Renal handling of thyroxine, 3,5,3'- and 3,3',5'-triiodothyronine, 3,3'- and 3',5'-diiodothyronine in man

The 24-h urinary excretion and renal clearance of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), 3,3'-diiodothyronine (3,3'-T2), and 3',5'-diiodothyronine (3',5'-T2) were measured in 17 healthy subjects. The median urinary excretion was (pmol/24h) T4: 1242, T3: 828, rT3: 12.9, 3,3'-T2: 331, and 3',5'-T2: 5.8. The corresponding renal clearances were in median (ml/min) T4: 31, T3: 133, rT3: 15, 3,3'-T2: 683, and 3',5'-T2: 4.5. The clearances differed mutually (P less than 0.01) as well as from the creatinine clearance (P less than 0.01) which was in median 87 ml/min. Thus, all iodothyronines studied were subject to tubular transport mechanisms besides glomerular filtration. The 3 iodothyronines with 2 iodine atoms in the phenolic ring of the thyronine molecule, T4, rT3 and 3',5'-T2, were mainly tubularly reabsorbed, whereas those with only one iodine atom in the phenolic ring, T3 and 3,3'-T2, were mainly tubularly secreted. It might be hypothesized that the number of iodine atoms in the phenolic ring determines the direction of the tubular transport (presence of 2 iodine atoms is associated with tubular reabsorption, and of one iodine atom with secretion), whereas the rate of tubular transport decreases with decreasing number of iodine atoms in the tyrosylic ring.     

Secretion of thyroxine, 3,5,3'-triiodothyronine and 3,3'5'-triiodothyronine in euthyroid man

The secretion of iodothyronines from the normal human thyroid gland was assessed by radioimmunoassay analyses of the concentrations of thyroxine (T4), 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (reverse T3, rT3) in thyroid venous and peripheral venous blood. The subjects studied were euthyroid patients undergoing parathyroid surgery. Measurements were carried out both under apparently normal conditions, following peroral T3 pre-treatment, and before and after acute administration of TSH into a thyroid artery. In the control subjects, significant gradients between thyroid venous and peripheral venous concentrations were recorded both for T4, T3 and rT3, suggesting that all three iodothyronines are secreted by the normal human thyroid. T3 pre-treatment seemed to reduce this secretion, and acute administration of TSH promoted rapid, marked, and concomitant increments in the thyroid venous concentrations of all three iodothyronines. Hence, it appears that not only T4 but also T3 and rT3 are secreted by the normal human thyroid gland, and that TSH stimulates the secretion of all three iodothyronines. On the other hand, calculations of the relative secretion rates uielded the relation T4:T3:rT3 as 85:9:1. This indicates that, in euthyroid subjects, most of T3, and almost all of rT3, is produced by extrathyroidal conversion of T4 and not by direct thyroidal secretion.     

The effects of phenytoin (diphenylhydantoin) on the extrathyroidal turnover of thyroxine, 3,5,3'-triiodothyronine, 3,3',5'-triiodothyronine, and 3',5'-diiodothyronine in man

The extrathyroidal metabolism of T4, T3, rT3, and 3',5'-diiodothyronine (3',5'-T2) was studied before and after treatment with 350 mg phenytoin (DPH) daily for 14 days in six hypothyroid patients receiving constant L-T4 replacement. The total and free serum concentrations of the four iodothyronines were reduced by approximately 30% during DPH treatment, whereas the free fractions in serum were unaltered. Concomitantly, serum TSH increased 137% (P less than 0.02). The production rate (PR) of T4 decreased 16% (P less than 0.005), indicating decreased intestinal absorption (bioavailability) of oral L-T4 during DPH treatment. The fractional rate of 5'-deiodination of T4 to T3 increased from 27% to 31% (P less than 0.05), whereas the rate of 5-deiodination of T4 to rT3 decreased from 45% to 25% (P less than 0.05). The urinary excretion of free and conjugated T4 was 2.3% of the T4 PR and was unaffected by DPH. Thus, the amount of T4 metabolized through nondeiodinative pathways apart from urinary excretion increased from 25% to 44% (P less than 0.05). The apparent distribution volume (Vd) of T4 increased (P less than 0.05), whereas the pool size was unchanged. The PR of T3 did not change during DPH treatment, nor did the mean transit time or the cellular clearance. The rT3 PR was reduced by 54% (P less than 0.02) during DPH treatment. Concomitantly, the transit time increased 10-fold (P less than 0.05), whereas Vd and pool size increased 5-fold (P less than 0.01 and P less than 0.05, respectively). The turnover of 3',5'-T2, in contrast to that of the other iodothyronines, did not change significantly during DPH treatment. T3 formation from T4 was measured in liver microsomal fractions from rats treated for 8 days with DPH and was almost identical to that in untreated animals. The data demonstrate that DPH in therapeutic concentrations did not affect serum protein binding of the iodothyronines. DPH reduced the intestinal absorption of T4 and increased the nondeiodinative metabolism of T4. The resulting decrease in total and free serum T4 and T3 was associated with an increase in serum TSH, demonstrating reduced negative feedback on the pituitary. Our data do not support the assumption that DPH induces increased hepatic deiodinating enzyme activity.(ABSTRACT TRUNCATED AT 400 WORDS)     

