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Thyroid hormones and multiple organ dysfunction syndrome*
Abstract
Marked changes in thyroid hormone levels occur in critical illness and multiple organ dysfunction syndrome (MODS), with a decrease in the active hormone T3 and an increase in the inactive metabolite rT3. The magnitude of these changes is related to the severity of the disease. Studies addressing the thyrotropic axis in critical illness do not make a clear distinction between patients with and without MODS. However, a distinction can be made between the acute and the more chronic phase of critical illness, and it can be assumed that patients who require intensive care for several days will have some degree of MODS. This review therefore focuses on the thyroid axis in patients receiving intensive care for several days. The mechanisms behind the observed changes, the potential positive and/or negative effects of them and their possible therapeutic consequences will be discussed.
Decreased thyroid hormone (TH) has been considered as one of the potential predictors of mortality in sepsis. This study aimed to evaluate the prognostic impact of decreased TH on mortality in septic patients during intensive care unit (ICU) admission. We included studies that assessed thyroid function by measuring the serum thyroid hormone level and in-hospital mortality in adult septic patients. Reviews, case reports, editorials, letters, commentaries, animal studies, duplicate studies, and studies with irrelevant populations and inappropriate controls were excluded. A total of 1,578 patients from eight studies were included. Triiodothyronine levels in non-survivors were relatively lower than that of survivors (6 studies; standardized mean difference [SMD] 2.31; 95% confidence interval (CI), 0.52-4.10; I2 = 97%; P = 0.01). Thyroxine levels in non-survivors were also lower than that of survivors (5 studies; SMD 2.40; 95% CI, 0.91-3.89). There were no statistically significant differences in thyroid-stimulating hormone levels between non-survivors and survivors. The present meta-analysis suggested that the decreased TH during ICU admission might be associated with the increase in mortality in adult septic patients. Hence, the measurement of TH could provide prognostic information on mortality in adult septic patients.
In a prospective study of critically ill hypothyroxinemic we assessed the relationship between serum TSH and T4 during the return of serum T4 to normal during recovery. In this longitudinal study of 60 patients with a variety of critical illnesses, including burns, septicemia, and acute renal failure, serum T4 fell to less than 2.7 micrograms/dl (35 nmol/liter) in 24 patients, of whom 14 survived with return of T4 to normal. A rise in total T4 of more than 1.9 microgram/dl (25 nmol/liter) within 96 h occurred 13 times in 10 patients, while 4 patients had slower increases in T4. All 13 episodes of rapid T4 rise [1.7 +/- 0.8 (+/- SD) to 5.6 +/- 2.1 micrograms/dl] were associated with a marked increase in serum TSH (1.1 +/- 0.8 to 7.0 +/- 5.2 mU/liter), and TSH was transiently above normal during 8 episodes of T4 recovery. In the 6 episodes with sampling less than 6 h apart, the TSH rise consistently preceded the T4 rise. In the 4 patients who received dopamine, TSH and T4 remained low until cessation of therapy. During the TSH rise, only minor changes, which could not account for the increase in total T4, occurred in T4-binding globulin (12.9 +/- 3.3 to 14.8 +/- 3.3 mg/liter), prealbumin (208 +/- 73 to 234 +/- 82 mg/liter), and albumin (28.3 +/- 2.9 to 31.9 +/- 2.9 g/liter). Mean free T4 increased (0.60 +/- 0.34 to 1.45 +/- 0.56 ng/dl), as did total T3 (16 +/- 14 to 76 +/- 44 ng/dl), during the phase of TSH rise, suggesting that the increase in TSH was not simply a consequence of diminished negative feedback due to increased plasma binding. The very close and consistent temporal relationship between TSH and T4 during the recovery phase suggests that TSH may have an essential role in the return of T4 to normal during recovery from critical nonthyroidal illness.
The reported failure of serum TSH to rise in response to the low serum T3 of severe systemic illness may be due to the known stress inhibition of TSH secretion. We therefore measured TSH and total and free thyroid hormones during the course of recovery from severe illness. During recovery, TSH increased at a time when T3 was rising but still below normal (mean TSH during recovery, 6.5 +/- 0.8 SEM microU/ml, n = 41 vs. normal, 2.5 +/- 0.2 SEM microU/ml; n = 31; P less than 0.001), TSH concentrations were negatively correlated with total and free T3 and less strongly correlated with total T4 but not with free T4. Average TSH concentrations were also significantly elevated in severely ill patients with hypothermia that was unrelated to cold exposure (mean TSH, 5.6 +/- 1.3 microU/ml; n = 11; P less than 0.005). The T3 concentrations in these sera were lower than those of other severely ill patients. Thus, during recovery from severe illness and during hypothermia not induced by cold, the relationship between serum T3 and TSH is qualitatively similar to that seen in primary hypothyroidism and may imply a pituitary response to a deficiency of thyroid hormone.
