrease in cellular ATP concentration results in a major reduction in the transport of T4 (and rT3) but only slightly affects T3 uptake.””
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hennemann et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    Any increase (high or high-normal) of rT3 is an indicator of tissue hypothyroidism and suggests that T4-only replacement would not be considered optimal therapy.

    “As a result, any increase (high or high-normal) of rT3 is not only an indicator of tissue hypothyroidism but also suggests that T4-only replacement would not be considered optimal therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    T4 uptake drops much faster than T3 utilization as severity increases, making T4 replacement inappropriate for such conditions.

    “T4 uptake (utilization) drops much faster than T3 utilization as severity increases, making T4 replacement inappropriate for such conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    Because pituitary thyroid hormone uptake is relatively unaffected by outside factors, intracellular hypothyroidism is not reflected by TSH testing, making TSH a poor marker for cellular thyroid function in any tissue other than the pituitary.

    “Since thyroid hormone uptake in the pituitary is relatively unaffected by outside factors, the presence of intracellular hypothyroidism is not reflected by TSH testing, which is why TSH is a poor marker for cellular thyroid function in any tissue other than the pituitary.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data
    § INTRODUCTION

    The second study found that a combination of T4/T3 is required to normalize tissue levels of T3, and that the pituitary was able to maintain normal levels of T3 despite the rest of the body being hypothyroid on T4-only preparations.

    “This study found that a combination of T4/T3 is required to normalize tissue levels of T3, and that the pituitary was able to maintain normal levels of T3 despite the rest of the body being hypothyroid on T4-only preparations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    This data help explain why standard thyroid blood tests are not accurate indicators of intracellular thyroid levels and why it is difficult for obese patients to lose weight; as calories are decreased, thyroid utilization is reduced and metabolism drops.

    “This data would help explain why standard thyroid blood tests are not accurate indicators of intracellular thyroid levels. This also explains why it is difficult for obese patients to lose weight; since, as calories are decreased, thyroid utilization is reduced and metabolism drops.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisereasoning
    § INTRODUCTION

    Because thyroid replacement is given orally, it must first undergo first pass metabolism in the liver, resulting in significantly higher hepatic levels than in other peripheral tissues.

    “Because thyroid replacement is given orally, it must first undergo first pass metabolism in the liver, resulting in significantly higher hepatic levels than in other peripheral tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    Utilizing the free T3/reverse T3 ratio does not suffer from the inaccuracies of standard tests and most closely correlates with cellular thyroid levels.

    “Utilizing the free T3/reverse T3 ratio does not suffer from the inaccuracies of standard tests and most closely correlates with cellular thyroid levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Sarne et al. showed that serum from individuals with significant physiologic stress inhibited uptake of T4 into cells, while serum from non-stressed individuals had no effect.

    “Sarne et al. added serum from different groups of individuals to cell cultures and measured the amount of T4 uptake from the serum into the cell. Their results showed that the serum from those with significant physiologic stress inhibited the uptake (transport) of T4 into the cell while the serum from the non-physiological stressed had no effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sarne et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisereasoning
    § INTRODUCTION

    Even slight reductions in cellular energy can result in dramatic declines in the cellular uptake of T4, while the uptake of T3 appears to be much less affected.

    “Even slight reductions in cellular energy (i.e., mitochondrial function) can result in dramatic declines in the cellular uptake of T4, while the uptake of T3 appears to be much less affected.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisereasoning
    § INTRODUCTION

    SHBG is more useful in women than men because the normal reference range is less broad in men, making it less sensitive and less clinically useful.

    “The SHBG is more useful in women than men because the normal reference range is less broad in men, making it less sensitive and less clinically useful.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § INTRODUCTION

    Pituitary thyroid hormone transporters are not energy dependent and can maintain or increase cellular uptake of T4 and T3 even in low energy states.

    “As mentioned previously, the pituitary thyroid hormone transporters are not energy dependent and can thus maintain or increase the cellular uptake of T4 and T3 even in low energy states.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Brownell et al. found that after repeated cycles of dieting, weight loss occurred at half the rate and weight gain occurred at three times the rate compared to controls with the same calorie intake.

    “In a highly controlled study, Brownell et al. found that after repeated cycles of dieting, weight loss occurred at half the rate and weight gain occurred at three times the rate compared to controls with the same calorie intake.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Brownell et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning
    § CONCLUSION

    Reduced thyroid transport results in an artificial elevation in serum thyroid levels (especially T4), making this a poor marker for tissue thyroid levels.

