Thyroid Hormone Transport

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Thyroid hormone transport is an extremely important topic. It must be clearly understood by any physician who hopes to accurately evaluate an individual’s thyroid status and to appropriately treat thyroid dysfunction. Unfortunately, only a small fraction physicians and endocrinologists understand even the basics of thyroid transport, because what they have learned in medical school and continue to be taught regarding this topic is incorrect. When one understands the physiology involved with thyroid hormone transport, it becomes clear that standard blood tests, including the TSH and T4 levels, cannot be used to accurately determine intracellular and tissue thyroid level in the presence of a wide range of common conditions, including chronic and acute dieting, anxiety, stress, insulin resistance, obesity, diabetes, depression and bipolar disorder, hyperlipidemia (high cholesterol and triglycerides), chronic fatigue syndrome, fibromyalgia, neurodegenerative diseases (Alzheimer’s, Parkinson’s and multiple sclerosis), migraines, cardiomyopathy, and aging.

Serum thyroid levels are, of course, commonly used as an indication of cellular thyroid activity. In order to have biological activity, the T4 and T3 must, however, cross the cellular membrane from the serum into the target cells. It follows that the activity of these transport processes may have an important influence on the regulation of biological activity of the thyroid hormones. For about two and half decades it was assumed that the uptake of thyroid into the cells is by simple diffusion and that the driving force for this diffusion is the concentration of the free hormones in the serum. This “free hormone” or “diffusion hypothesis” was formulated in 1960 and assumes the concentration of free hormones (free T4 and free T3) in the serum determines the rate and extent of uptake into the cell and thus intracellular thyroid hormone concentration.

This hypothesis and mechanism of thyroid uptake into the cell has been shown to be totally incorrect (1-43). It has clearly been shown that the rate-limiting (most important) step in the determination of thyroid activity is the rate of thyroid hormone transport into the cell (5,20,41,44,45) and that this transport has nothing to do with diffusion, but rather it is energy requiring active transport (1-43,45,46,47,48-64,65,66,67). The incorrect “diffusion hypothesis,” however, continues to be taught in medical school and is believed to be true by most physicians and endocrinologists (see thyroid transport graph).

Conditions associated with abnormal thyroid transport

It is important to note that because this transport of thyroid hormones into the cell is energy dependent, any condition associated with reduced production of the cellular energy (mitochondrial dysfunction) will also be associated with reduced transport of thyroid into the cell, resulting in cellular hypothyroidism despite having standard blood tests in the “normal” range. Conditions associated with reduced mitochondrial function and impaired thyroid transport include: insulin resistance, diabetes and obesity (68,69,70,71,106); chronic and acute dieting (4,51,66,72,112,113,114,115,116,117,118); diabetes (69,73,74,75,76); depression (73,77,78,79); anxiety (73,80); bipolar depression (73,77,81,82); neurodegenerative diseases (73,83,84,85,86,87); aging (73,74,88-100); chronic fatigue syndrome (73,101,102); fibromyalgia (73,103,104); migraines (73); chronic infections (73); physiologic stress and anxiety (73,79); cardiovascular disease (73,99,104,105,108); inflammation and chronic illness (73,109,110,111); and those with high cholesterol and triglyceride levels (58,60,72,106,107). Thus, standard blood tests can be very unreliable if any of these commonly occurring conditions are present (1-107).

The exact cause of the inhibition of the transport of thyroid is unknown, but it is clear that there are a number of substances that are produced by the body in response to dieting and physiologic stress that negatively effect thyroid hormone transport (5,41). This is clearly shown by studies where cell cultures are incubated with the serum from physiologically stressed or dieting individuals; there is shown to be a dramatic reduction of the uptake of T4 by the cells that correlates with the degree of stress (41,42).

Additionally, it has been clearly shown that there are different transporters that are specific and necessary for the transport of T4 and T3 into the cell where they have their effect. The transporter for T4 is much more energy dependent (it requires more energy) than the transporter for T3 (see figure 1) (5,40,41,49,52,53,66). Even slight reductions in cellular energy (mitochondrial function) results in dramatic declines in the uptake of T4 while the uptake of T3 is much less affected (5,41,62,67). Thus, the conditions listed above have, in particular, an impaired transport of T4 that results in cellular hypothyroidism. This cellular hypothyroidism is not detected by serum T4 levels because the less T4 transported into the cell and the lower the cellular level of T4, the higher the serum T4 level. The TSH will also not detect such cellular hypothyroidism because the pituitary has completely different transporters that are not energy dependent and increase transport activity, while the rest of body has impaired thyroid transport (see thyroid transport graph).

Pituitary thyroid transport determines TSH levels

As discussed previously, the pituitary is different than every cell in the body with different deiodinases and different high affinity thyroid receptors. It is also shown to have unique thyroid transporters that are different than those in the rest of the body (1,17,43,50,52,55,59,60,61). The pituitary thyroid hormone transporters are shown not to be energy dependent and will maintain or increase the uptake of T4 and T3 in low energy states, while this is not the case for transporters in other parts of the body that have significantly reduced transport (1,17,22,43,50,52,55,59,60,61).

The transporters for T4 and T3 in the pituitary are also not inhibited by numerous environmental toxins and substances produced by the body during physiologic stress and calorie reduction that inhibit thyroid transport into other cells in the body, including bilirubin and fatty acids. Thus, the reduced uptake of T3 and T4 and subsequent intracellular hypothyroidism that occurs throughout the body from numerous conditions stated above is not reflected by TSH testing because thyroid uptake in the pituitary cells is not effected, making the TSH a poor marker for cellular thyroid in any tissue other than the pituitary (1,43,55).

Even common medications, including benzodiazepines such as diazepam (Valium), lorazapam (Atavan) and alprazolam (Xanax), are shown to inhibit T3 uptake into the cells of the body but have no effect on transport of T3 into the pituitary (61).

This difference in pituitary thyroid transport was investigated by Germain et al. This study demonstrated that with calorie restriction (dieting), pituitary T3 content is independent of the rest of the body. The dramatically reduced serum T4 and T3 levels seen with dieting are associated with an increase in pituitary T3 receptor saturation (percent of activated T3 receptors), which results in a decrease in TSH even when serum levels were reduced by 50% (55).

Studies show that numerous conditions are associated with reduced transport of thyroid into the cells, which can lead to dramatic cellular hypothyroidism and symptoms that are not detected by standard blood tests because the TSH will be normal and serum T4 may actually increase due to reduced uptake into the cells (54). Most physicians and endocrinologist are unaware of the importance of the difference of this rate-limiting step in cellular thyroid activity in the pituitary and the rest of the body. Physicians are often quick to declare a person with numerous symptoms of low thyroid as having “normal” thyroid function based on a normal TSH and T4 level.

Wassen FS et al states in the Journal of Endocrinology that “These observations lend further support to the view that thyroid hormone transport into the pituitary is regulated differently than that in the liver (50).” As stated, the T4 level may be high normal. This high-normal T4 and low-normal TSH often leads an endocrinologist to erroneously make a diagnosis of “normal” or “high-normal” thyroid level while a patient is in fact suffering from low cellular thyroid levels (see thyroid transport graph).