Serum 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine concentrations during acute heat load.

To determine the changes in thyroid hormone metabolism during short periods of exposure to heat, 30 euthyroid healthy male volunteers (aged 23--40 yr) were placed in a climatic chamber for 2 h (35 C, 50% relative humidity). The subjects were at complete rest during the first hour and performed light work (40 watts) during the second hour. Blood samples for T4, T3 and rT3 were drawn at 0, 60, and 120 min. Rectal temperature and heart rate were monitored continuously. No significant changes in T4, T3, rT3, rectal temperature, or heart rate were observed after the first hour (basal levels, 8.5 +/- 0.3 microgram/dl, 160 +/- 5 ng/dl, 14.5 +/- 2.5 ng/dl, 37.2 +/- 0.1 C, and 78 +/- 8 beats/min, respectively; mean +/- SEM). During the second hour, a significant rise in body temperature was recorded (38.5 +/- 0.1 C), accompanied by a significant decrease in mean serum T3 concentration and a rise in mean serum rT3 concentration, T4 concentration remained unchanged. Our findings suggest that, parallel to the elevation in body temperature, there is a shift in the conversion of T4 to the noncalorigenic rT3 metabolite rather than to T3.     

Plasma thyroxine, 3,3',5-triiodothyronine and 3,3',5'-triiodothyronine during beta-adrenergic blockade in hyperthyroidism

Plasma thyroxine (T4), 3,3',5-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) were measured in 16 patients with Graves' disease. Patients were studied under the following conditions: first without any treatment, then, during beta-adrenergic blockade with propranolol, and finally after euthyroidism had been attained by carbimazole. During propranolol T3/T4 ratio decreased, whereas T4 remained unchanged. After carbimazole T3/T4 ratio returned to its pretreatment value. rT3/T4 ratio showed opposite changes. These results suggest that peripheral conversion of T4 into T3 and rT3 in hyperthyroidism is, at least partly, dependent on the functional status of the beta-adrenergic system. Suppressed peripheral conversion of T4 into T3 during beta-adrenergic blocking agents may contribute to the beneficial effects of these drugs in thyrotoxicosis.     

Changes in serum concentrations of 3,3',5'-triiodothyronine and 3,5,3'-triiodothyronine during prolonged moderate exercise.

The effect of moderate bicycle exercise (3.5 h) on peripheral thyroid hormone metabolism was studied under two conditions (with and without glucose infusion) in four normal males. Serum T3, rT3, total protein, plasma glucose, and FFA were determined. Exercise induced an increase in rT3 from 29 to 40 ng/dl (P less than 0.01), a decrease in T3 from 154 to 147 ng/dl (P less than 0.01), and an increase in T4 from 7.1 to 7.5 micrograms/dl (P less than 0.05). When glucose was infused during exercise, the changes in rT3 were blunted (P less than 0.01) and the changes in T3 and T4 were diminished. During exercise, rT3 correlated with FFA (r = 0.95) and plasma glucose (r = -0.87). When glucose was infused during exercise, these correlations decreased (r = 0.81 and -0.56, respectively). Since moderate, prolonged exercise induces a state of early or acute starvation it is concluded that the changes in peripheral thyroid hormone metabolism reported here are similar to those found in starvation. The temporal changes of rT3, FFA, and plasma glucose during exercise suggest a relationship between thyroid hormone metabolism and the uptake and utilization of FFA and glucose or the mixture of these body fuels.     