    “Reduced thyroid transport results in an artificial elevation in serum thyroid levels (especially T4), making this a poor marker for tissue thyroid levels, as well.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    The first study's authors concluded that neither plasma T4 nor plasma T3 alone permit prediction of the degree of change in T4 and T3 concentrations in tissues, and that current replacement therapy of hypothyroidism giving T4 should no longer be considered adequate.

    “The authors conclude: “It is evident that neither plasma T4 nor plasma T3 alone permit the prediction of the degree of change in T4 and T3 concentrations in tissues… the current replacement therapy of hypothyroidism [giving T4] should no longer be considered adequate….””
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    A high rT3 can occasionally be associated with hyperthyroidism as the body tries to reduce cellular thyroid levels, but this can be differentiated on the basis of symptoms and by utilizing the free T3/rT3 ratio, which correlates with intracellular thyroid levels.

    “While a high rT3 can occasionally be associated with hyperthyroidism, as the body tries to reduce cellular thyroid levels, this can be differentiated on the basis of symptoms and by utilizing the free T3/rT3 ratio, which correlates with intracellular thyroid levels (see Figure 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § INTRODUCTION

    Women with adequate estrogen levels should have an SHBG above 70 nmol/L and men above 25 nmol/L; if not, the diagnosis of low tissue levels of thyroid should be considered.

    “Women with adequate estrogen levels should have an SHBG above 70 nmol/L and men above 25 nmol/L. If not, the diagnosis of low tissue levels of thyroid should be considered.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § INTRODUCTION

    Serum T4 levels can be artificially elevated among physiologically stressed individuals, and thus serum T4 and TSH levels are poor markers for tissue thyroid levels in this population.

    “These results demonstrate that serum T4 levels can be artificially elevated among physiologically stressed individuals, and thus serum T4 and TSH levels are poor markers for tissue thyroid levels in this patient population (see Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Because the T4 transporter is more energy dependent than the transporter for T3, T4 preparations are generally ineffective in the presence of such conditions, while T3 replacement is shown to be beneficial.

    “Because the T4 transporter is more energy dependent than the transporter for T3, it is also not surprising that T4 preparations are generally ineffective in the presence of such conditions, while T3 replacement is shown to be beneficial.”
    • Also stated in: § CONCLUSION · plain
      “Additionally, it is not surprising that T4 preparations are generally ineffective in the presence of such conditions, while T3 replacement is shown to be beneficial, with potentially dramatic results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § Abstract

    Reduced T4 and T3 transport into the cells in peripheral tissues is seen with a wide range of common conditions, including insulin resistance, diabetes, depression, bipolar disorder, hyperlipidemia, chronic fatigue syndrome, fibromyalgia, neurodegenerative diseases, migraines, stress, anxiety, chronic dieting and aging, while the intracellular T3 level in the pituitary often remains unaffected.

    “Reduced T4 and T3 transport into the cells in peripheral tissues is seen with a wide range of common conditions, including insulin resistance, diabetes, depression, bipolar disorder, hyperlipidemia, chronic fatigue syndrome, fibromyalgia, neurodegenerative diseases, migraines, stress, anxiety, chronic dieting and aging, while the intracellular T3 level in the pituitary often remains unaffected.”
    • Also stated in: § CONCLUSION · plain
      “Reduced thyroid transport into the cell is seen with a wide range of common conditions, including insulin resistance, diabetes, depression, bipolar disorder, hyperlipidemia (high cholesterol and triglycerides), chronic fatigue syndrome, fibromyalgia, neurodegenerative diseases (Alzheimer’s, Parkinson’s and multiple sclerosis), migraines, stress, anxiety, chronic dieting and aging.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Thyroid hormone transport across cellular membranes plays an important role in intracellular triiodothyronine (T3) levels of peripheral and pituitary tissues and has considerable clinical significance.

    “New research is demonstrating that thyroid hormone transport across cellular membranes plays an important role in intracellular triiodothyronine (T3) levels of peripheral and pituitary tissues and is proving to have considerable clinical significance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § INTRODUCTION

    The pituitary has its own distinct deiodinases, thyroid transporters, and high affinity thyroid receptors.

    “The pituitary is different than every cell in the body with its own distinct deiodinases, thyroid transporters, and high affinity thyroid receptors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given
    § CONCLUSION

    An elevated or high-normal rT3 along with symptoms is a reliable marker for reduced transport of thyroid hormones and an indication that a person has low cellular thyroid levels despite having normal TSH, free T4, and free T3 levels.