Stress

Chronic emotional or physiologic stress can cause the significant reduction of T4 into the cells of the body while the pituitary is unaffected. A study published in the Journal of Clinical Endocrinology and Metabolism studied the effect of adding serum from different groups of individuals to cell cultures and measured the amount of T4 uptake from the serum into the cell. The study found that the serum from those with significant physiologic stress inhibited the uptake (transport) of T4 into the cell while the serum from non-physiological stress had no effect, demonstrating that serum T4 levels are artificially elevated in physiologically stressed individuals and that serum T4 and TSH levels are poor markers for tissue thyroid levels in stressed individuals (4).

A number of studies have shown that significant physiologic stress reduces cellular uptake T4 and T3 by up to 50% (63,64,109,110,111). Arem et al found that with significant physiological stress, tissue levels of T4 and T3 were dramatically reduced by up to 79% without an increase in TSH. Additionally, when comparing the T4 and T3 levels in different tissues in different individuals, there is significant variation. This large variation of T4 and T3 levels in different tissues (not reflected by TSH or serum T4 and T3 levels) explains the wide range of symptoms that are due to tissue specific hypothyroidism not reflected or detected by standard blood tests, including TSH and T4 (56).

A confirming study published in the Journal of Clinical Endocrinology and Metabolism also found that serum from non-stress individuals had no effect on T4 cellular uptake, while those with significant physiologic stress had up to a 44% reduction in T4 uptake into the cell (42). It was shown that the free T3/reverse T3 ratio was the most accurate marker for reduced cellular uptake of T4 (42).

A number of substances have been identified that are produced in response to physiologic stress or calorie reduction. These include 3-carboxy-4-methyl-5-propyl-2-furna propanoic acid (CMPF), indoxyl sulfate, billirubin and fatty acids (1,3,57,58,60). The addition of these substances to cell cultures in concentrations comparable to those seen in patients results in a 27%-42% reduction in cellular uptake of T4 but has no effect on T4 or T3 uptake into the pituitary (1,17,57,58,60) (see thyroid transport graph).

Dieting

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 (118). Chronic and yo-yo dieting, frequently done by a large percentage of the population, is shown to be associated with reduced cellular T4 uptake of 25%-50% (3,49,112,114,115,116). Successful weight loss is doomed to failure unless the reduced intracellular thyroid levels are addressed, but this reduced cellular thyroid level is generally not detected by standard laboratory testing unless a free T3/reverse T3 ratio is done.

In a study published in the American Journal of Physiology-Endocrinology and Metabolism, Van der Heyden et al studied the effect of calorie restriction (dieting) on the transport of T4 and T3 into the cell (49). It was found that dieting obese individuals had a 50% reduction of T4 into the cell and a 25% reduction of T3 into the cell due to the reduced cellular energy stores, demonstrating that in such patients standard thyroid blood tests are not accurate indicators of intracellular thyroid levels. This also demonstrates why it is very difficult for obese patients to lose weight; as calories are decreased, thyroid utilization is reduced and metabolism drops. This will, however, not be detected by standard TSH, T4 and T3 testing (a free T3/reverse T3 can aid in the diagnosis of reduced uptake of thyroid hormones and intracellular hypothyroidism). Additionally, there are increased levels of free fatty acids in the serum with chronic dieting, which further suppresses T4 uptake into the cells and further cellular hypothyroidism (106,72,57,58,114).

Many overweight individuals fail to lose weight with dieting. While it is always assumed they are doing a poor job of dieting, it has been shown, however, that chronic dieting in overweight individuals results in increased levels of NEFA, which suppresses T4 uptake into the cells (3). This suppressed T4 uptake results in reduced intracellular T4 levels and subsequent T4 to T3 conversion and a reduced metabolism (3,112,114,115,116) (see thyroid transport graph).

Reverse T3

TSH and serum T4 levels fail to correlate with intracellular thyroid levels. Additionally, the free T3 will also tend to be less accurate with reduced cellular energy. This artificial elevation of T3 due to be reduced uptake into the cell is generally offset by a reduced T4 to T3 conversion due to reduced uptake and T4 and subsequent conversion to T3, making T3 a more accurate marker than the TSH or T4 with physiologic stress. Also, the transporter for reverse T3 (rT3) is similar to T4 in that it is energy dependent and has the same kinetics as the T4 transporter (6,41,45,62,66,67). This property (among others) makes it the most useful indicator of diminished transport of T4 into the cell (45).

Thus, a high reverse T3 demonstrates that there is either an inhibition of reverse T3 uptake into the cell and/or there is increased T4 to reverse T3 formation. These always occur together in a wide range of physiologic conditions and both cause reduced intracellular T4 and T3 levels and cellular hypothyroidism. Thus, reverse T3 is an excellent marker for reduced cellular T4 and T3 levels not detected by TSH or serum T4 and T3 levels. Because increased rT3 is a marker for reduced uptake of T4 and reduced T4 to T3 conversion, any increase (high or high normal) in rT3 is not only an indicator of tissue hypothyroidism but also that T4 only replacement would not be considered optimal in such cases and would be expected to have inadequate or sub-optimal results. A high reverse T3 can be associated with hyperthyroidism as the body tries to reduce cellular thyroid levels, but this can be differentiated by symptoms and by utilizing the free T3/reverse T3 ratio, which is proving to be the best physiologic marker of intracellular thyroid levels (see Diagnosis of low thyroid due to stress & illness Graph).

Treatment

Levothyroxine (T4)-only replacement with products such as Synthroid and Levoxyl are the most widely accepted forms of thyroid replacement. This is based on a widely held assumption that the body will convert what it needs to the biologically active form T3. Based on this assumption, most physicians and endocrinologists believe that the normalization of TSH with a T4 preparation demonstrates adequate tissue levels of thyroid. This assumption, however, had never been directly tested until two studies were published (119,120). The first study investigated whether or not giving T4 only preparations will provide adequate T3 levels in varying tissues. Plasma TSH, T4 and T3 levels and 10 different tissue levels of T4 and T3 were measured after the infusion of 12-13 days of thyroxine.

This study demonstrated that the normalization of plasma TSH and T4 levels with T4-only preparations provide adequate tissue T3 levels to only a few tissues, including the pituitary (hence the normal TSH), but almost every other tissue will be deficient. This study demonstrated that it is impossible to achieve normal tissue levels of T3 by giving T4 only preparations unless supra-physiological levels of T4 are given. 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…(119).”

The second study compared the plasma TSH, T4 and T3 levels and 13 different tissue levels of T4 and T3 when T4 or T4/T3 preparations were utilized (120). This study found that a combination of T4/T3 is required to normalize tissue levels of T3. The study found that the pituitary was able to maintain normal levels of T3 despite the rest of the body being hypothyroid on T4 only preparations. Under normal conditions it was shown that the pituitary will have 7 to 60 times the concentration of T3 of other tissues of the body; and when thyroid levels drop, the pituitary was shown to have 40 to 650 times the concentration of T3 of other tissues. Thus, the pituitary is unique in its ability to concentrate T3 in the presence of diminished thyroid levels that are not present in other tissues. Consequently, the pituitary levels of T3 and the subsequent level of TSH are poor measures of tissue hypothyroidism, as almost the entire body can be severely hypothyroid despite having a normal TSH level (120).

