Pathway Of Thyroid Hormone Metabolism Research Articles

Thyroid Hormone Metabolism: A Historical Perspective.

In this article, starting with the recognition that iodine is essential for normal thyroid function and is a component of thyroid hormone (TH) molecules, we discuss the many seminal observations and discoveries that have led to identification of various pathways of TH metabolism and their potential roles in TH economy and action. We then recount evidence that TH metabolism participates in maintaining the appropriate content of active hormone in a TH-responsive tissue or cell. Thus, metabolism of the TH is not merely a means by which it is degraded and eliminated from the body, but an essential component of an intricate system by which the thyroid exerts its multiple regulatory effects on almost all organs and tissues. The article ends with a summary of the current concepts and some outstanding questions that are awaiting answers.

The classic pathways of thyroid hormone metabolism

Thyroid hormones (TH) are crucial for growth and development and play an important role in energy homeostasis. Although serum TH levels are relatively constant in the physiological state, TH bioavailability at the tissue and cellular level is dependent on local TH metabolism. Circulating TH produced by the thyroid can be metabolized by a number of different pathways resulting in 1) activation of TH 2) deactivation of TH or 3) excretion of TH and subsequent metabolites. These pathways play an essential role in determining local TH levels and action. The major classical pathways of TH metabolism are deiodination, sulfation, glucuronidation, and ether-link cleavage. This review provides an overview of these pathways, their relative contributions to TH levels in the serum and in various organs and the changes in these pathways elicited by fasting and illness.

Environmental factors affecting thyroid function of wild sea bass (Dicentrarchuslabrax) from European coasts

Thyroid functional status of wild fish in relation with the contamination of their environment deserves further investigation. We here applied a multi-level approach of thyroid function assessment in 87 wild sea bass collected near several estuaries: namely the Scheldt, the Seine, the Loire, the Charente and the Gironde. Thyroxine (T4) and triiodothyronine (T3) concentrations in muscle were analyzed by radioimmunoassay. The activity of hepatic enzymes involved in extrathyroidal pathways of thyroid hormone metabolism, viz. deiodination, glucuronidation and sulfatation were analyzed. Last, follicle diameter and epithelial cell heights were measured. We observed changes that are predicted to lead to an increased conversion of T4–T3 and lowered thyroid hormone excretion. The changes in the metabolic pathways of thyroid hormones can be interpreted as a pathway to maintain thyroid hormone homeostasis. From all compounds tested, the higher chlorinated PCBs seemed to be the most implicated in this perturbation.

Biochemical Mechanisms of Thyroid Hormone Deiodination

Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T(4)) is activated by outer ring deiodination (ORD) to 3,3',5-triiodothyronine (T(3)), whereas both T(4) and T(3) are inactivated by inner ring deiodination (IRD) to 3,3',5-triiodothyronine and 3,3'-diiodothyronine, respectively. These reactions are catalyzed by three iodothyronine deiodinases, D1-3. Although they are homologous selenoproteins, they differ in important respects such as catalysis of ORD and/or IRD, deiodination of sulfated iodothyronines, inhibition by the thyrostatic drug propylthiouracil, and regulation during fetal and neonatal development, by thyroid state, and during illness. In this review we will briefly discuss recent developments in these different areas. These have resulted in the emerging view that the biological activity of thyroid hormone is regulated locally by tissue-specific regulation of the different deiodinases.