    “Rather, an elevated or high-normal rT3 along with symptoms is shown to be a reliable marker for reduced transport of thyroid hormones and an indication that a person has low cellular thyroid levels despite having normal TSH, free T4, and free T3 levels (see Figure 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    Even a minimally elevated TSH (above 2 mU/L) demonstrates diminished intra-pituitary T3 and is a clear indication (except in unique situations such as a TSH-secreting tumor) that the rest of the body is suffering from inadequate thyroid activity because the pituitary T3 level is always significantly higher than the rest of the body.

    “While a normal TSH cannot be used as a reliable indicator of global tissue thyroid effect, even a minimally elevated TSH (above 2 mU/L) demonstrates that there is a diminished intra-pituitary T3 level and is a clear indication (except in unique situations such as a TSH-secreting tumor) that the rest of the body is suffering from inadequate thyroid activity because the pituitary T3 level is always”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § INTRODUCTION

    The most rigorously screened individuals for absence of thyroid disease have a TSH below 2 to 2.5 mU/L.

    “Additionally, the most rigorously screened individuals for absence of thyroid disease have a TSH below 2 to 2.5 mU/L.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § INTRODUCTION

    Substances produced by physiologic stress or calorie reduction (CMPF, indoxyl sulfate, bilirubin, and fatty acids) reduce cellular uptake of T4 by up to 42%, while having no effect on T4 or T3 uptake into the pituitary.

    “Substances produced by physiologic stress or calorie reduction (e.g., 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF), indoxyl sulfate, bilirubin and fatty acids), have been shown to reduce the cellular uptake of T4 by up to 42%, while having no effect on T4 or T3 uptake into the pituitary.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation
    § INTRODUCTION

    It is inappropriate to use T4-only preparations when treating any condition associated with reduced mitochondrial function or ATP production.

    “This makes it inappropriate to use T4-only preparations when treating any condition associated with reduced mitochondrial function or ATP production, Thus, it is not surprising that T3 has been shown to be superior in such patient populations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    Even though production of T4 and T3 is diminished in chronic illness, reduced transport into cells tends to raise serum levels, making serum T4 and T3 remain normal or high-normal.

    “Thus, even though the production of T4 and T3 is diminished in chronic illness, the reduced transport into the cell will tend to raise serum levels, making the serum T4 and T3 remain normal or high-normal (see Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Zulewski et al. found TSH to be an unsuitable measure of optimal or proper thyroid replacement, as they observed no correlation between TSH and tissue thyroid levels; however, serum T4 and T3 levels had some correlation, with T3 being a better indicator than T4.

    “Likewise, Zulewski et al. found TSH to be an unsuitable measure of optimal or proper thyroid replacement, as they observed no correlation between TSH and tissue thyroid levels. However, serum T4 and T3 levels had some correlation, with T3 being a better indictor than T4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zulewski et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § INTRODUCTION

    The reduced T4 and T3 uptake during dieting is thought to be due to reduced cellular energy stores as well as increased levels of free fatty acids and non-esterified fatty acids (NEFA) in the serum.

    “This is thought to be due to the reduced cellular energy stores as well as increased levels of free fatty acids and non-esterified fatty acids (NEFA) in the serum.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    TSH and serum T4 levels do not correlate well with intracellular thyroid levels.

    “TSH and serum T4 levels do not correlate well with intracellular thyroid levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    A relatively low SHBG, a slow reflex relaxation time, a low resting metabolic rate, and a low basal body temperature can be useful indicators of low tissue thyroid levels and can aid in the diagnosis of tissue hypothyroidism.

    “Additionally, a relatively low SHBG, a slow reflex relaxation time, a low resting metabolic rate (metabolism), and a low basal body temperature can also be useful indicators of low tissue thyroid levels and can aid in the diagnosis of tissue hypothyroidism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    While the rest of the body has impaired thyroid transport, the pituitary experiences increased transport activity.

    “Therefore, while the rest of body has impaired thyroid transport, the pituitary experiences increased transport activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    With chronic stress, depression, chronic dieting, diabetes, insulin resistance (obesity), or high cholesterol levels, TSH, T4 and T3 levels are not accurate measures of intracellular thyroid levels and cannot be used as reliable markers to determine the need for thyroid hormone supplementation.