Hypometabolic effect of 3,3',5'-triiodothyronine in chickens: interaction with hypermetabolic effect of 3,5,3'-triiodothyronine

The effect of 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine (T3) on O2 consumption in 1-day-old chickens was studied. The birds were divided into five groups, each of six chickens: (1) control--without injection; (2) control--injected with 100 microliters of solvent (0.01 N NaOH in saline); (3) injected with 10 micrograms rT3/chicken; (4) injected with 0.5 micrograms T3/chicken; and (5) injected with 10 micrograms rT3 + 0.5 microgram T3/chicken. O2 consumption was measured using a Kipp & Zonen diaferometer at neutral temperature (30 degrees) 0, 1, 2, 3, and 4 hr after injection of hormones. Corresponding groups of other chickens served only for blood collection. rT3 and T3 were measured by radioimmunoassay. Reverse T3 decreased O2 consumption by 10.87%. Contrary to this, T3 increased O2 consumption by 29.41%. Reverse T3, injected together with T3, interacted with the hypermetabolic effect of T3 up to 2 hr after injection; then, O2 consumption started to increase, and was about 16.7% higher compared with the basal level 3 hr after injection. The blood plasma level of rT3 increased about 29-fold at the first hour after injection, without changes in the basal level of T3. Administration of T3 increased its level 6-fold 2 hr after injection, which was accompanied by a gradual decrease in the basal level of rT3 (3.7-fold) 4 hr after injection. Administration of rT3 + T3 increased the rT3 level 30-fold at 2 hr and the T3 level 1.7-fold at the first hour after injection. Thus, rT3 acts hypometabolically and interacts with the hypermetabolic effect of T3; administration of T3 lowered the basal level of rT3; and the plasma level of T3 did not change after administration of rT3.     

The hidden, nonexchangeable pool of 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine in man: does it exist?

The validity of estimation of the production rates of T3 and rT3 in man based on noncompartmental analysis of blood-derived data has been questioned owing to incomplete exchangeability of T3 and rT3 between plasma and extrathyroidal tissues in which a local production of these iodothyronines takes place. The possible existence of a nonexchangeable or hidden pool of T3 and rT3 would result in an underestimation of the daily production. By contrast, the production rate of T4 can be estimated reliably using noncompartmental analysis. We have studied 16 women with pretreatment severe hypothyroidism on constant levothyroxine therapy. Simultaneous measurements of T4, T3 and rT3 production rates were performed using bolus injection of radiolabelled iodothyronines. The tracers were isolated from plasma using gel separation/antibody extraction, and production rates were calculated by noncompartmental analysis. Mean (+/- SD) production rate of T4, T3 and rT3 were: 119 +/- 43, 40.0 +/- 22.0 and 54.9 +/- 20.0 nmol.day-1.(70 kg)-1, respectively. Thus 79.5 +/- 7.0% of T4 was deiodinated into T3 and rT3. This leaves 20.5% to other metabolic pathways of T4 and to a possible underestimation of T3 and rT3 production rate. Based on conservative estimates from the literature, the other metabolic pathways of T4 amount: oxidative deamination 1.1%; ether link cleavage 0%; urinary excretion 2.5%; and fecal excretion 14%. Thus, the various metabolic pathways seem to explain 97% of daily produced and degradated T4 in man. Therefore the understimation of T3 and rT3 production rates in man using noncompartmental analysis seems of little if any importance, and existence of a hidden pool of these iodothyronines may be questioned.     

Conversion of thyroxine to 3,3',5'-triiodothyronine in the guinea pig placenta: in vivo studies

Studies of placental inner-ring deiodination of T4 were carried out in pregnant guinea pigs, by in situ placental perfusion. When [131I]T4 and [125I]rT3 were administered to the mother, the ratio of fetal side to maternal side [131I]rT3 was more than 10 times greater than the corresponding ratio for [125I]rT3. When radiolabeled T4 was supplied to the fetal side of the placenta in perfusion fluid, and the perfusate recycled through the placental circuit, there was a progressive increase in labeled rT3 concentration in the perfusate. These results indicate that the guinea pig placenta actively deiodinates both maternal and fetal T4 in the inner ring in vivo. We found evidence of very little outer ring deiodination of either T4 or rT3. The quantitative contribution of placental deiodination of maternal T4 to circulating rT3 in the fetus appears to be small; however, placental deiodination of fetal T4 (about 0.5 nmol/kg fetal BW X day) could contribute significantly to fetal rT3 levels. Our observations are consistent with the hypothesis that placental inner-ring deiodination of T4 plays a part in the regulation of fetal iodothyronine metabolism.     