We have studied whether, or not, tissue-specific regulatory mechanisms provide normal 3,5,3'-triiodothyronine (T3) concentrations simultaneously in all tissues of a hypothyroid animal receiving thyroxine (T4), an assumption implicit in the replacement therapy of hypothyroid patients with T4 alone. Thyroidectomized rats were infused with placebo or 1 of 10 T4 doses (0.2-8.0 micrograms per 100 grams of body weight per day). Placebo-infused intact rats served as controls. Plasma and 10 tissues were obtained after 12-13 d of infusion. Plasma thyrotropin and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine-deiodinase activities were assayed using cerebral cortex, liver, and lung. No single dose of T4 was able to restore normal plasma thyrotropin, T4 and T3, as well as T4 and T3 in all tissues, or at least to restore T3 simultaneously in plasma and all tissues. Moreover, in most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations. Notable exceptions were the cortex, brown adipose tissue, and cerebellum, which maintained T3 homeostasis over a wide range of plasma T4 and T3 levels. Deiodinase activities explained some, but not all, of the tissue-specific and dose related changes in tissue T3 concentrations. In conclusion, euthyroidism is not restored in plasma and all tissues of thyroidectomized rats on T4 alone. These results may well be pertinent to patients on T4 replacement therapy.
To provide new insights into the in vivo regulation of iodothyronine deiodinases in the different tissues of the rat, we have evaluated the effects on these enzymatic activities of T4 or T3 infusions into thyroidectomized rats. Thyroidectomized rats were infused with placebo, T4, or T3. Placebo-infused intact rats served as euthyroid controls. Plasma and samples of cerebral cortex, brown adipose tissue, pituitary, liver, and lung were obtained after 12-13 days of infusion. Plasma TSH, plasma and tissue T4 and T3, and iodothyronine deiodinase activities were determined. Type II 5'-deiodinase (DII) was increased in cortex, brown adipose tissue, and pituitary from animals infused with placebo. DII activity returned to normal only with T4 infusion, remaining elevated in the animals infused with T3 alone despite normal tissue T3 concentrations. Cortex type III 5-deiodinase was only increased when hyperthyroidism was induced by infusion of T3. Liver type I 5'-deiodinase (DI) paralleled the changes in plasma and tissue T3 regardless of whether T4 or T3 was infused. On the contrary, the increase in lung DI, proportional to the increases in plasma and tissue T3, was higher when T4 was infused. As a rule, the tissues with DII presented a tighter homeostasis in their T3 concentrations than the tissues with DI. In conclusion, the regulation of iodothyronine deiodinases depends on the hormone infused into the thyroidectomized animals and on the tissue in which the deiodinase is studied, demonstrating the existence of tissue-specific regulation of its thyroid hormone concentrations.
The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-microgram/kg bolus and infused (1 microgram/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, insulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40-54%) and in T3 (52-116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified > 6- and > 10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected. In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.
The importance of local formation of T3 in the feedback effect of the thyroid gland on hypothalamic TRH-producing cells has been established. Primary failure of the thyroid gland results in a fall in circulating T4 and T3 levels, leading to an elevation in the production and release of TRH in the hypothalamic paraventricular nucleus. In contrast, during short term fasting, declining plasma levels of thyroid hormones coincide with suppressed TRH production and release. In the brain, the prevalent enzyme that converts T4 to T3 is type II iodothyronine deiodinase (DII). The present study was undertaken to determine whether a differential hypothalamic expression of type II deiodinase may exist in fasted rats and in animals that are hypothyroid due to the failure of the thyroid gland. Using in situ hybridization, we assessed type II deiodinase messenger RNA (mRNA) levels in the hypothalamus of rats that were control euthyroid, hyperthyroid (T4), hypothyroid induced by propylthiouracil (PTU), and fasted. A group of fasted rats also received exogenous T4. DII mRNA was detected around the third ventricle, including the ependymal layer and adjacent periventricular regions as well as in the arcuate nucleus and the external layer of the median eminence. Quantitative in situ hybridization analysis demonstrated that PTU treatment and short term fasting resulted in significant elevations in DII messenger levels compared with those in euthyroid controls. Three weeks of PTU administration induced a consistent decline in circulating T3 and undetectable T4 levels, whereas 3 days of fasting resulted in only a 50% fall in the concentration of serum thyroid hormones. Interestingly, however, the expression of the DII mRNA was more than 2-fold higher in fasted animals compared with the values in PTU-treated rats. Furthermore, although T4 administration repressed DII mRNA expression in euthyroid animals, the same treatment had no effect on the fasting-induced elevations of DII message. To assess whether DII enzymatic activity is also affected during food deprivation, hypothalami were dissected out, and DII activity was measured in control euthyroid, fasted, and fasted plus T4-treated rats. To determine whether comparable changes in plasma thyroid hormone levels induced by fasting and PTU treatment could have affected DII enzymatic activity in a similar manner, animals were injected ip with PTU for 5 days to decrease plasma thyroid hormones to levels similar to those caused by fasting. DII enzymatic assay showed a significant increase in DII activity in fasted and fasted plus T4-treated animals compared with those in euthyroid controls and PTU-treated rats. No significant changes were found in PTU-treated rats compared with euthyroid animals. These data indicate that during short term fasting, a signal of nonthyroid origin underlies the robust elevation of DII production and activity in the hypothalamus. Thus, we propose that during the initial phase of food deprivation, an increased negative thyroid feedback exists on the hypothalamus due to locally formed T3. This local hyperthyroidism may, in turn, induce the suppression of TRH under these conditions.