Alternate Pathways of Thyroid Hormone Metabolism

The major thyroid hormone (TH) secreted by the thyroid gland is thyroxine (T(4)). Triiodothyronine (T(3)), formed chiefly by deiodination of T(4), is the active hormone at the nuclear receptor, and it is generally accepted that deiodination is the major pathway regulating T(3) bioavailability in mammalian tissues. The alternate pathways, sulfation and glucuronidation of the phenolic hydroxyl group of iodothyronines, the oxidative deamination and decarboxylation of the alanine side chain to form iodothyroacetic acids, and ether link cleavage provide additional mechanisms for regulating the supply of active hormone. Sulfation may play a general role in regulation of iodothyronine metabolism, since sulfation of T(4) and T(3) markedly accelerates deiodination to the inactive metabolites, reverse triiodothyronine (rT(3)) and T(2). Sulfoconjugation is prominent during intrauterine development, particularly in the precocial species in the last trimester including humans and sheep, where it may serve both to regulate the supply of T(3), via sulfation followed by deiodination, and to facilitate maternal-fetal exchange of sulfated iodothyronines (e.g., 3,3'-diiodothyronine sulfate [T(2)S]). The resulting low serum T(3) may be important for normal fetal development in the late gestation. The possibility that T(2)S or its derivative, transferred from the fetus and appearing in maternal serum or urine, can serve as a marker of fetal thyroid function is being studied. Glucuronidation of TH often precedes biliary-fecal excretion of hormone. In rats, stimulation of glucuronidation by various drugs and toxins may lead to lower T(4) and T(3) levels, provocation of thyrotropin (TSH) secretion, and goiter. In man, drug induced stimulation of glucuronidation is limited to T(4), and does not usually compromise normal thyroid function. However, in hypothyroid subjects, higher doses of TH may be required to maintain euthyroidism when these drugs are given. In addition, glucuronidates and sulfated iodothyronines can be hydrolyzed to their precursors in gastrointestinal tract and various tissues. Thus, these conjugates can serve as a reservoir for biologically active iodothyronines (e.g., T(4), T(3), or T(2)). The acetic acid derivatives of T(4), tetrac and triac, are minor products in normal thyroid physiology. However, triac has a different pattern of receptor affinity than T(3), binding preferentially to the beta receptor. This makes it useful in the treatment of the syndrome of resistance to thyroid hormone action, where the typical mutation affects only the beta receptor. Thus, adequate binding to certain mutated beta receptors can be achieved without excessive stimulation of alpha receptors, which predominate in the heart. Ether link cleavage of TH is also a minor pathway in normal subjects. However, this pathway may become important during infections, when augmented TH breakdown by ether-link cleavage (ELC) may assist in bactericidal activity. There is a recent claim that decarboxylated derivates of thyronines, that is, monoiodothyronamine (T(1)am) and thyronamine (T(0)am), may be biologically important and have actions different from those of TH. Further information on these interesting derivatives is awaited.

Regulation of JAK2 protein expression by chronic, pulsatile GH administration in vivo: A possible mechanism for ligand enhancement of signal transduction

Growth hormone (GH) is a key factor controlling postnatal growth and development. Despite growth-promoting effects in mammals, GH is not associated with muscle growth in the chicken. Janus kinase 2 (JAK2) has been identified as the first intracellular step in GH receptor (GHR) signaling in many species, however, there is limited knowledge regarding the GH signaling pathway in the chicken. In this study, GH-responsive, JAK2 immunoreactive proteins were first assessed in an avian hepatoma cell line (LMH). Tyrosine phosphorylation of a 120–122 kDa JAK2 immunoreactive protein was GH dose-dependent. In addition to in vitro studies, the timecourse of JAK2 activation in liver and skeletal muscle ( Pectoralis superficialis) in response to a single intravenous (i.v.) injection of chicken GH (cGH), and the effect of chronic exposure to GH in a physiologically relevant pattern on JAK2 protein expression and tyrosine phosphorylation in vivo were assessed. At a dose of GH that was previously demonstrated to elicit a maximal metabolic response (6.25 μg/kg BW), maximum tyrosine phosphorylation of JAK2 appeared at 10 min post-GH administration in the pectoralis muscle, but was not detectable in liver. To assess whether chronic enhancement of GH would alter expression of JAK2, we utilized a dynamic model of pulsatile GH infusion that mimicked the early pattern of circulating GH expressed in younger, rapidly growing birds (high amplitude peaks with an inter-peak interval of 90 min). A 120–122 kDa protein in liver and muscle, and a dominant 130–136 kDa protein in the muscle, that was phosphorylated in response to GH, were specifically recognized by the JAK2 antibody. Chronic, pulsatile infusion of cGH into 8-week-old chickens was associated with increased abundance and tyrosine phosphorylation of JAK2 protein in both liver and muscle ( P < 0.05), which were GH dose-dependent, and mirrored previously reported biological responses for the same birds [Vasilatos-Younken, R., Zhou, Y., Wang, X., McMurtry, J.P., Rosebrough, R.W., Decuypere, E., Buys, N., Darras, V.M., Van Der Geyten, S., Tomas, F., 2000. Altered chicken thyroid hormone metabolism with chronic GH enhancement in vivo: Consequences for skeletal muscle growth. Journal of Endocrinology 166, 609–620.]. In summary (1) JAK2 immunoreactive proteins that associate with the GHR and are tyrosine phosphorylated in response to GH were identified in an avian hepatoma cell line and expressed in both GH responsive (liver) and “non-responsive” (skeletal muscle) tissues; (2) tyrosine phosphorylation of JAK2 occurred within minutes of exposure to a single i.v. injection of GH in vivo in muscle but not liver of 8-week-old birds; and 3) there were GH dose-dependent increases in abundance of JAK2 protein and tyrosine phosphorylation in both tissues when chronically exposed to GH in a physiologically relevant pattern, that mirrored dose-dependent biological responses, including alterations in the pathway of thyroid hormone metabolism, previously reported. Enhanced JAK2 suggests one possible mechanism whereby chronic, physiologically appropriate exposure to the ligand enhances GH biological action via increased abundance of a key upstream component of the signal transduction pathway.