The effect of free radicals on hepatic 5'-monodeiodination of thyroxine and 3,3',5'-triiodothyronine

Free radicals have been implicated in many pathological processes, including ischemia, inflammation, and malignancy. Since a reduction in extrathyroidal outer ring monodeiodination of T4 and rT3 occurs in virtually all systemic illnesses, we have studied the effect of free radicals on iodothyronine (T4 and rT3) 5'-monodeiodinating activity (MA) of liver tissue in vitro. Rat liver microsomes or homogenate were preincubated in Tris buffer for 30 min with a free radical-generating system (FRGS) and then incubated with T4 (2.5 microM) or [125I]rT3 (0.4 nM) and dithiothreitol (DTT; 5-20 mM with T4 and 20-150 mM with [125I]rT3) in the same buffer for 10 or 30 min. T3 generated during incubation was quantified by RIA of ethanol extracts of the incubation mixture. 125I generated from [125I]rT3 was quantified after precipitation of the incubation mixture with trichloroacetic acid or by paper chromatography. Free radicals caused 55% or more reduction in hepatic T4 MA and 44% or more reduction in rT3 MA in various experiments. The inhibition of hepatic rT3 MA after incubation with FRGS persisted despite removal of FRGS and washing of microsomes preincubated with FRGS before studying the MA. However, inclusion of DTT (1-60 mM) during preincubation of tissue with FRGS prevented the FRGS-induced inhibition of rT3 MA. Depletion of the iodothyronine substrate did not occur when FRGS inhibited T4 and rT3 5'-monodeiodination. Free radical scavengers, i.e. superoxide dismutase (600 IU/ml), catalase (300 U/ml), tocopherol (10 mg/ml), thiourea (0.15 M), and tert-butanol (0.15 M), all significantly reduced the inhibition of hepatic rT3 MA caused by FRGS. The FRGS-induced inhibition of hepatic T4 MA was reduced by the same doses of tocopherol, thiourea, and tert-butanol, but not by superoxide dismutase or catalase. Since free radicals may effect tissue damage by lipid peroxidation and since the latter results in generation of malondialdehyde (MDA) as a by-product of the reaction, we studied MDA by its reaction with 2-thiobarbituric acid. Incubation with FRGS caused an approximately 100-fold increase in MDA formation in liver microsomes. Serum MDA was significantly higher in 16 NTI patients than in 8 normal subjects and also higher in turpentine oil-injected rats [an experimental model of nonthyroidal illness (NTI)] than in saline-injected control rats. The data suggest that generation of free radicals may contribute to the reduced extrathyroidal 5'-monodeiodination of T4 and rT3 in NTI.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparison of thyroxine and 3,3',5'-triiodothyronine metabolism in rat kidney and liver homogenates.

The effects of agents added in vitro, in vivo PTU treatment, and fasting for 72 hr on T₄-T₃ conversion rates and rT₃ degradation rates in rat kidney and liver homogenates were compared. In kidney homogenates, 5 mM DTT stimulated both reactions, whereas 0.3 mM diamide, 0.1 μM iopanoic acid, 17 μM PTU and 1 mM 2,4-dinitrophenol inhibited both reactions; 25 μM methimazole had no effect. DTT also stimulated both of these reactions in liver homogenates. Diamide was a less potent inhibitor in liver than in kidney homogenates. Kinetic analysis showed that the k_m for T₄ in kidney and liver homogenates were similar, but not identical, and that the k_m for rT₃ in kidney and liver homogenates were again similar, but not precisely the same. When a particulate fraction of the homogenates was employed, the k_m for T₄ in two kidney preparations was 0.8 and 1.0 μM, and in two liver preparations it was 2.9 and 5.5 μM. PTU administered in vivo reduced the T₄-T₃ conversion rates and rT₃ degradation rates in kidney and liver homogenates to < 20% of control, reduced the mean serum T₃ concentration to < 33% of control, raised the mean serum rT₃ concentration to nine times control, but did not alter the mean serum T₄ concentration or the hepatic glutathione content. A 72-hr fast had no effect on T₄-T₃ conversion or rT₃ degradation rates in kidney homogenates and had no effect on renal glutathione content, but fasting had the expected inhibitory effect on T₄-T₃ conversion in liver homogenates and lowered the hepatic glutathione content to 79% of control. These results, along with previous findings from this and other laboratories, strongly suggest that there is a single iodothyronine 5′-monodeio-dinase in rat kidney that metabolizes both T₄ and rT₃. The results are also compatible with the hypothesis that the iodothyronine 5′-monodeiodinases in rat kidney and liver are the same enzyme.     