Although the tripeptide thyrotropin-releasing hormone (TRH) was the first hypothalamic hormone to be isolated and characterized, only very few data were available on the central component of the hypothalamus-pituitary-thyroid (HPT) axis in the human brain until recently. We used immunocytochemistry to describe, for the first time, the distribution of TRH-containing cells and fibers in the human hypothalamus. Brain material was obtained with a short postmortem delay followed by fixation in paraformaldehyde, glutaraldehyde, and picric acid. Many TRH-containing cells were present in the paraventricular nucleus (PVN), especially in its dorsocaudal part. Some TRH cells were found in the suprachiasmatic nucleus (SCN), which is the circadian clock of the brain, and in the sexually dimorphic nucleus (SDN), which is in agreement with earlier observations in the rat hypothalamus. Dense TRH-containing fiber networks were present not only in the median eminence but also in a number of other hypothalamic areas, suggesting a physiological function of TRH as a neuromodulator or neurotransmitter in the human brain, in addition to its neuroendocrine role in pituitary secretion of thyroid-stimulating hormone (TSH). As a next step, we developed a technique for TRH mRNA in situ hybridization using a [35S] CTP-labeled TRH cRNA antisense probe in formalin-fixed paraffin-embedded sections. Numerous heavily labeled TRH mRNA-containing neurons were detected in the caudal part of the PVN, while some cells were present in the SCN and in the perifornical area. These results demonstrated the value of in situ hybridization for elucidating the chemoarchitecture of the human hypothalamus in routinely fixed autopsy tissue and enabled us to perform quantitative studies. As part of the neuroendocrine response to disease, serum concentrations of thyroid hormone decrease without giving rise to elevated concentrations of TSH, suggesting altered feedback control at the level of the hypothalamus and/or pituitary. In order to establish whether decreased activity of TRH cells in the PVN contributes to the persistence of low TSH levels in nonthyroidal illness (NTI), hypothalamic TRH gene expression was investigated in patients whose plasma concentrations of thyroid hormones had been measured just before death. Quantitative in situ hybridization showed a positive correlation of total TRH mRNA in the PVN and serum concentrations of TSH and triiodothyronine (T3) less than 24 hours before death, supporting our hypothesis. Current experiments aim at elucidating the mechanism by which hypothalamic thyroid hormone feedback control in TRH cells of patients with NTI is changed.
Protracted critical illness is marked by protein wasting resistant to feeding, by accumulation of fat stores, and by suppressed pulsatile release of GH and TSH. We previously showed that the latter can be reactivated by brief infusion of GH-releasing peptide (GHRP-2) and TRH. Here, we studied combined GHRP-2 and TRH infusion for 5 days, which allowed a limited evaluation of the metabolic effectiveness of this novel trophic endocrine strategy.
Fourteen patients (mean ± sd age, 68 ± 11 yr), critically ill for 40 ± 28 days, were compared to a matched group of community-living control subjects at baseline and subsequently received 5 days of placebo and 5 days of GHRP-2 plus TRH (1+1μ g/kg·h) infusion in random order.
At baseline, impaired anabolism, as indicated by biochemical markers (osteocalcin and leptin), was linked to hyposomatotropism [reduced pulsatile GH secretion, as determined by deconvolution analysis, and low GH-dependent insulin-like growth factor and binding protein (IGFBP) levels]. Biochemical markers of accelerated catabolism (increased protein degradation and bone resorption) were related to tertiary hypothyroidism and the serum concentration of IGFBP-1, but not to hyposomatotropism. Metabolic markers were independent of elevated serum cortisol.