These studies add to the large amount of medical literature demonstrating that pituitary thyroid levels are not indicative of other tissues in the body and showing why the TSH level is a poor indicator of a proper thyroid dose. These studies also demonstrate that it is impossible to achieve normal tissue thyroid levels with T4 preparations such as Synthroid and Levoxyl. It is no surprise that the majority of patients on T4 preparations will continue to suffer from symptoms of hypothyroidism despite being told their levels are “normal.” Patients on T4 only preparations should seek out a physician who is well-versed in the medical literature and understands the physiologic limitations and inadequacy of commonly used thyroid preparations.

The dramatic reduction of T4 cellular uptake with a wide variety of conditions (T3 being less affected) also explains why T4 preparations are often associated with poor clinical response and continued residual symptoms that the unknowing physician assumes is not due to low thyroid, because serum levels look “good” if the physician does not understand the potential effects of reduced thyroid hormone transport. As stated by Hennemann G 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 (5).” This makes it inappropriate to use T4-only preparations if treating any condition associated with the following: reduced mitochondrial function or ATP production, which includes insulin resistance, diabetes and obesity 68,69,70,71,106); chronic and acute dieting (4,51,66,72,112,113,114,115,116,117,118); diabetes (69,73,74,75,76); depression (73,77,78,79); anxiety (73,80); bipolar depression (73,77,81,82); neurodegenerative diseases (73,83,84,85,86,87); aging (73,74,88-100); chronic fatigue syndrome (73,101,102); fibromyalgia (73,103,104); migraines (73); chronic infections (73); physiologic stress and anxiety (73,79); cardiovascular disease (73,99,104,105,108) and inflammation and chronic illness (73,109,110,111); Likewise, high cholesterol, fatty acids or triglyceride levels also selectively inhibit T4 transport into the cell as opposed to T3 (57,58,60,72,106,107,114), making T4-only preparations physiologically inappropriate for individuals with high cholesterol or triglycerides or who are chronic dieters, which dramatically increases serum free fatty acids (72). It is not surprising that T3 has been shown to be superior in such patient populations.

Fraser et al investigated the correlation between tissue thyroid activity and serum blood tests (TSH, free T4 and T3) and published their results in the British Medical Journal. The study 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).” They found a suppressed or undetectable TSH was not an indication or a reliable marker of over replacement or hyperthyroidism. 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…Further adjustments to the dose should be made according to the patient’s clinical response.” (121)

The positive predictive value of the TSH, which is the likelihood that as suppressed TSH indicates over replacement or hyperthyroidism, was determined to be 16%. In other words, a suppressed TSH is not associated with hyperthyroidism or over-replacement 84% of the time, making it an inaccurate and inappropriate marker to determine appropriate replacement dosing. Additionally, the TSH becomes an even worse indicator the optimal replacement dose in the following situations: if a person has insulin resistance or obesity (68,69,70,71,106); is a chronic dieter (4,51,66,72,112,113,114,115,116,117,118); has diabetes (69,73,74,75,76); has depression (73,77,78,79); has bipolar depression (73,77,81,82); has a neurodegenerative diseases (73,83,84,85,86,87); is of older age (73,74,88-100); has chronic fatigue syndrome (73,101,102); has fibromyalgia (73,103,104); migraines (73); has a chronic infections (MT63)(73); is stressed or anxious (73,79,80); has heart failure or cardiovascular disease (73,99,104,105,108); suffers from migraines (73); has inflammation or a chronic illness (73,109,110,111); or has high cholesterol or triglyceride levels (57,58,60,72,106,107,114).

In a study published in the British Medical Journal, Meir et al also investigated the correlation of TSH and tissue thyroid effect. It was shown that the TSH level had no correlation with tissue thyroid levels and could not be used to determine a proper or optimal thyroid replacement dose. 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.” They stated that signs and symptoms of thyroid effect and not the TSH should be used to determine the proper replacement dose (122).

Alevizaki et al also studied the accuracy of using the TSH to determine the proper thyroid replacement dose in T4 treated individuals. The study found that such a practice of using the TSH, although common, results in the majority of tissues being hypothyroid, except for the pituitary. They conclude, “TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues (123).”

In a study published in the Journal of Clinical Endocrinology and Metabolism, Zulewski et al also investigated the accuracy of TSH to determine proper thyroid replacement. The study found that the TSH was not a useful measure of optimal or proper thyroid replacement, as there was no correlation between the TSH and tissue thyroid levels. Serum T4 and T3 levels had some correlation, with T3 being a better indictor than T4. In contrast, a clinical score that involved a thorough assessment of signs and symptoms of hypothyroidism was shown to be the most accurate method to determine proper replacement dosing. The authors also agreed that it is improper to use the TSH as the major determinant of the proper or optimal doses of thyroid replacement, stating “The ultimate test of whether a patient is experiencing the effects of too much or too little thyroid hormone is not the measurement of hormone concentration in the blood but the effect of thyroid hormones on the peripheral tissues [symptoms] (124).”

Conclusion

The most important determinant of thyroid activity is the intra-cellular level of T3, and the most important determinant of the intracellular T3 level is the activity of the cellular thyroid transporters (1-67). 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 (1-43,46,49,51,52,53,58,60,66,68,69,72-118).

This high incidence of reduced cellular thyroid transport seen with these conditions makes standard thyroid tests a poor indicator of cellular thyroid levels in the presence of such conditions. The pituitary has different transporters than every other tissue in the body; the thyroid transporters in the body are very energy dependent and affected by numerous conditions while the pituitary is minimally affected. Because the pituitary remains unaffected, there is no elevation in TSH despite wide-spread tissue hypothyroidism, making the TSH an inaccurate marker for tissue T3 levels under the numerous conditions listed above (1,3,4,17,22,43,50,52,55,59,60,61).

The reduced thyroid transport seen with these conditions results in an artificial elevation in serum thyroid levels (especially T4), making this a poor marker for tissue thyroid levels as well (5,40,41,49,52,53,62,66,67). An elevated or high-normal reverse T3 is shown to currently be the best marker for reduced transport of thyroid hormones and an indication that a person has low cellular thyroid levels despite the fact that standard thyroid tests such as TSH, free T4, and free T3 are normal (6,32,41,45,62,66,67,125-172) (see Diagnosis of low thyroid due to stress & illness Graph).

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. 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 (71,74,75,76,80,81,82,86,97,98,99,100,101,102,103,104,105,173-198). In the presence of such conditions, it should be understood that significant intracellular hypothyroidism may exist that remains undiagnosed by standard blood tests (the freeT3/reverse T3 ratio may aid in the diagnosis). Thus, more appropriated testing beyond standard thyroid function tests should be considered and supplementation with T3 should be considered with such patients.