Free thyroxine and 3,3',5'-triiodothyronine levels in cerebrospinal fluid in patients with endogenous depression

Total and free concentrations of T4 and rT3 in serum and cerebrospinal fluid were estimated by ultrafiltration in 12 patients with unipolar endogenous depression before and after electroconvulsive treatment. Recovery from depression resulted in a decrease in CSF concentrations of free T4 (median) (26.2 to 21.4 pmol/l, p less than 0.02) and free rT3 (14.1 to 12.3 pmol/l, p less than 0.05). Concentrations of free T4 in the cerebrospinal fluid were lower than those in serum (p less than 0.02), the ratio being 0.6. In contrast, levels of free rT3 in the cerebrospinal fluid were considerably higher than those found in serum (p less than 0.01), the ratio being 25. These ratios did not change following recovery from depression. In 9 patients with nonthyroidal somatic illness, concentrations of free T4 and rT3 in the cerebrospinal fluid were similar to those found in patients with endogenous depression, whereas 4 hypothyroid patients and one hyperthyroid patient had considerably lower and higher, respectively, concentrations of both free T4 and rT3. In conclusion, levels of free T4 and free rT3 in the cerebrospinal fluid are increased during depression compared with levels after recovery, probably reflecting an increased supply of T4 from serum and an increased production of rT3 from T4 in the brain. The data also suggest that the transport of iodothyronines between serum and the cerebrospinal fluid is restricted.     

Comparison of inhibitory effects of 3,5,3'-triiodothyronine (T3), thyroxine (T4), 3,3,',5'-triiodothyronine (rT3), and 3,3'-diiodothyronine (T2) on thyrotropin-releasing hormone-induced release of thyrotropin in the rat in vitro.

In order to compare, in vitro, the TSH suppressive effects of iodothyronines, rat pituitary quarters were first preincubated with T4, T3, rT3, or 3,3'-diiodothyronine (T2) in Gey and Gey buffer containing 1% bovine serum albumin for 2 h at 37 C and then incubated at 37 C for 1 h with the iodothyronine under study and TRH. TSH released into the medium during incubation was compared to that released by control pituitary fragments, which were not exposed to iodothyronines. All four iodothyronines (T3, T4, rT3, and T2) were able to significantly inhibit the TRH-induced release of TSH from pituitary fragments in a dose range of 0.015-2.2 microgram/ml. However, much larger doses of sodium iodide (1.25 mg/ml) and diiodotyrosine (10 and 30 microgram/ml) had no significant effect on the release of TSH. Among T3, rT3, and T4, T3 was the most potent and rT3 was the least potent. The relative potency of T3:T4:rT3 appeared to be approximately 100:12:1 when estimated from the lowest doses that caused significant inhibition of TRH-induced release of TSH, and approximately 100:6:0.5 when estimated from the doses that caused 50% inhibition of TSH release; the TSH inhibiting potency of T2 was similar to that of rT3. The activity of T4 could not be explained entirely on the basis of contamination of T4 with T3 or by in vitro conversion of T4 to T3. Similarly, the available data suggested that rT3 and T2 possess some, albeit modest, intrinsic TSH-Suppressive activity. TSH-inhibiting activities of T3, T4, and rT3 were also studied using pituitary fragments from starved and iodine-deficient rats. There was no evidence of a change in the sensitivity of the thyrotroph to either T3 or T4 in starvation. Similarly, comparison of the responses to several doses of rT3 did not indicate any significant abnormality in the sensitivity of the thyrotroph to rT3 in starvation or iodine deficiency. However, comparison of the TSH-suppressive effects of T4 in the iodine-deficient and normal rat indicated a significant increase in the sensitivity of the thyrotroph to T4 in iodine deficiency. A similar trend was also evident in the effect of T3 in iodine deficiency, but it fell short of statistical significance.     