After 5 days of GHRP-2 plus TRH infusion, osteocalcin concentrations increased 19% vs. −6% with placebo, and leptin had rose 32% vs. -15% with placebo. These anabolic effects were linked to increased IGF-I and GH-dependent IGFBP, which reached near-normal levels from day 2 onward. In addition, protein degradation was reduced, as indicated by a drop in the urea/creatinine ratio, an effect that was related to the correction of tertiary hypothyroidism, with near-normal thyroid hormone levels reached and maintained from day 2 onward. Concomitantly, a spontaneous tendency of IGFBP-1 to rise and of insulin to decrease was reversed. Cortisol concentrations were not detectably altered.
In conclusion, 5-day infusion of GHRP-2 plus TRH in protracted critical illness reactivates blunted GH and TSH secretion, with preserved pulsatility, peripheral responsiveness, and feedback inhibition and without affecting serum cortisol, and induces a shift toward anabolic metabolism. This provides the first evidence of the metabolic effectiveness of short term GHRP-2 plus TRH agonism in this particular wasting condition.
Thyroid hormones are essential for the development and repair of the peripheral nervous system. The type 2 deiodinase, which is responsible for the activation of T4 into T3, is induced in injured sciatic nerve. To obtain information on the type 3 deiodinase (D3) responsible for the degradation of thyroid hormones, we looked for its expression (mRNA and activity) in the sciatic nerve after injury. D3 was undetectable in the intact sciatic nerve of adult rats, but was rapidly and highly increased in the distal and proximal segments after nerve lesion. After cryolesion, D3 up-regulation disappeared after 3 d in the proximal segment, whereas it was sustained for 10 d in the distal segment, then declined to reach basal levels after 28 d, when functional recovery was completed. After a transsection preventing the nerve regeneration, up-regulation of D3 persisted up to 28 d at high levels in the distal segment. D3 was expressed in peripheral connective sheaths and in the internal endoneural compartment. D3 mRNA was inducible by 12-O-tetradecanoylphorbol-13-acetate in cultured fibroblasts or Schwann cells. In conclusion, induction of D3 in the peripheral nervous system after injury may play an important role during the regeneration process by adjusting intracellular T3 levels.
Thyroid hormone uptake into cultured human hepatocytes was studied using measurement of cell-associated radioactivity of radioiodinated thyroid hormones after 10-min incubation in culture medium with 0.5% BSA. Furthermore, 20-h incubations were performed to study transport and further intracellular metabolism. The results indicate the presence of saturable active uptake systems for T4, T3, and rT3, as addition of the unlabeled hormone (1, 5, and 2 mumol/L, respectively) to the medium resulted in a decrease in cell-associated radioactivity of 20-30%. Inhibition was also achieved after 30-min preincubation with fructose (10 mmol/L), which induces a decrease in intracellular ATP or ouabain (0.5 mmol/L), indicating energy dependence and the necessity for a sodium gradient for at least part of the transport process, respectively. After 20-h incubation, iodide production was inhibited in the presence of ouabain (0.5 mmol/L), propylthiouracil (100 mumol/L), or a monoclonal antibody (81-1A1-10; ascites dilution, 1:200) directed against thyroid hormone transport systems in rat hepatocytes. These data indicate that there is a high degree of similarity between the properties of the uptake process and subsequent conversion of thyroid hormones in human and rat hepatocytes, although the rates of uptake and conversion are lower in human hepatocytes. Furthermore, regulation of thyroid hormone uptake at the level of the plasma membrane may also be operative in human hepatocytes.
During illness, major changes in thyroid hormone metabolism and regulation occur; these are collectively known as non-thyroidal illness and are characterized by decreased serum triiodothyronine (T 3 ) and thyroxine (T 4 ) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus–pituitary–thyroid (HPT) axis precede changes in peripheral thyroid hormone metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the timecourse of changes in thyroid hormone metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS). LPS rapidly induced interleukin-1 mRNA expression in the hypothalamus, pituitary, thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of thyroid receptor (TR)-2, TSH and 5-deiodinase (D1) mRNAs), the thyroid (decreased TSH receptor mRNA) and the liver (decreased TR1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas preproTRH mRNA expression did not change after LPS. Serum T 3 and T 4 fell only after 24 h. Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness.