References

1. Everts ME, De Jong M, Lim CF, Docter R, et al. Different regulation of thyroid hormone transport in liver and pituitary: Is possible role in the maintenance of low T3 production during nonthyroidal illness and fasting in man. Thyroid 1996;6(4):359-368

2. Peeters RP, Geyten SV, Wouters PJ, et al. Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 2005;12:6498–507.

3. Lim C-F, Docter R, Krenning EP, et al. Transport of thyroxine into cultured hepatocytes: effects of mild nonthyroidal illness and calorie restriction in obese subjects. Clin Endocrinol (Oxf) 1994;40:79-85.

4. Sarne DH, Refetoff S. Measurement of thyroxine uptake from serum by cultured human hepatocytes as an index of thyroid status: Reduced thyroxine uptake from serum of patients with nonthyroidal illness. J Clin Endocrinol Metab 1985;61:1046–52.

5. Hennemann G, Docter R, Friesema EC, De Jong M et al. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocrine Reviews 2001;22(4):451-476.

6. Holm AC, Jacquemin C. Membrane transport of l-triiodothyronine by human red cell ghosts. Biochem Biophys Res Commun 1979;89:1006–1017.

7. 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 J1982;208:27–34.

8. Holm AC, Kagedal B. Kinetics of triiodothyronine uptake by erythrocytes in hyperthyroidism, hypothyroidism, and thyroid hormone resistance. J Clin Endocrinol Metab 1989;69:364–368.

9. Osty J, Valensi P, Samson M, Francon J, Blondeau JP. Transport of thyroid hormones by human erythrocytes: kinetic characterization in adults and newborns. J Clin Endocrinol Metab 1990;71:1589–1595

10. Moreau X, Azorin J-M, Maurel M, Jeanningros R. Increase in red blood cell triiodothyronine uptake in untreated unipolar major depressed patients compared to healthy controls. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:293–310.

11. Osty J, Jego L, Francon J, Blondeau JP. Characterization of triiodothyronine transport and accumulation in rat erythrocytes. Endocrinology 1988;123:2303–2311.

12. Osty J, Zhou Y, Chantoux F, Francon J, Blondeau JP. The triiodothyronine carrier of rat erythrocytes: asymmetry and mechanism of transinhibition. Biochim Biophys Acta 1990;1051:46–51.

13. Moreau X, Lejeune PJ, Jeanningros R. Kinetics of red blood cell T3 uptake in hypothyroidism with or without hormonal replacement, in the rat. J Endocrinol Invest 1999;22:257–261.

14. McLeese JM, Eales JG. 3,5,3-Triiodo-l-thyronine and lthyroxine uptake into red blood cells of rainbow trout (Oncorhynchus mykiss). Gen Comp Endocrinol 1996;102:47–55.

15. McLeese JM, Eales JG. Characteristics of the uptake of 3,5,3- triiodo-l-thyronine and l-thyroxine into red blood cells of rainbow trout (Oncorhynchus mykiss). Gen Comp Endocrinol 1996;103:200–208.

16. Everts ME, Docter R, van Buuren JC, et al. Evidence of carrier-mediated uptake of triiodothyronine in cultured anterior pituitary cells of euthyroid rats. Endocrinology 1993;132:1278–1285.

17. Everts ME, Docter R, Moerings EP, van Koetsveld PM, Visser TJ, et al. Uptake of thyroxine in cultured anterior pituitary cells of euthyroid rats. Endocrinology 1994;134:2490–2497.

18. Yan Z, Hinkle PM. Saturable, stereospecific transport of 3,5,3- triiodo-l-thyronine and l-thyroxine into GH4C1 pituitary cells. J Biol Chem 1993;268:20179–20184.

19. Goncalves E, Lakshmanan M, Pontecorvi A, Robbins J. Thyroid hormone transport in a human glioma cell line. Mol Cell Endocrinol 1990;69:157–165.

20. Francon J, Cantoux F, Blondeau JP. Carrier-mediated transport of thyroid hormones into rat glial cells in primary culture. J Neurochem 1989;53:1456–1463.

21. Beslin A, Chantoux F, Blondeau JP, Francon J. Relationship between the thyroid hormone transport system and the Na-H exchanger in cultured rat brain astrocytes. Endocrinology 1995;136:5385–5390.

22. Chantoux F, Blondeau JP, Francon J. Characterization of the thyroid hormone transport system of cerebrocortical rat neurons in primary culture. J Neurochem 1995;65:2549–2554.

23. Kastellakis A, Valcana T. Characterization of thyroid hormone transport in synaptosomes from rat brain. Mol Cell Endocrinol 1989;67:231–241.

24. Lakshmanan M, Goncalves E, Lessly G, et al. The transport of thyroxine into mouse neuroblastoma cells, NB41A3: the effect of L-system amino acids. Endocrinology 1990;126:3245–3250.

25. Pontecorvi A, Lakshmanan M, Robbins J. Intracellular transport of 3,5,3-triiodo-l-thyronine in rat skeletal myoblasts. Endocrinology 1987;121:2145–2152.

26. Everts ME, Verhoeven FA, Bezstarosti K, et al. Uptake of thyroid hormones in neonatal rat cardiac myocytes. Endocrinology 1996;137:4235–4242.

27. Zonefrati R, Rotella CM, Toccafondi RS, Arcangeli P. Thyroid hormone receptors in human cultured fibroblasts: evidence for cellular T4 transport and nuclear binding. Horm Metab Res 1983;15:151–154.

28. Docter R, Krenning EP, Bernard HF, Hennemann G. Active transport of iodothyronines into human cultured fibroblasts. J Clin Endocrinol Metab 1987;65:624–628.

29. Cheng SY. Characterization of binding of uptake of 3,3,5- triiodo-l-thyronine in cultured mouse fibroblasts. Endocrinology 1983;112:1754–1762.

30. Mitchell AM, Manley SW, Mortimer RH. Uptake of l-triiodothyronine by human cultured trophoblast cells. J Endocrinol 1992;133:483–486.

31. Mitchell AM, Manley SW, Mortimer RH. Membrane transport of thyroid hormone in the human choriocarcinoma cell line JAR. Mol Cell Endocrinol 1992;87:139–145.

32. Mitchell AM, Manley SW, Rowan KA, Mortimer RH. Uptake of reverse T3 in the human choriocarcinoma cell line JAR. Placenta 1999;20:65–70.

33. Bernus I, Mitchell AM, Manley SW, Mortimer RH. Uptake of l-triiodothyronine sulfate by human choriocarcinoma cell line JAR. Placenta 1999;20(2-3):161-165.

34. Mitchell AM, Manley SW, Payne EJ, Mortimer RH. Uptake of thyroxine in the human choriocarcinoma cell line JAR. J Endocrinol 1995;146:233–238.

35. Landeta LC, Gonzales-Padrones T, Rodriguez-Fernandez C. Uptake of thyroid hormones (l-T3 and l-T4) by isolated rat adipocytes. Biochem Biophys Res Commun 1987;145:105–110.

36. Kostrouch Z, Felt V, Raska J, Nedvidkova J, Holeckova E. Binding of (125I) triiodothyronine to human peripheral leukocytes and its internalization. Experientia 1987;43:1117–1118.

37. Kostrouch Z, Raka I, Felt V, Nedvidkova J, Holeckova E. Internalization of triiodothyronine-bovine serum albumin-colloidal gold complexes in human peripheral leukocytes. Experientia 1987;43:1119–1120.