Evidence that the 5'-monodeiodinases for thyroxine and 3,3',5'-triiodothyronine in the rat pituitary are separate enzymes

Studies were directed at the question of whether the enzyme that mediates the 5'- or outer ring monodeiodination of T4 is the same as that which mediates the 5'-monodeiodination of rT3. Advantage was taken of previous observations which indicated that T3, when administered to the hypothyroid rat, acutely inhibits the 5'-monodeiodination of T4 to yield T3 in hemipituitaries in vitro. In the present experiments, these effects of T3 on the generation of T3 from T4 were confirmed in both hemipituitaries and homogenates, indicating that they were not due to an effect of T3 on the cellular penetration of the [125I]T4 used as substrate. In contrast, in separate experiments with both hemipituitaries and homogenates, T3 had no effect on the metabolism of [125I]rT3, including its 5'-monodeiodination to yield 3,3'-diiodothyronine. In other experiments, the divergent effects of T3 on the metabolism of T4 and rT3 were also observed when the two substrates were studied in paired hemipituitaries and paired aliquots of the same pituitary homogenate. Failure of T3 to inhibit the 5'-monodeiodination of rT3 in pituitary homogenates could not be explained by the presence of marked enzyme excess, since T3 was also without effect when homogenates were incubated with rT3 at a concentration of 1 microgram/ml. In additional experiments, propylthiouracil (PTU) in vitro (1 mM) was found to have no effects on either the rapid metabolism of [125I]T4 seen in the pituitaries of hypothyroid rats or the less rapid metabolism of [125I]T4 seen in pituitaries of hypothyroid rats given T3. In contrast, though PTU failed to alter the metabolism of [125I]rT3 in pituitaries of hypothyroid rats, it greatly inhibited the metabolism of [125I]rT3 in the pituitaries of hypothyroid rats given T3. These results are consistent with those in previous reports which indicate that the pituitary contains two enzymes that mediate the deiodination of T4 and rT3. One is a PTU-insensitive enzyme that mediates the 5'-monodeiodination of T4; its activity is increased in hypothyroidism and is decreased by T3 replacement. The other is a PTU-sensitive enzyme that mediates much of the 5'-monodeiodination of rT3 in the pituitary of the T3-replaced rat, as in the euthyroid rat, but whose activity is largely supplanted by that of the PTU-insensitive enzyme in hypothyroidism.     

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

INTRODUCTION AND METHODS: Critical illness is associated with reduced TSH and thyroid hormone secretion, and with changes in peripheral thyroid hormone metabolism, resulting in low serum T3 and high rT3. In 451 critically ill patients who received intensive care for more than 5 d, serum thyroid parameters were determined on d 1, 5, 15, and last day (LD). All patients had been randomized for intensive or conventional insulin treatment. Seventy-one patients died, and postmortem liver and skeletal muscle biopsies were obtained from 50 of them for analysis of deiodinase (D1-3) activities. RESULTS: Insulin treatment did not affect thyroid parameters. On d 1, rT3 was higher and T3/rT3 was lower in nonsurvivors as compared with survivors (P = 0.001). Odds ratio for survival of the highest vs. the lowest quartile was 0.3 for rT3 and 2.9 for T3/rT3. TSH, T4, and T3 were lower in nonsurvivors from d 5 until LD (P < 0.001). TSH, T4, T3, and T3/rT3 increased over time in survivors, but decreased or remained unaltered in nonsurvivors. Liver D1 activity was positively correlated with LD serum T3/rT3 (R = 0.83, P < 0.001) and negatively correlated with rT3 (R = -0.69, P < 0.001). Both liver and skeletal muscle D3 activity were positively correlated with LD serum rT3 (R = 0.32, P = 0.02 and R = 0.31, P = 0.03). CONCLUSION: In critically ill patients who required more than 5 d of intensive care, rT3 and T3/rT3 were already prognostic for survival on d 1. On d 5, T4, T3, but also TSH levels are higher in patients who will survive. Serum rT3 and T3/rT3 were correlated with postmortem tissue deiodinase activities.