Differential expression of sulfotransferase enzymes involved in thyroid hormone metabolism during human placental development.

Thyroid hormone is essential for normal human development, and disruption of thyroid hormone homeostasis at critical developmental stages can result in severe and often long-term effects on crucial organs such as the brain and lungs. Numerous factors control the bioavailability of receptor active thyroid hormone T(3). Sulfation, catalyzed by sulfotransferase enzymes (SULTs), is an important pathway of thyroid hormone metabolism by which T(4) is irreversibly converted to inactive reverse T(3) rather than active T(3). The human fetus and neonate have high levels of circulating sulfated iodothyronines, although the source of these is not clear. The placenta forms the link between the fetus and its mother and is involved in transfer of thyroid hormone early in pregnancy, although its capacity for sulfation is unknown. We therefore examined expression of the SULTs involved in iodothyronine metabolism during human placental development. SULT activity was measured in human placental cotyledon and membranes (amnion, chorion, and decidua basalis) from 13-42 wk of gestation, and Western blot analysis was employed to verify enzyme activity data. Phenol and catecholamine sulfotransferases were expressed at the highest levels and were generally higher in the villous than membranous tissues. SULT1A1 activity showed significant correlation with sulfation of 3,3'-T(2), suggesting that this enzyme is primarily responsible for placental T(2) sulfation. Estrogen sulfotransferase was present at extremely low levels during early pregnancy, although in mid- and late gestation increased expression in the (predominantly maternal-derived) decidual component of the placenta was observed. Hydroxysteroid sulfotransferase, T(3), reverse T(3), and T(4) SULT activities were also low in all tissues examined, and expression of SULTs 1B1 and 1C2 were essentially undetectable by Western blot analysis. The results highlight a tissue-specific regulation of SULT expression during placental development, demonstrate very low sulfation of iodothyronines suggesting that the placenta is not a major source of circulating sulfated iodothyronines in the fetus.

Fetal-to-maternal transfer of 3,3',5-triiodothyronine sulfate and its metabolite in sheep.

Earlier studies have shown that sulfoconjugation is a major pathway of thyroid hormone metabolism in fetal mammals. To assess the placental transfer of sulfoconjugates in the pregnant sheep model, we measured 3,3',5-triiodothyronine (T(3)) sulfate (T(3)S), 3, 3'-diiodothyronine sulfate (T(2)S), and T(3) concentrations in fetal serum and in maternal serum and urine after T(3)S infusion to the fetus (n = 5) or the ewe (n = 6). Maternal infusion of T(3)S did not increase fetal serum T(2)S, T(3)S, or T(3) concentrations. In contrast, fetal infusion of T(3)S produced significant increases in maternal serum T(2)S and T(3)S but not T(3) concentrations. Fetal T(3)S infusion also increased maternal urine excretion of T(3)S. However, the 4-h cumulative maternal urinary excretion of T(2)S and T(3)S after fetal T(3)S infusion was less than the excretion observed after fetal infusion of equimolar amounts of T(3) in our previous study. It is concluded that fetal serum T(2)S and T(3)S can be transferred to maternal compartments. However, compared with T(3), these sulfoconjugates may be less readily transferred.

Characterization of human iodothyronine sulfotransferases.