    “Thus, with such conditions, TSH, T4 and T3 levels are not accurate measures of intracellular thyroid levels and cannot be used as reliable markers to determine the need for thyroid hormone supplementation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § CONCLUSION

    T4 preparations are generally ineffective in the presence of such conditions, while T3 replacement is shown to be beneficial, with potentially dramatic results.

    “Additionally, it is not surprising that T4 preparations are generally ineffective in the presence of such conditions, while T3 replacement is shown to be beneficial, with potentially dramatic results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Cell cultures incubated with serum from physiologically stressed or dieting individuals exhibit a dramatic reduction in the uptake of T4 into cells, and this reduction correlates with the degree of stress.

    “For instance, studies have shown that cell cultures incubated with serum from physiologically stressed or dieting individuals exhibit a dramatic reduction in the uptake of T4 into cells. This reduction correlated with the degree of stress.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § INTRODUCTION

    Nuclear thyroid receptors in the pituitary (TR-B2) are different from those in other tissues (TR-a1 and TR-B1), and pituitary receptors can become saturated and turn off TSH while other tissues are lacking thyroid stimulation.

    “Another reason that the standard TSH level may not detect cellular hypothyroidism is that the nuclear thyroid receptors in the pituitary (TR-B2) are different from those in other tissues (TR-a1 and TR-B1). Pituitary receptors can become saturated and turn off TSH while other tissues are lacking thyroid stimulation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning
    § CONCLUSION

    On the basis of the data presented, the free T3/rT3 ratio and a low SHBG, along with signs and symptoms including basal body temperature and the reflex relaxation phase, appear to be a more appropriate method for assessing the presence of hypothyroidism and determining whether supplementation with T3 rather than T4 only should be considered in a particular patient.

    “On the basis of the data presented here, the free T3/rT3 ratio and a low SHBG, along with signs and symptoms, including basal body temperature and the reflex relaxation phase, appear to be a more appropriate method for assessing the presence of hypothyroidism and determining whether supplementation with T3 (rather than T4 only) should be considered in a particular patient.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § INTRODUCTION

    Sex hormone binding globulin (SHBG) is formed in the liver in response to the tissue level of estrogen and thyroid.

    “Sex hormone binding globulin (SHBG) is formed in the liver in response to the tissue level of estrogen and thyroid.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    Reverse T3 mirrors T4 uptake, so high or high-normal reverse T3 is a marker for reduced uptake of T4 into the cell (and to a lesser extent T3), showing reduced overall tissue thyroid level requiring T3 supplementation rather than T4.

    “Reverse T3 mirrors T4 uptake so high or high-normal reverse T3 is a marker for reduced uptake of T4 into the cell (and to a lesser extent T3) showing that there is a reduced overall tissue thyroid level requiring T3 supplementation (not T4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning
    § CONCLUSION

    The most important determinant of thyroid activity is the intra-cellular level of T3, and a major determinant of the intracellular T3 level is the activity of the cellular thyroid transporters.

    “The most important determinant of thyroid activity is the intra-cellular level of T3, and a major determinant of the intracellular T3 level is the activity of the cellular thyroid transporters.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Under normal conditions the pituitary has 7 to 60 times the concentration of T3 compared to other tissues of the body; when thyroid levels drop, the pituitary has 40 to 650 times the concentration of T3 in other tissues.

    “Under normal conditions it was shown that the pituitary will have 7 to 60 times the concentration of T3 when compared to other tissues of the body; and when thyroid levels drop, the pituitary was shown to have 40 to 650 times the concentration of T3 in other tissues.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § INTRODUCTION

    A free T3/rT3 ratio below 0.2 is a useful indicator of low tissue thyroid levels.

    “As discussed, a free T3/rT3 ratio below 0.2 is a useful indicator of low tissue thyroid levels.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § INTRODUCTION

    Benzodiazepine medications such as diazepam, lorazepam, and alprazolam can inhibit T3 uptake into cells of the body but have no effect on transport of T3 into the pituitary.

    “Benzodiazepine medications such as diazepam (Valium®), lorazapam (Atavan®), and alprazolam (Xanax®) are further examples where a given compound can inhibit T3 uptake into the cells of the body, but have no effect on transport of T3 into the pituitary.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § INTRODUCTION

    Fraser et al. concluded that serum TSH concentration is unsatisfactory as the thyrotrophs in the anterior pituitary are more sensitive to changes in thyroxine in the circulation than other tissues, which rely more on T3.