38. Centanni M, Mancini G, AndreoliM1989 Carrier-mediated [125I]-T3 uptake by mouse thymocytes. Endocrinology 124:2443–2448

39. Centanni M, Sapone A, Taglienti A, Andreoli M. Effect of extracellular sodium on thyroid hormone uptake by mouse thymocytes. Endocrinology 1991;129:2175–2179.

40. de Jong M, Docter R, Bernard HF, et al. T4 uptake into the perfused rat liver and liver T4 uptake in humans are inhibited by fructose. Am J Physiol 1994;266:E768–E775.

41. Hennenmann G, Everts ME, de Jong M, et al. The significance of plasma membrane transport in the bioavailability of thyroid hormone. Clin Endo 1998;48:1-8.

42. Vos RA, de Jong M, Bernard BF, et al. Impaired thyroxine and 3,5,3′-triiodothyronine handling by rat hepatocytes in the presence of serum of patients with nonthyroidal illness. J Clin Endocrinol Metab 1995;80:2364-2370.

43. Hennemann G, Krenning EP. The kinetics of thyroid hormone transporters and their role in non-thyroidal illness and starvation. Best Practice & Res Clin Endor Metab 2007;21(2):323-338.

44. Francon J, Chantoux F, Blondeau JP. Carrier-Mediated Transport of Thyroid Hormones into Rat Glial Cells in Primary Culture. J Neurochemistry 1989;53:1456-1463.

45. Hennemann G, Vos RA, de Jong M, et al. Decreased peripheral 3,5,3’-triiodothyronine (T3) production from thyroxine (T4): A syndrome of impaired thyroid hormone activation due to transport inhibition of T4- into T3-producing tissues. J Clin Endocrinol Metabol 1993;77(5):1431-1435.

46. Stump CS, Short KR, Bigelow ML, et al. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci 2003;100(13):7996–8001.

47. Krenning EP, Docter R, Bernard HF,et al. The essential role of albumin in the active transport of thyroid hormones into primary cultured rat hepatocytes. FEBS Lett 1979;1;107(1):227-30.

48. Krenning EP, Docter R, Bernard HF, et al. Regulation of the active transport of 3,3′,5-triiodothyronine (T3) into primary cultured rat hepatocytes by ATP. FEBS Letters 1979;10(1):227-230.

49. van der Heyden JT, Docter R, van Toor H, et al. Effects of caloric deprivation on thyroid hormone tissue uptake and generation of low-T3 syndrome. Am J Physiol Endocrinol Metab 1986;251(2):156-E163.

50. Wassen FWJS, Moerings EPCM, van Toor H, et al. Thyroid hormone uptake in cultured rat anterior pituitary cells: effects of energy status and bilirubin. J Endocrinol 2000;165:599-606.

51. Jenning AS, Ferguson DC, Utiger RD. Regulation of the conversion of thyroxine to triiodothyronine in the perfused rat liver. J Clin Invest 1979;64:1614–1623

52. Krenning E, Docter R, Bernard B, Visser T, Hennemann G. Characteristics of active transport of thyroid hormone into rat hepatocytes. Biochim Biophys Acta 1981;676:314–320.

53. Riley WW, Eales JG. Characterization of 3,5,3-triiodo-lthyronine transport into hepatocytes isolated from juvenile rainbow trout (Oncorhynchus mykiss), and comparison with l-thyroxine transport. Gen Comp Endocrinol 1994;95:301–309.

54. Spencer CA, Lum SMC, Wilber JF, et al. Dynamics of Serum Thyrotropin and Thyroid Hormone Changes in Fasting. J Clin Endocrin Metab 1983;(5):883-888.

55. St Germain DL, Galton VA. Comparative study of pituitary-thyroid hormone economy in fasting and hypothyroid rats. J Clin Invest 1985;75(2):679–688.

56. Arem R, Wiener GJ, Kaplan SG, Kim HS, et al. Reduced tissue thyroid hormone levels in fatal illness. Metabolism 1993;42(9):1102-8.

57. Lim C-F, Bernard BF, De Jong M, et al. A furan fatty acid and indoxyl sulfate are the putative inhibitors of thyroxine hepatocyte transport in uremia. J Clin Endocrinol Metab 1993;76:318-324.

58. Lim C-F, Docter R, Visser TJ, Krenning EP, Bernard B, et al. Inhibition of thyroxine transport into cultured rat hepatocytes by serum of non-uremic critically ill patients: Effects of bilirubin and nonesterified fatty acids. J Clin Endocrinol Metab 1993;76:1165-1172.

59. Lim VS, Passo C, Murata Y, Ferrari E, et al. Reduced triiodothyronine content in liver but not pituitary of the uremic rat model: demonstration of changes compatible with thyroid hormone deficiency in liver only. Endocrinology 1984;114:280-286.

60. Everts ME, Lim C-F, Moerings EPCM, Docter R, et al. Effects of a furan fatty acid and indoxyl sulfate on thyroid hormone uptake in cultured anterior pituitary cells. Am J Physiol 1995;268:E974-E979.

61. Doyle D. Benzodiazepines inhibit temperature dependent L-[125I] triiodothyronine accumulation into human liver, human neuroblast, and rat pituitary cell lines. Endocrinology 1992;130:1211-1216.

62. Krenning EP, Docter R, Bernard HF, et al. Decreased transport of thyroxine (T4), 3,3′,5-triiodothyronine (T3) and 3,3′,5′-triiodothyronine (rT3) into rat hepatocytes in primary culture due to a decrease of cellular ATP content and various drugs. FEBS Lett 1982;140:229-233.

63. Kaptein EM, Robinson WJ, et al. Peripheral serum thyroxine, triiodothyronine, and reverse triiodothyronine in the low thyroxine state of acute nonthyroidal illness. A noncompartmental analysis. J Clin Invest 1982;69:526–535.

64. Kaptein EM, Kaptein JS, Chang EI, et al. Thyroxine transfer and distribution in critical nonthyroidal illness, chronic renal failure, and chronic ethanol abuse. J Clin Endocrinol Metab 1987;65:606–616.

65. Everts ME, Visser TJ, Moerings EM, Docter R, et al. Uptake of triiodothyroacetic acid and its effect on thyrotropin secretion in cultered anterior pituitary cells. Endocrinology 1994;135(6):2700-2707.

66. De Jong M. Docter R, van der Hoek HJ, Vos RA. Transport of 3,5,3’-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting. Endocrinology 1992;131(1):463-470.

67. Hennemann G, Krenning EP, Bernard B, Huvers F, et al. Regulation of Influx and efflux of thyroid hormones in rat hepatocytes: Possible physiologic significance of plasma membrane in the regulation of thyroid hormone activity. Horm Metab Res Suppl 1984;14:1-6.

68. Petersen KF, Dufour S, Shulman GI. Decreased Insulin-Stimulated ATP Synthesis and Phosphate Transport in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Parents. PLoS Med 2005;2(9):e233.

69. Szendroedi J, Schmid AI, Meyerspeer M, et al. Impaired mitochondrial function and insulin resistance of skeletal muscle in mitochondrial diabetes. Diabetes Care 2009;32(4):677-9.