Sulfation is an important pathway of thyroid hormone metabolism that facilitates the degradation of the hormone by the type I iodothyronine deiodinase, but little is known about which human sulfotransferase isoenzymes are involved. We have investigated the sulfation of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3'-diiodothyronine (3,3'-T2) by human liver and kidney cytosol as well as by recombinant human SULT1A1 and SULT1A3, previously known as phenol-preferring and monoamine-preferring phenol sulfotransferase, respectively. In all cases, the substrate preference was 3,3'-T2 >> rT3 > T3 > T4. The apparent Km values of 3,3'-T2 and T3 [at 50 micromol/L 3'-phosphoadenosine-5'-phosphosulfate (PAPS)] were 1.02 and 54.9 micromol/L for liver cytosol, 0.64 and 27.8 micromol/L for kidney cytosol, 0.14 and 29.1 micromol/L for SULT1A1, and 33 and 112 micromol/L for SULT1A3, respectively. The apparent Km of PAPS (at 0.1 micromol/L 3,3'-T2) was 6.0 micromol/L for liver cytosol, 9.0 micromol/L for kidney cytosol, 0.65 micromol/L for SULT1A1, and 2.7 micromol/L for SULT1A3. The sulfation of 3,3'-T2 was inhibited by the other iodothyronines in a concentration-dependent manner. The inhibition profiles of the 3,3'-T2 sulfotransferase activities of liver and kidney cytosol obtained by addition of 10 micromol/L of the various analogs were better correlated with the inhibition profile of SULT1A1 than with that of SULT1A3. These results indicate similar substrate specificities for iodothyronine sulfation by native human liver and kidney sulfotransferases and recombinant SULT1A1 and SULT1A3. Of the latter, SULT1A1 clearly shows the highest affinity for both iodothyronines and PAPS, but it remains to be established whether it is the prominent isoenzyme for sulfation of thyroid hormone in human liver and kidney.

Characterization of thyroid hormone sulfotransferases

Sulfation is an intriguing pathway of thyroid hormone metabolism since it facilitates the degradation of the hormone by the type I deiodinase (D1). This study reports the preliminary characterization of iodothyronine sulfotransferase activities of rat and human liver cytosol and recombinant rSULT1C1 and hSULT1A1 isoenzymes. All these enzyme preparations catalyzed the sulfation of—in decreasing order of efficiency—3,3′-diiodothyronine (3,3′-T2)>3,3′,5-triiodothyronine (T3)≈3,3′,5′-triiodothyronine (rT3)>thyroxine (T4). 3,3′-T2 sulfotransferase activity was found to be higher in male than in female rat liver, which has also been shown by others for the expression of rSULT1A1 and rSULT1C1. No sulfation of iodothyronines was observed with rSULT1A1. Different phenol derivatives were found to be potent inhibitors of the sulfation of 3,3′-T2 by native and recombinant sulfotransferases, with pentachlorophenol and 2,4,6-tribromophenol being the most potent. The inhibitions exerted by the different phenols on 3,3′-T2 sulfation by rSULT1C1 correlated better with the effects observed in male than with those in female liver. A strong correlation was also observed between the inhibition profiles of human liver cytosol and hSULT1A1. These results suggest that: (1) rSULT1C1 is an important isoenzyme for the sulfation of thyroid hormone in male rat liver; (2) another isoenzyme with similar properties, perhaps rSULT1B1, is responsible for thyroid hormone sulfation in female rat liver and may also contribute to this process in male rat liver; and (3) hSULT1A1 is an important isoenzyme for thyroid hormone sulfation in human liver.

Gender-specific changes in thyroid hormone-glucuronidating enzymes in rat liver during short-term fasting and long-term food restriction

Glucuronidation is a major pathway of thyroid hormone metabolism in rats, involving at least three different hepatic UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT and androsterone UGT. We have studied the effects of short-term (3 days) fasting and long-term (3 weeks) food restriction to one-third of normal intake (FR33) on hepatic UGT activities for thyroxine (T4), triiodothyronine (T3), bilirubin and androsterone in male and female Wistar rats with either a functional (high activity, HA) or a defective (low activity, LA) androsterone UGT gene. Because food deprivation is known to induce centrally mediated hypothyroidism in rats, results were compared with those obtained in methimazole (MMI)-induced hypothyroid rats. Both fasting and FR33 produced largely parallel increases in T4 and bilirubin UGT activities. These effects were greater in males than in females, and were reproduced in MMI-treated rats. In male and female HA rats, fasting induced insignificant increases in T3 UGT activity and had no effect on androsterone UGT activity. In male HA rats, FR33 was associated with an increase in T3 UGT activity, while androsterone UGT activity showed little change. However, in female HA rats both T3 and androsterone UGT activities were markedly decreased by FR33. Triiodothyronine UGT activity in LA rats was strongly decreased compared with HA rats, but was not further decreased by FR33 in female LA rats, supporting the importance of androsterone UGT for T3 glucuronidation. These results demonstrate different sex-dependent effects of food deprivation on hepatic T4 and T3 glucuronidation that are associated with changes in the expression of bilirubin UGT and androsterone UGT, respectively. For the increased T4 and bilirubin UGT activities at least, these effects appear to be mediated by the hypothyroid state of the (semi)starved animals.