    “The authors concluded that “The serum concentration of thyroid stimulation hormone is unsatisfactory as the thyrotrophs in the anterior pituitary are more sensitive to changes in the concentration of thyroxin in the circulation than other tissues, which rely more on triiodothyronine (T3).””
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fraser et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § INTRODUCTION

    Meier et al. concluded that TSH is a poor measure for estimating clinical and metabolic severity of primary overt thyroid failure, and found no correlations between different parameters of target tissues and serum TSH.

    “The authors concluded that “TSH is a poor measure for estimating the clinical and metabolic severity of primary overt thyroid failure... We found no correlations between the different parameters of target tissues and serum TSH.””
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Meier et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § INTRODUCTION

    Fraser et al. stated that serum thyroid hormone and TSH concentrations cannot be used with confidence to classify patients as receiving satisfactory, insufficient, or excessive thyroxine replacement, and that adjustments should be made according to clinical response.

    “They state “It is clear that serum thyroid hormone and thyroid stimulating hormone concentrations cannot be used with any degree of confidence to classify patients as receiving satisfactory, insufficient, or excessive amounts of thyroxine replacement… The poor diagnostic sensitivity and high false positive rates associated with such measurements render them virtually useless in clinical practice…”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fraser et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION

    Van der Heyden et al. found that obese individuals in the process of dieting exhibited a 50% reduction of T4 into the cell and a 25% reduction of T3 into the cell.

    “Van der Heyden et al. studied the effect of calorie restriction (dieting) on the transport of T4 and T3 into the cell. They found that obese individuals in the processes of dieting exhibited a 50% reduction of T4 into the cell and a 25% reduction of T3 into the cell.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Van der Heyden et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisereasoning
    § INTRODUCTION

    Conditions linked with reduced mitochondrial function and impaired thyroid transport include insulin resistance, diabetes and obesity, chronic and acute dieting, depression, anxiety, bipolar depression, neurodegenerative diseases, aging, chronic fatigue syndrome, fibromyalgia, migraines, chronic infections, physiologic stress and anxiety, cardiovascular disease, inflammation and chronic illness,

    “Conditions linked with reduced mitochondrial function and impaired thyroid transport include: insulin resistance, diabetes and obesity; chronic and acute dieting; depression; anxiety; bipolar depression; neurodegenerative diseases; aging; chronic fatigue syndrome; fibromyalgia; migraines; chronic infections; physiologic stress and anxiety; cardiovascular disease; inflammation and chronic illness;”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § INTRODUCTION

    A suppressed TSH is not associated with hyperthyroidism or over-replacement 84% of the time, making it an inaccurate marker for determining an appropriate thyroid hormone replacement dose.

    “In other words, a suppressed TSH is not associated with hyperthyroidism or over-replacement 84% of the time, making it an inaccurate marker for determining an appropriate thyroid hormone replacement dose.”
    Quote in the paperNot a substantial claim
58 of 58

  • The paper relies on this without support.

    Many physicians rely solely on standard thyroid blood tests to determine the presence or absence of hypothyroidism, resulting in misdiagnosis of many hypothyroid patients as euthyroid.

    “Unfortunately, many physicians are not aware of new developments in the current understanding of thyroid hormone transport, which has resulted in an overreliance on the sole use of standard thyroid blood tests (e.g., thyroid-stimulating hormone (TSH) and T4 levels) to determine the presence or absence of hypothyroidism. This has resulted in the misdiagnosis of many hypothyroid patients as being”

  • The paper relies on this without support.

    The conditions associated with reduced thyroid transport are common and present in a large percentage of the population.

    “This overreliance on standard thyroid blood tests and the overconfidence of the diagnostic accuracy of standard thyroid blood tests may be particularly troublesome in the presence of a wide range of common comorbid conditions present in a large percentage of the population.”
2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 22