70. Abdul-Ghani MA, Jani R, Chavez A, Molina-Carrion M, et al. Mitochondrial reactive oxygen species generation in obese non-diabetic and type 2 diabetic participants. Diabetologia 2009;52(4):574-82.

71. Verga SB, Donatelli M, Orio L, Mattina A, et al. A low reported energy intake is associated with metabolic syndrome. J Endorcinol Invest 2009;32:538-541.

72. DeMarco NM, Beitz DC, Whitehurst GB. Effect of fasting on free fatty acid, glycerol and cholesterol concentrations in blood plasma and lipoprotein lipase activity in adipose tissue of cattle. J Anim Sci 1981;52:75-82.

73. MT 63. Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 2007;83(1):84–92.

74. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Ann Rev Genetics 2005;39(1):359–407.

75. Fosslien, E. Mitochondrial medicine—Molecular pathology of defective oxidative phosphorylation. Ann Clin Lab Sci 2001;31(1):25–67.

76. West IC. Radicals and oxidative stress in diabetes. Diabet. Med 2000;17(3):171–180.

77. Modica-Napolitano JS, Renshaw PF. Ethanolamine and phosphoethanolamine inhibit mitochondrial function in vitro: implications for mitochondrial dysfunction hypothesis in depression and bipolar disorder. Biological Psychiatry 2004;55(3):273-277.

78. Gardner A, Boles RG. Mitochondrial Energy Depletion in Depression with Somatization. Psychother Psychosom 2008;77:127-129.

79. Burroughs S, French D. Depression and anxiety: Role of mitochondria. Current Anesthesia Crit Care 2007;18:34-41.

80. Einat H, Yuan P, Manji HK. Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders. Behav Brain Res 2005;165(2):172–180.

81. Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol. Psychiatry 2005;10(10):900–919.

82. Fattal O, Budur ., Vaughan AJ, Franco K. Review of the literature on major mental disorders in adult patients with mitochondrial diseases. Psychosomatics 2006;47(1):1–7.

83. Hutchin T and Cortopassi G. A mitochondrial DNA clone is associated with increased risk for Alzheimer’s disease. Proc Natl Acad Sci USA 1995;92:6892-95.

84. Sherer TB, Betarbet R, Greenamyre JT. Environment, mitochondria, and Parkinson’s disease. Neuroscientist 2002;8(3):192–7.

85. Gomez C, Bandez MJ, Navarro A. Pesticides and impairment of mitochondrial function in relation with the Parkinsonian syndrome. Front Biosci 2007;12:1079–93.

86. Stavrovskaya IG, Kristal BS. The powerhouse takes control of the cell: is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death? Free Radic Biol Med 2005;38 (6):687–697.

87. Schapira AHV. Mitochondrial disease. Lancet 2006;368:70-82.

88. Richter, C. Oxidative damage to mitochondrial DNA and its relationship to aging. Int J Biochem Cell Biol 1995;27(7):647-653.

89. Papa, S. Mitochondrial oxidative phosphorylation changes in the life span. Molecular aspects and physiopathological implications. Biochimica Biophysica Acta 1996;87-105.

90. Cortopassi G,Wang A. Mitochondria in organismal aging and degeneration. Biochimica Biophysica Acta, 1999;1410:183-193.

91. Harman, Denham. The Biologic Clock: the Mitochondria? J Am Geriatr Soc 1972;20:145-147.

92. Miquel J, Economos AC, Fleming J and Johnson JE. Mitochondrial role in cell aging. Exp Gerontol 1980;15:575-91.

93. Miquel J. An integrated theory of aging as the result of mitochondrial DNA mutation in differentiated cells. Arch Gerontol Geriatr 1991;12:99-117.

94. Miquel J. An update on the mitochondrial-DNA mutation hypothesis of cell aging. Mutation Research 1992;275:209-16.

95. Zs.-Nagy I. A membrane hypothesis of aging. J Theor Biol 1978;75:189-195.

96. Zs.-Nagy I. The role of membrane structure and function in cellular aging: a review. Mach Aging Dev 1979;9:37-246.

97. Savitha S, Sivarajan K, Haripriya D, et al. Efficacy of levo carnitine and alpha lipoic acid in ameliorating the decline in mitochondrial enzymes during aging. Clin. Nutr 2005;24(5):794–800.

98. Skulachev VP, Longo VD. Aging as a mitochondria-mediated atavistic program: can aging be switched off? Ann NY Acad Sci 2005;1057:145–164.

99. Corral-Debrinski M, Shoffner JM, Lott MT, Wallace DC. Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res 1992;275(3–6):169-180.

100. Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci SA 1993;90(17):7915–7922.

101. Fulle, S., Mecocci, P., Fano, G., et al. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med 2000;29 (12),1252-1259.

102. Buist, R. Elevated xenobiotics, lactate and pyruvate in C.F.S. patients. J Orthomolec Medicine 1989;4 (3):170-172.

103. Park, J.H., Niermann, K.J., Olsen, N.Evidence for metabolic abnormalities in the muscles of patients with fibromyalgia. Curr Rheumatol Rep 2000;2(2):131–140.

104. Yunus, M.B., Kalyan-Raman, U.P., Kalyan-Raman, K. Primary fibromyalgia syndrome and myofascial pain syndrome: clinical features and muscle pathology. Arch Phys Med Rehabil 1988;69 (6):451-454.

105. Puddu, P., Puddu, G.M., Galletti, L., Cravero, E., Muscari, A. Mitochondrial dysfunction as an initiating event in atherogenesis: a plausible hypothesis. Cardiology 2005;103 (3):137–141.

106. Brehm A, Krssak M, Schmid AI, Nowothy P, et al. Increased Lipid Availability Impairs Insulin-Stimulated ATP Synthesis in Human Skeletal Muscle. Diabetes 2006;55:136-140.

107. Kigoshi S, Akiyama M, Ito R. Close correlation between levels of cholesterol and free fatty acids in lymphoid cells. Cellular and Molecular Life Sciences 1976;32(10):1244-1246.

108. Chen L, Knowlton AA. Depressed mitochondrial fusion in heart failure. Circulation 2007;116:259.

109. Kaptein EM, Feinstein EI, Nicoloff JT, Massry SG. Serum reverse triiodothyronine and thyroxine kinetics in patients with chronic renal failure. J Clin Endocrinol Metab 1983;57:181–189.

110. Kaptein EM. Thyroid hormone metabolism and thyroid disease in chronic renal failure. Endocr Rev 1996;17:45–63.

111. KapteinEM. Clinical relevance of thyroid hormone alterations in nonthyroidal illness. Thyroid Int 1997;4:22–25.

112. Leibel RL, Jirsch J. Diminshed energy requirements in reduced-obese patients. Metabolism 1984;33(2):164-170.

113. Steen SN, Opplieger RA, Brownell KD. Metabolic effects of repeated weight and regain in adolescent wrestlers. JAMA 1988;260:47-50.

114. Elliot DL, Goldberg L, Kuehl KD, Bennett WM. Sustained depression of the resting metabolic rate after massive weight loss. Am J Clin Nutr 1989;49:93-6.