Effect of amiodarone on non-deiodinative pathway of thyroid hormone metabolism

Amiodarone, an iodine containing anti-arrhythmic drug, causes a significant decrease in molar ratio of daily production rates of T3 and T4 from 0.75 in controls to 0.36 in amiodarone-treated rabbits. A model was constructed from the above data which showed that metabolism of T4 via non-deiodinative pathways (e.g. tetraiodothyroacetic acid and/or conjugates) increased from 29% in untreated controls to 66% in amiodarone-treated rabbits. In this study, we have examined the metabolic clearance rate of tetraiodothyroacetic acid in rabbits given amiodarone (20 mg.kg-1.day-1 ip for 3 weeks) or saline (controls). Serum amiodarone and desethylamiodarone levels under the above experimental conditions were 0.20 +/- 0.067 and 0.17 +/- 0.058 mg/l, respectively, which were in the near-therapeutic range observed in humans. Control and amiodarone-treated rabbits were administered [125I]-tetraiodothyroacetic acid (10 muCi/rabbit) iv and blood was collected at 0.5, 1, 2, 4, 6, 10, 32 and 48 h. Serum tetraiodothyroacetic acid radioactivity was determined by trichloroacetic acid precipitation and ethanol extraction and metabolic clearance rates were calculated from the area under the curve of computer fits to tetraiodothyroacetic acid radioactivity data. Amiodarone treatment decreased metabolic clearance rates significantly from 0.107 +/- 0.008 in controls to 0.074 +/- 0.009 l/day in amiodarone-treated rabbits (p less than 0.05). However, when expressed per unit body weight (1.day-1.kg-1), the metabolic clearance rates were not significantly different between the controls and amiodarone-treated rabbits. The terminal serum elimination half-life in the two groups were similar (32.0 +/- 6.7 h in controls vs 49.2 +/- 12.4 h in amiodarone-treated).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum Triiodothyronine Sulfate in Man Measured by Radioimmunoassay

In humans deiodination and perhaps glucuronidation are important pathways of thyroid hormone metabolism. In animals, sulfation plays an important role in T4 and especially in T3 metabolism, but little is known about sulfate conjugation of thyroid hormone in humans. In this study we used a specific T3 sulfate (T3S) RIA to address this question. Eight normal subjects were given oral T3 (1 microgram/day.kg BW) for 7 weeks. During the fifth week they also received propylthiouracil (PTU; four doses of 250 mg/day) for 2 days and during the seventh week iopanoic acid (IOP; 1 g/day) for 3 days. The mean pre-T3 serum iodothyronine values were: T4, 92 +/- 6 (+/- SE) nmol/L; rT3, 0.24 +/- 0.02 nmol/L; T3, 2.30 +/- 0.10 nmol/L; and T3S, less than 0.1 nmol/L (at or below the detection limit of the RIA). After 4 weeks of T3 administration the mean serum values were: T4, 39 +/- 6; rT3, 0.11 +/- 0.01; T3, 5.31 +/- 0.39; and T3S, 0.10 +/- 0.01 nmol/L. After 2 days of PTU administration, mean serum T4 increased to 48 +/- 7 (P less than 0.005), rT3 to 0.20 +/- 0.03 (P less than 0.025), and T3S to 0.13 +/- 0.01 nmol/L (P = NS), but serum T3 did not change (4.91 +/- 0.35 nmol/L). The effect of IOP was more pronounced; after its administration for 3 days the mean serum T4 was 49 +/- 8 (P less than 0.001), rT3 was 0.48 +/- 0.09 (P less than 0.005), and T3S was 0.29 +/- 0.04 nmol/L (P less than 0.005), and serum T3 decreased to 3.95 +/- 0.25 nmol/L (P less than 0.005). The T3S/T3 ratio was increased by PTU from 0.018 +/- 0.003 to 0.024 +/- 0.004 (P less than = NS) and by IOP to 0.055 +/- 0.007 (P less than 0.005). In conclusion, 1) serum T3S is virtually undetectable (less than 0.1 nmol/L) in normal subjects; 2) low serum T3S concentrations are detected in humans given T3; 3) serum T3S in T3-treated subjects is increased by inhibition of type I deiodinase activity with PTU and especially IOP; and 4) in comparison with previous estimates of the serum T3S/T3 ratio in rats, the low ratio in humans may indicate that sulfation is not an important mechanism of T3 metabolism in humans and/or the kinetics of plasma T3 and T3S differ in humans and rats.