Prolonged critical illness has high morbidity and mortality. The acute neuroendocrine response to critical illness involves an activated anterior pituitary function. In prolonged critical illness, however, a reduced pulsatile secretion of anterior pituitary hormones and the so-called ‘wasting syndrome’ occur. The impaired pulsatile secretion of growth hormone (GH), thyrotropin and gonadotropin can be re-amplified by relevant combinations of releasing factors, which also substantially increase circulating levels of insulin-like growth factor (IGF)-I, GH-dependent IGF-binding proteins, thyroxine, tri-iodothyronine, and testosterone. Anabolism is clearly re-initiated when GH secretagogues, thyrotropin-releasing and gonadotropin-releasing hormones are co-administered but the effect on survival remains unknown. A lethal outcome of critical illness is predicted by a high serum concentration of IGF-binding protein 1, pointing to impaired insulin effect rather than pituitary function, and survival was recently shown to be dramatically improved by strict normalization of glycemia with exogenous insulin. The recent progress in the knowledge of the neuroendocrine response to critical illness and its interrelation with peripheral hormonal and metabolic alterations during stress allows for potential new therapeutic perspectives to safely reverse the wasting syndrome and improve survival. These novel insights will be reviewed herein.
Nonthyroidal illness is characterized by low thyroid hormone levels and inappropriately normal or decreased TSH levels. To determine whether the hypothalamus contributes to these responses, TRH gene expression in hypophysiotropic neurons of the paraventricular nucleus (PVN) was investigated using semiquantitative in situ hybridization histochemistry in an animal model of nonthyroidal illness. Following the systemic administration of bacterial lipopolysaccharide (LPS; 250 μg/100 g BW), plasma T4, T3 and TSH were reduced but this was not associated with an increase in the content of proTRH mRNA in the PVN as occurs when plasma T4 and T3 concentrations fall during primary hypothyroidism. Constant infusion of human interleukin-1β (IL-1β) into the cerebrospinal fluid also reduced plasma T4 concentration. This persisted for the duration of the infusion but TSH was only suppressed after 7 days of infusion when body weight had declined. By 24 h, the content of proTRH mRNA in the PVN in IL-1β infused animals was significantly reduced from control values. These studies indicate that the peripheral administration of endotoxin or central administration of IL-1β in the rat is associated with a proTRH mRNA content in the PVN that may be inappropriately normal or reduced for the level of circulating thyroid hormone. We propose that the inability of hypophysiotropic neurons to induce TRH gene expression in nonthyroidal illness, when circulating thyroid hormone levels are low, is one of several factors that contributes to the inability of the anterior pituitary to increase its secretion of TSH.Copyright © 1994 S. Karger AG, Basel
OBJECTIVE
Infusion of GH secretagogues appears to be a novel endocrine approach to reverse the catabolic state of critical illness, through amplification of the endogenously blunted GH secretion associated with a substantial IGF‐I rise. Here we report the dynamic characteristics of spontaneous nightly TSH and PRL secretion during prolonged critical illness, together with the concomitant effects exerted by the administration of GH‐secretagogues, GH‐releasing hormone (GHRH) and GH‐releasing peptide‐2 (GHRP‐2) in particular, on night‐time TSH and PRL secretion.
PATIENTS AND DESIGN
Twenty‐six critically ill adults (mean ± SEM age: 63 ± 2 years) were studied during two consecutive nights (2100–0600 h). According to a weighed randomization, they received 1 of 4 combinations of infusions, within a randomized, cross‐over design for each combination: placebo (one night) and GHRH (the next night) ( n = 4); placebo and GHRP‐2 ( n = 10); GHRH and GHRP‐2 ( n = 6); GHRP‐2 and GHRH + GHRP‐2 ( n = 6). Peptide infusions (duration 21 hours) were started after a bolus of 1 μg/kg at 0900 h and infused (1 μg/kg/h) until 0600 h.
MEASUREMENTS
Serum concentrations of TSH and PRL were determined by IRMA every 20 minutes and T4, T3 and rT3 by RIA at 2100 h and 0600 h in each study night. Hormone secretion was quantified using deconvolution analysis.
RESULTS
During prolonged critical illness, mean night‐time serum concentrations of TSH (1.25 ± 0.42 mIU/l) and PRL (9.4 ± 0.9 μg/l) were low–normal. However, the proportion of TSH and PRL that was released in a pulsatile fashion was low (32 ± 6% and 16 ± 2.6%) and no nocturnal TSH or PRL surges were observed. The serum levels of T3 (0.64 ± 0.06 nmol/l) were low and were positively related to the number of TSH bursts ( R ² = 0.32; P = 0.03) and to the log of pulsatile TSH production ( R ² = 0.34; P = 0.03).