  1. Docter R, Krenning EP, Bos G, Fekkes DSF, Hennemann G. Evidence that the uptake of triiodo-L-thyronine by human erythrocytes is carrier-mediated but not energy-dependent. Biochem J. 1982; 208:27–34.
  2. Cheng SY. Characterization of binding of uptake of 3,3,5-triiodo-L-thyronine in cultured mouse fibroblasts. Endocrinology. 1983; 112:1754–62.
  3. Schapira AHV. Mitochondrial disease. Lancet. 2006; 368:70–82.
  4. Buist R. Elevated xenobiotics, lactate and pyruvate in C.F.S. patients. J Orthomolec Med. 1989; 4(3):170–2.
  5. Chen L, Knowlton AA. Depressed mitochondrial fusion in heart failure. Circulation. 2007; 116:259.
  6. Kaptein EM. Clinical relevance of thyroid hormone alterations in nonthyroidal illness. Thyroid Int. 1997; 4:22–5.
  7. Zulewski H, Müller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997; 82:771–6.
  8. Barnes B. Temperature versus basal metabolism. J Am Med Assoc. 1942; 119(14):1072–4.
  9. Ellingsen DG, Efskind J, Haug E, et al. Effects of low mercury vapour exposure on the thyroid fucniton in Chloralkai workers. J Appl Toxicol. 2000; 20:483–9.
  10. O’Brian JI, Baybee DE, Wartofsky L, et al. Altered peripheral thyroid hormone metabolism and diminished hypothalamic pituitary responsiveness with changes in dietary composition. Clin Res. 1978; 26:310A.
  11. du Pont JS. Is reverse T3 a physiological nonactive competitor of the action of T3 upon the electrical properties of GH3 cells?Neuroendocrinology. 1991; 54:146–50.
  12. Danforth EJ, Desilets EJ, Jorton ES, et al. Reciprocal serum triiodothryronine (T3) and reverse (rT3) induced by altering the carbohydrate content of the diet. Clin Res. 1975; 23:573.
  13. McCormack PD, Thomas J, Malik M, Staschen CM. Cold stress, reverse T3 and lymphocyte function. Alaskan Med. 1998; 40(3):55–62.
  14. Szabolcs I, Weber M, Kovacs Z, et al. The possible reason for serum 3,3′5′-(reverse T3) triiodothyronine increase in old people. Acta Med Acad Sci Hung. 1982; 39(1–2):11–17.
  15. Spaulding SW, Chopra IJ, Swherwin RS, et al. Effect of caloric restriction and dietary compostion on serum T3 and reverse T3 in man. J Clin Endocrrinol Metab. 1976; 42(197):197–200.
  16. Desai M, Irani AJ, Patil K, et al. The importance of reverse triiodothyroinine in hypothyroid children on replacement treatement. Arch Dis Child. 1984; 59:30–5.
  17. Benua RS, Kumaoka S, Leeper RD, Rawson RW. The effect of DL-3,3′,5′-triiodothyronine in Grave’s disease. J Clin Endocrinol Metab. 1959; 19:1344–6.
  18. Chopra IJ. Study of extrathyroidal conversion of T4 to T3 in vitro: evidence that reverse T3 is a potent inhibitor of T3 production. Clin Res. 1976; 24:142A.
  19. Lowe JC, Garrison RL, Reichman AJ, et al. Triiodothyronine (T3) treatment of euthyroid fibromyalgia: a small-n replication of a double-blind placebo-controlled crossover study. Clin Bull Myofasc Ther. 1997; 2(4):71–88.
  20. Meyer T, Husch M, van den Berg E, et al. Treatment of dopamine-dependent shock with triiodothyronine: preliminary results. Deutsch Med Wochenschr. 1979; 104:1711–14.
  21. Novitzsky D, Cooper DKC, Human PA, et al. Triiodothyronine therapy for heart donor and recepient. J Heart Transplant. 1988; 7:370–6.
  22. Dulchavsky SA, Maitra SR, Maurer J, et al. Beneficial effects of thyroid hormone administration in metabolic and hemodynamic function in hemorrhagic shock. FASEB J. 1990; 4:A952.

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Authors
Holtorf, K.
Corresponding author
Holtorf, Kent
Venue
Journal of Restorative Medicine
Publisher
Association for the Advancement of Restorative Medicine
Published
2014-04-01
Volume
3
Issue
1
Pages
53-68
ISSN
2165-7971 (ISSN-L)
DOI
10.14200/jrm.2014.3.0104
OpenAlex
W2144744234
Semantic Scholar
cacdf47adc26f64001462d90efff0228afc24641
Cited by
16
References
186
Citations by year
2026: 1 · 2024: 1 · 2022: 3 · 2021: 4 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 1
FWCI
0.96
Type
journal article
Language
en
Open access
Locations
Journal of Restorative Medicine (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
Keywords
thyroid hormone transport, thyroid-stimulating hormone, free thyroxine, thyroid dysfunction, comorbidities

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