Plasma kinetics, tissue distribution, and cerebrocortical sources of reverse triiodothyronine in the rat.

Studies in vitro have shown that rT3 is a potent and competitive inhibitor of T4 5'-deiodination (5'D). Recent studies in vivo have shown that cerebrocortical (Cx) T4 5'D-type II (5'D-II) activity [propylthiouracil (PTU) insensitive pathway], is reduced by T4 and rT3, the latter being more potent than T3 in Cx 5'D-II suppression. Some other reports had described rT3 production in rat brain as a very active pathway of thyroid hormone metabolism. To examine the possibility that rT3 plays a physiological role in regulating Cx 5'D-II, we have explored rT3 plasma kinetics, plasma to tissue exchange, and uptake by tissues in the rat, as well as the metabolic routes of degradation and the sources of rT3 in cerebral cortex (Cx). Plasma and tissue levels were assessed with tracer [125I]rT3. Two main compartments were defined by plasma disappearance curves in euthyroid rats (K1 = -6.2 h-1 and K2 = -0.75 h-1). In Cx of euthyroid rats, [125I]rT3 peaked 10 min after iv injection, tissue to plasma ratio being 0.016 +/- 0.004 (SE). In thyroidectomized rats, plasma and tissue [125I]rT3 concentrations were higher than in euthyroid rats, except for the Cx that did not change. PTU caused further increases in all the tissues studied, except for the Cx and the pituitaries of thyroidectomized rats. From the effect of blocking 5'D-I with PTU or reducing its activity by making the animals hypothyroid, we concluded that 5'D-I accounts for most of the rT3 clearance from plasma. In contrast, in Cx and pituitary the levels of rT3 seem largely affected by 5'D-II activity. Since the latter results suggest that plasma rT3 does not play a major role in determining rT3 levels in these tissues, we explored the sources of rT3 in Cx using [125I]T4. The [125I]rT3 (T4) to [125I]T4 ratio remained constant at 0.03 from 1 up to 5 h after injection of [125I]T4. From plasma levels of T4 and rT3, Cx concentration was calculated to be 30 pg rT3/g Cx in euthyroid rats, more than 98% locally produced from T4 deiodination. We conclude that rT3 has a very rapid metabolism, mainly attributed to 5'D-I activity, but that 5'D-II could also play a role in certain tissues. Nearly all rT3 present in Cx is locally derived from T4.

The Effect of Major Trauma on the Pathways of Thyroid Hormone Metabolism

In order to evaluate the effects of severe trauma on the levels of thyroxine (T4), 3,3',5-triiodothyronine (T3), and 3,3',5'-triiodothyronine (reverse-T3, r-T3), blood samples were collected from traumatized patients on the first post-trauma day. The plasma concentrations of T3 were significantly decreased (mean, 47.4 ng/dl); T4 levels were in the normal range (mean, 6.6 mcg/dl) and r-T3 levels were significantly elevated (mean, 80.8 ng/dl). The oxygen extraction by the muscular tissue was also determined in these patients and found to be elevated; however, no correlation could be established between the extraction ratios and the thyroid hormone levels. This deviation in the peripheral conversion of T4 into r-T3 with a decreased production of T3 also accompanies severe systemic illnesses and probably represents a form of T4 inactivation conditioned by the metabolic demands of the body. This alternate pathway of thyroid hormone metabolism is enhanced by elevated blood levels of catecholamines, glucose, or glucocorticoids as well as by decreased insulin plasma concentrations, all known to follow major trauma and other catabolic conditions.