GHRP‐2 infusion further reduced the proportion of TSH released in a pulsatile fashion to half that during placebo infusion ( P = 0.02), without altering mean TSH levels. GHRH infusion increased mean TSH levels and pulsatile TSH production, 2‐fold compared to placebo ( P = 0.03) and 3‐fold compared to GHRP‐2 ( P = 0.008). The addition of GHRP‐2 to GHRH infusion abolished the stimulatory effect of GHRH on pulsatile TSH secretion. GHRP‐2 infusion induced a small increase in mean PRL levels (21%; P = 0.02) and basal PRL secretion rate (49%; P = 0.02) compared to placebo, as did GHRH and GHRH + GHRP‐2.
CONCLUSIONS
The characterization of the specific pattern of anterior pituitary function during prolonged critical illness is herewith extended to the dynamics of TSH and PRL secretion: mean serum levels are low‐normal, no nocturnal surge is observed and the pulsatile fractions of TSH and PRL release are reduced, as was shown previously for GH. Low circulating thyroid hormone levels appear positively correlated with the reduced pulsatile TSH secretion, suggesting that they have, at least in part, a neuroendocrine origin. Finally, the opposite effects of different GH‐secretagogues on TSH secretion further delineate particular linkages between the somatotrophic and thyrotrophic axes during critical illness.
We have measured 3,5,3`triiodothyronine (T3) in 12 tissues from thyroidectomized (Tx) rats infused with increasing doses of T3, and related them to their corresponding plasma levels. Young adult Wistar rats were surgically Tx. After 4 weeks, the animals were infused with placebo or T3 (0.25, 0.50, 0.75, 1.00 or 2.00 μg/100 g body weight/day). Placebo-infused intact rats served as euthyroid controls. Plasma and samples of cerebral cortex, cerebellum, brown adipose tissue (BAT), pituitary, liver, heart, lung, kidney, spleen, skeletal muscle, ovary and adrenal were obtained after 12–13 days of infusion. We determined plasma T3 and thyrotropin (TSH), and tissue T3 and thyroxine (T4), the latter being virtually undetectable. Results were compared with the relationships between tissue and plasma T3 in Tx rats on T4 infusions. Most tissues presented changes which paralleled those in plasma T3, irrespective of its source (infusion of T3, or generation from infused T4). However, at similar plasma T3 concentrations, cerebral cortex, cerebellum and BAT (containing type II 5′ iodothyronine deiodinase (DII) activity), reached much lower T3 levels in the T3-infused Tx rats, than in Tx rats on T4, and required elevated plasma T3 levels for normal tissue T3. In these tissues, and in the pituitary, T3 concentrations were always lower than expected from plasma T3 levels. On the contrary, the lung and ovary of the T3-infused Tx rats contained more T3 than expected from plasma T3. Unexpectedly, both the ovary and adrenal attained higher tissue T3 concentrations in Tx rats on T3 than on T4 at comparable plasma T3 levels. In conclusion, the patterns of changes of the concentrations of T3 as a function of increasing plasma T3 are not only tissue-specific when T4 is provided, but also when circulating T3 is the only source of this iodothyronine. Further studies are needed to identify the mechanisms involved in the regulation of tissue T3 concentrations.
To determine the implication of decreased T3 production during fasting, seven normal men were fasted for 80 hours on two occasions; they received 5 microgram of T3 every three hours durnig the second fast. The mean serum T3 concentration declined during the control fast from 120 to 73 ng per deciliter (P less than 0.01), but remained slightly above base-line values during the T3 fast. Mean serum T4 concentrations did not change, and mean serum rT3 concentrations increased, during both fasts. The peak serum TSH increment after TRH was 11.1 micromicron per milliliter before fasting, 8.9 (not significant) after the control fast and 2.2 (P less than 0.01) after the T3 fast. Urea excretion was 9.1 per cent higher during the T3 fast; there were no differences in the changes in blood glucose, plasma fatty acids or other substrates during the two fasts. Pretreatment with potassium iodide lowered serum T4 concentrations and increased the serum TSH response to TRH after fasting. We conclude that the decrease in serum T3 concentrations during fasting spares muscle protein. Fasting is accompanied by a lower set point of TSH secretion, which remains sensitive to changes in serum thyroid hormone concentrations.