115. Manore MM, Berry TE, Skinner JS, Carroll SS. Energy expenditure at rest and during exercise in nonobese female cyclical dieters and in nondieting control subjects. Am J Clin Nutr 1991;54:41-6.

116. Croxson MS, Ibbertson HK, Low serum triiodothyronine (T3) and hypothyroidism in anorexia nervosa. J Clin Endorinol Metab 1977;44:167-174.

117. Carlin K, Carlin S. Possible etiology for euthyroid sick syndrome. Med Hypotheses 1993;40:38-43.

118. Brownell KD, Greenwood MR, Stellar E, Shrager EE. The effects of repeated cycles of weight loss and regain in rats. Physiol Behav 1986;38(4):459-64.

119. Escobar-Morreale HF, Obregón MJ, Escobar del Rey F, et al. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J. Clin Invest 1995;96(6):2828-2838.

120. Escobar-Morreale HF, Obregón MJ, Escobar del Rey F. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinol 1996;137:2490-2502.

121. Fraser WD, Biggart EM, OReilly DJ, et al. Are biochemical tests of thyroid function of any value in monitoring patients receiving thyroxine replacement? The British Medical Journal 1986;293:808-810.

122. Meier C, Trittibach P, Guglielmetti M, Staub JJ, Muller B. Serum TSH in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey. BMJ 2003;326:311-312.

123. Alevizaki M, Mantzou E, cimponeriu AT, et al. TSH may not be a good marker for adequate thyroid hormone replacement therapy. Wien Klin Wochenschr 2005;117/18:636-640.

124. Zulewski H, Muller B, Exer P, et al. Estimation of tissue hypothyrodisim by a new clinical score: Evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82(3):771-776.

125. Hackney AC, Feith S, Pozos, R, Seale J. Effects of high altitude and cold exposure on resting thyroid hormone concentrations. Aviat Space Environ Med 1995;66(4):325-9.

126. Opstad PK, Falch D, Oktedalen O, et al. The thyroid function in young men during prolonged exercise and the effect of energy and sleep deprivation. Clin Endo 1984;20:657-669.

127. 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;20:483-489.

128. den Brinker M, Joosten KFM, Visser, et al. euthyroid sick syndrome in meningococcal sepsis: The impact of peripheral thyroid hormone metabolism and binding proteins. J Clin Endocrinol Metab 2005;90(10):5613-5620.

129. Chopra IJ, Solomon DH, Hepner GW, et al. Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroidal illnesses. Ann Intern Med 1979;90(6):905–12.

130. van den Beld AW, Visser TJ, Feelders RA, et al. Thyroid hormone concentrations, disease, physical function and mortality in elderly men. J Clin Endocrinol Metab 2005;90(12):6403–9.

131. Chopra IJ. A study of extrathyroidal conversion of thyroxine (T4) to 3,3′,5-triiodothyronine (T3) in vitro. Endocrinology 1977;101(2):453-63.

132. Sechman A, Niezgoda J, Sobocinski R. The relationship between basal metabolic rate (BMR) and concentrations of plasma thyroid hormones in fasting cockerels. Folia Biol (Krakow) 1989;37(1-2):83-90.

133. Magri F, Cravello L, Fioravanti M, et al. Thyroid function in old and very old healthy subjects. J Endocrinol Invest 2002;25(10):60-63.

134. 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.

135. Friberg L, Drvota V, Bjelak AH, Eggertsen G, Ahnve S. Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction Am J Med.2001;111(9):699-703.

136. McCormack PD. Cold stress, reverse T3 and lymphocyte function. Alaska Med 1998;40(3):55-62.

137. Effects of obesity, total fasting and re-alimentation on L-thyroxine (T 4 ), 3,5,3-L-triiodothyronine (T3), 3,3,5-L-triiodothyronine (rT3), thyroxine binding globulin (TBG), transferrin, 2 –haptoglobin and complement C3 in serum. Acta Endocrinol 1979;91:629–43.

138. Kvetny J. Thyroxine binding and cellular metabolism of thyroxine in mononuclear blood cells from patients with anorexia nervosa. J Endocrinol. 1983 Sep;98(3):343-50.

139. Germain DL. Metabolic effect of 3,3′,5′-triiodothyronine in cultured growth hormone-producing rat pituitary tumor cells. Evidence for a unique mechanism of thyroid hormone action. J Clin Invest 1985;76(2):890–893.

140. Szymanski PT, Effects of thyroid hormones and reverse T3 pretreatment on the betaadrenoreceptors in the rat heart. Acta Physiol Pol 1986;37:131-138.

141. du Pont JS. Is reverse T3 a physiological nonactive competitor of the action of T3 upon the electrical properties of GH3 cells? Neuroendo 1991;54:146-150.

142. Schulte C. Low T3 syndrome and nutritional status as prognostic factors in patients undergoing bone marrow transplantation. Bone Marrow Transplant 1998;22:1171-1178.

143. Goichot B, Schlienger JL, Grunenberger F, et al. Thyroid hormone status and nutrient intake in the free-living elderly. Interest of reverse triiodothyronine assessment. Eur J Endo 1994;130:244-252.

144. Okamoto R, Leibfritz. Adverse effects of reverse triodothyronine on cellular metabolism as assessed by 1H and 31P NMR spectroscopy. Res Exp Med 1997;197:211-217.

145. de Jong FJ, den Heijer T, Visser TJ, et al. Thyroid hormones, dementia, and atrophy of the medial temporal lobe. J Clin Endo Metab 2006;91(7):2569-2573.

146. Forestier E, Vinzio S, Sapin R, et al. Increased Reverse T3 is Associated With Shorter Survival in Independently-living Elderly. The Alsanut Study. Eur J Endocrinol 2009;160(2):207-14.

147. Visser TJ, Lamberts WJ, Wilson JHP, et al. Serum thyroid hormone concentrations during prolonged reduction of dietary intake. Metabolism 1978;27(4):405-409.

148. Linnoila M, Lamberg BA, Potter WZ, et al. High reverse T3 levels in manic and unipolar depressed women. Psych Res 1982;6:271-276.

149. McCormack PD, Reed HL, Thomas JR, et al. Increased in rT3 serum levels observed during extended Alaskan field operations of naval personnel. Alaska Med 1996;38(3):89-97.

150. Mariotti S, Barbesino G, Caturegli P, et al. Complex alteration of thyroid function in healthy centenarians. J Clin Endo Metab 1993;77(5):1130-1134.

151. Danforth EJ, Desilets EJ, Jorton ES, Sims EAH, et al. Reciprocal serum triiodothryronine (T3) and reverse (rT3) induced by altering the carbohydrate content of the diet. Clin Res 1975;23:573.

152. McCormack PD, Thomas J, Malik M, Staschen CM. Cold stress, reverse T3 and lymphocyte function. Alaskan Med 1998;40(3):55-62.

153. Peeters RP, Wouters PJ, van Toor H, et al. Serum 3,3’,5’-triiodothyronine (rT3) and 3,5,3’-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005;90(8):4559–65.