Tumor necrosis factor-alpha (TNF) is believed to be an important mediator in many diseases that are associated with the sick euthyroid syndrome. To investigate the effect of TNF on thyroid hormone metabolism, we performed a controlled study in six healthy postabsorptive males, in whom plasma thyroid hormones and TSH were sequentially measured after iv bolus injections of recombinant human TNF (50 micrograms/m2) and isotonic saline. During the 10.5-h study TNF produced the characteristic changes in circulating thyroid hormones and TSH observed in the sick euthyroid syndrome. Compared with the control experiment, TNF induced significant decreases in T3 (-36 +/- 2%; saline, -20 +/- 3%; P less than 0.05) and TSH levels (-68 +/- 3%; saline, -44 +/- 8%; P less than 0.05) and a significant increase in rT3 values (+48 +/- 11%; saline, -12 +/- 7%; P less than 0.05). T4 and free T4 index were not affected by TNF. Free T4 showed a mean transient increase of 18% in five subjects (nonsignificant), which occurred synchronically with a transient 3.5-fold rise in circulating FFA levels. Our results suggest that TNF is involved, either directly or indirectly, in the pathogenesis of the sick euthyroid syndrome.
The effect of fasting on circadian and pulsatile TSH secretion was investigated in eight healthy subjects (four men and four women in the follicular phase). Each subject was studied twice, once during 24 h with normal food intake and once during the last 24 h of a 60-h fast. Blood was sampled every 10 min during 24 h for measurement of TSH by a sensitive immunoradiometric assay. Fasting induced a decrease in plasma T3 [1.73 +/- 0.06 vs. 1.36 +/- 0.04 nmol/L; P less than 0.01 (mean +/- SE), control period vs. fasting] and thyroglobulin (52 +/- 8 vs. 35 +/- 7 pmol/L; P less than 0.001) and an increase in plasma rT3 (0.30 +/- 0.06 vs. 0.44 +/- 0.09 nmol/L; P less than 0.02). Plasma T4, thyroid hormone binding index, and free T4 were not statistically different in both periods. The mean plasma 24-h TSH concentration was lower during fasting than in the control period (2.0 +/- 0.3 vs. 1.0 +/- 0.2 mU/L; P less than 0.005). This was associated with a decrease in mean TSH pulse amplitude during fasting (Desade program: 0.6 +/- 0.1 vs. 0.3 +/- 0.1 mU/L; P less than 0.01; Cluster program: 0.5 +/- 0.1 vs. 0.2 +/- 0.1 mU/L; P less than 0.05), whereas TSH pulse frequency during fasting was unchanged (Desade program: 8.4 +/- 0.9 vs. 9.8 +/- 0.8 pulses/24 h; Cluster program: 9.5 +/- 0.5 vs. 7.9 +/- 0.9 pulses/24 h). There was a highly significant correlation between the mean 24-h TSH concentration and the mean TSH pulse amplitude during both the control period and fasting. Although the decrease in TSH concentration during fasting was evident over 24 h, fasting especially decreased the absolute (1.3 +/- 0.3 vs. 0.4 +/- 0.1 mU/L, P less than 0.02) and the relative (101 +/- 18% vs. 40 +/- 14%; P less than 0.02) nocturnal TSH surge (mean TSH 0000-0400 h vs. mean TSH 1500-1900 h). The decreased nocturnal TSH surge during fasting was associated with a significantly decreased TSH pulse amplitude, but with an unaltered number of TSH pulses between 2000-0400 h. In conclusion, fasting decreases 24-h TSH secretion and the nocturnal TSH surge in the absence of a change in plasma T4 concentration. This is associated with a decreased TSH pulse amplitude, whereas TSH pulse frequency remains unchanged.
In a study of serum levels of tumor necrosis factor (TNF alpha) and interleukin-1 beta (IL-1 beta) in patients developing sepsis in the ICU, high TNF alpha levels were found in patients with septic shock. Normal values are 75 +/- 15 pg/ml; in these patients, TNF alpha serum level ranged from 100 to 5000 pg/ml with a mean of 701 +/- 339 pg/ml and a median of 250 pg/ml. There was a correlation between TNF alpha level and sepsis severity score as well as with mortality. In contrast, IL-1 beta serum levels were only slightly increased and were not correlated with severity or mortality.