154. Szabolcs I, Weber M, Kovacs Z, et al. The possible reason for serum 3,3’5’-(reverse T3) triiodothyronine increase in old people. Acta Medica Acad Sci Hun, Tomus 1982;39(1-2):11-17.

155. Silberman H, Eisenberg D, Ryan J, et al. The relation of thyroid indices in the critically ill patient to prognosis and nutritional factors. Surg Gynecol Obstet 1988;166(3):223-228.

156. Mitchell AM, Manley SW, Rowan KA, Mortimer RH. Uptake of reverse T3 in the human choriocarcinoma cell line Jar. Placebta 1999;20:65-70.

157. Stan M, Morris JC. Thyrotropin-axis adaptation in aging and chronic disease. Endocrinol Metab Clin N Am 2005;34:973-992.

158. LoPresti JS, Eigen A, Kaptein E, et al. Alterations in 3,3′,5′-Triiodothyronine metabolism in response to propylthiouracil, Dexamethasone, and Thyroxine Administration in Man. J Clin Invest 1989;84:1650-1656.

159. Palmblad J, Levi L, Burger A, et al. Effects of total energy withdrawal (fasting) on the levels of growth hormone, thyrotropin, cortisol, adrenaline, noradrenaline, T4, T3, and rT3 in healthy males. Acta Med Scand 1977;201:15-22.

160. Reinhardt W, Misch C, Jockenhovel F, et al. Triiodothyronine (T3) reflects renal graft function after renal transplantation. Clin Endo 1997;46:563-569.

161. Chopra IJ, Chopra U, Smith SR, et al. Reciprocal changes in serum concentrations of 3,3’5’-triiodothyronine (reverse T3) and 3,3’5-triiodothyronine (T3) in systemic illnesses. J Clin Endocrinol Met 1975;41(6):1043-1049.

162. 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 Endorcrinol Metab 1976;42(197):197-200.

163. Girdler SS, Pedersen CA, Light KC. Thyroid axis function during the menstrual cycle in women with premenstrual syndrome. Psychoneruoendocrinology 1995;20(4):395-403.

164. Peeters RP, Wouters PJ, Kaptein E, et al. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 2003;88:3202–11.

165. Pittman JA, Tingley JO, Nickerson JF, Hill SR. Antimetabolic activity of 3,3’,5’-triiodo-dl-thyronine in man. Metabolism 1960;9:293-5.

166. Desai M, Irani AJ, Patil K, et al. The importance of reverse triiodothyroinine in hypothyroid children on replacement treatement. Archives Dis Childhood 1984;59:30-35.

167. Chopra IJ. A radioimmunoassay for measurement of 3, 3′, 5′-triiodothyronine (reverse T3). J Clin Invest 1974; 54:583-92.

168. Kodding R, Hesch RD. L-3′, 5′-diiodothyronine in human serum. Lancet 1978;312(8098):1049.

169. 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.

170. 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.

171. Gavin LA, Moeller M, Shoback D, Cavalieri RR. Reverse T3 and modulators of the calcium messenger system rapidly decrease T4-5’-deiodinase II activity in cultured mouse neuroblastoma cells. Thyroidology 1988;(1):5-12.

172. Chopra IJ, Williams DE, Orgiazzi J, Solomon DH. Opposite effects of dexamethasone on serum concentrations of 3,3′,5′- triiodothyronine (reverse T3) and 3,3’5-triiodothyronine (T3). JCEM 1975;41:911-920.

173. Brent GA, Hershman JM. Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. J Clin Endocrinol Metab 1986;63(1):1-8.

174. Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, et al. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest 1995;96(6):2828–2838.

175. Lomenick JP, El-Sayyid M, Smith WJ . Effect of levo-thyroxine treatment on weight and body mass index in children with acquired hypothyroidism. The Journal of Pediatrics 2008;152(1):96-100.

176. 200. Acker CG, Singh AR, Flick RP, et al. A trial of thyroxine in acute renal failure. Kidney Int 2000;57:293-8.

177. Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS. Health status, psychological symptoms, mood, and cognition in L-thyroxine-treated hypothyroid subjects. Thyroid 2007;17(3):249-58.

178. Krotkiewski M, Holm G, Shono N. Small doses of triiodothyronine can change some risk factors associated with abdominal obesity. Inter J Obesity 1997;21:922-929.

179. Krotkiewski M. Thyroid hormones and treatment of obesity. Int J of Obesity 2000;24(2):S116-S119.

180. 121. Lowe JC, Garrison RL, Reichman AJ, et al. Effectiveness and safety of T3 (triiodothyronine) therapy for euthyroid fibromyalgia: a double-blind placebo-controlled response-driven crossover study. Clinical Bulletin of Myofascial Therapy 1997;2(2/3):31-58.

181. Lowe JC, Reichman AJ, Yellin J. The process of change during T3 treatment for euthyroid fibromyalgia: a double-blind placebo-controlled crossover study. Clinical Bulletin of Myofascial Therapy 1997;2(2/3):91-124.

182. 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. Clinical Bulletin of Myofascial Therapy 1997;2(4):71-88.

183. Yellin BA, Reichman AJ, Lowe JC. The process of Change During T3 Treatment for Euthyroid Fibromyalgia: A Double-Blind Placebo-Controlled Crossover Study. The Metabolic Treatment of Fibromyalgia. McDowell Publishing 2000.

184. Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS. Health status, psychological symptoms, mood, and cognition in L-thyroxine-treated hypothyroid subjects. Thyroid 2007;17(3):249-58.

185. Cooke RG, Joffe RT, Levitt AJ. T3 augmentation of antidepressant treatment in T4-replaced thyroid patients. J Clin Psychiatry1992;53(1):16-8.

186. Bettendorf M, Schmidt KG, Grulich-Henn J, et al. Tri-idothyronine treatment in children after cardiac surgery: a double-blind, randomized, placebo-controlled study. The Lancet 2000;356:529-534.

187. Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothryronine replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized placebo-controlled study. J Clin Endocrin Metab 2008;93(4):1351-8.

188. 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.

189. Dulchavsky SA, Hendrick SR, Dutta S. Pulmonary biophysical effects of triiodothyronine (T3) augmentation during sepsis induced hypothyroidism. J Trauma 1993;35:104-9.

190. Novitzsky D, Cooper DKC, Human PA, et al. Triiodothyronine therapy for heart donor and recepient. J Heart Transplant 1988;7:370-6.

191. 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.

192. 209. Klemperer JD, Klein I, Gomez M, et al. Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med 1995;333:1522-7.

193. Gomberg-Maitland M. Thyroid hormone and cardiovascular disease. Am Heart J 1998;135:187-96.

194. Dulchavsky SA, Kennedy PR, Geller ER, et al. T3 preserves respiratory function in sepsis. J Trauma 1991;31:753–9.

195. Novitzky D, Cooper DK, Reichart B. Hemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors. Transplantation 1987;43:852–5.

196. Hamilton MA, Stevenson LW, Fonarow GC, et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol 1998;81:443–7.

197. Klemperer JD, Klein IL, Ojamaa K, et al. Triidothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996;61:1323–9.

198. Smidt-Ott UM, Ascheim DD. Thyroid hormone and heart failure. Curr Heart Fail Rep 2006;3:114–9.