Starvation in laboratory rodents results in significant alterations in thyroid hormone economy characterized by decreased circulating levels of thyroxine (T4) and 3,5,3'-triiodothyronine (T3) and a decline in serum thyrotropin (TSH) concentration. To investigate this apparent paradox, we have compared in fasted and hypothyroid animals the intracellular parameters mediating thyroid hormone action in the anterior pituitary gland. In vitro saturation analysis combined with quantitation of nuclear T3 content by radioimmunoassay allowed for characterization of pituitary nuclear T3 receptors and estimation of the endogenous fractional receptor occupancy. In rats, thyroidectomized 4 wk earlier, the 10-fold increase in serum TSH levels and decline in peripheral thyroid hormone concentrations were accompanied by a 61% decrease in pituitary nuclear T3 content and a marked decline in fractional T3 receptor occupancy as compared with control animals. In euthyroid animals subjected to short-term starvation (72 h), serum T3, T4, and TSH levels declined by 52, 43, and 48%, respectively. Despite these marked decreases in circulating thyroid hormone levels, pituitary nuclear T3 content in fasted rats declined by only 15% (P less than 0.05) relative to control levels. This modest decline in nuclear T3 content, combined with a 23% decrease in total T3 receptor number, resulted in an estimated fractional receptor occupancy in fasted animals which was equal to or greater than that noted in controls. The effects of fasting and hypothyroidism on the pituitary were further investigated by quantifying low Michaelis constant (Km) T4 5'-deiodinase activity in the crude cytosol fraction of pituitary homogenates. In thyroidectomized animals, maximum velocity was increased ninefold, whereas fasting resulted in a 37% decrease (P less than 0.025) in this parameter compared with controls. Km values were similar in all experimental groups (4.7 +/- 0.6 nM). These results demonstrate that, despite significant reductions in circulating thyroid hormone concentrations and pituitary T4 5'-deiodinase activity, nuclear T3 levels are maintained at relatively normal levels in the pituitary of the fasted animal and fractional T3 receptor occupancy may actually increase. These findings are in marked contrast to those noted in thyroidectomized animals and suggest that the suppression of TSH secretion accompanying starvation in the rat is mediated, at least in part, by local pituitary mechanisms that serve to maintain and possibly enhance nuclear T3 receptor occupancy.
A randomized prospective study was done to assess the response of hypothyroxinemic patients with severe nonthyroidal illnesses to T4 therapy. Patients admitted to a medical intensive care unit who had a total serum T4 concentration less than 5 micrograms/dl were randomly assigned to a control (12 patients) or a T4 treatment group (11 patients). L-T4 in a dose of 1.5 micrograms/kg was given iv each day for 2 weeks. In the treatment group, serum T4 and free T4 concentrations significantly increased by day 3 and were normal on day 5. Serum TSH levels decreased significantly in the T4 treatment group, as did the TSH response to TRH. A significant rise in serum T3 occurred in the control group on day 7, but was delayed until day 10 in the treatment group. Mortality was equivalent in the 2 groups (75% control vs. 73% treatment). Regardless of group assignment, survivors and nonsurvivors were completely separable based on baseline T3 to T4 ratios [17.0 +/- 1.8 (+/- SE) ng/micrograms in survivors vs. 7.0 +/- 0.7 in nonsurvivors; P less than 0.001]. Angiotensin-converting enzyme was significantly reduced in the T4 treatment group, but did not rise significantly in response to treatment. T4 therapy was not beneficial in this population of intensive care unit patients, and by inhibiting TSH secretion, it may suppress an important mechanism for normalization of thyroid function during recovery.
In order to elucidate at which level glucocorticoids act in inhibiting thyrotropin (HTSH) secretion in man, 200 μgm of synthetic thyrotropin releasing hormone (TRH) were injected i.v. in 8 normal subjects before and after oral administration of dexamethasone, 1.0 mg every 8 hr for 5 consecutive days. After dexamethasone, the mean basal plasma HTSH levels were significantly reduced, as was the plasma HTSH response to TRH: this reduced increase occurred in all subjects. The glucocorticoid did not alter significantly the serum thyroxine and triiodothyronine uptake. The data obtained are compatible with a direct inhibiting action of dexamethasone at pituitary level.
GENERALLY, the purpose of assessing thyroid function in a given patient is to determine his metabolic status. In patients with systemic nonthyroidal illness, as well as in those undergoing a variety of other stresses, this determination is complicated by effects at all levels of the hypothalamic-pituitary-thyroid axis. With the availability of thyrptropin releasing hormone (TRH) and the recent development of sensitive methods for the direct measurement of serum 3,5,3′-triiodothyronine (T3) and 3,3′,5′-triiodothyronine (reverse T3 (rT3)), considerable progress has been made in gaining an understanding of the significance of the alterations in thyroid hormone economy that accompany nonthyroidal illness, stress, and the administration of certain pharmacological agents.
According to basic tenets of negative feedback control of thyrotropin (TSH) secretion by circulating free thyroid hormones, alterations in hormone binding in nonthyroidal illness that produce increases in free hormone should result in predictably decreased TSH responses to TRH stimulation. Indeed, the magnitude of TSH response to TRH is often taken to be the most specific clue to the true metabolic state of the organism, and the recent publication of studies that examined the status of TRH responsiveness in nonthyroidal illness has provided critical information in this regard.
To evaluate the role of cytokines in the sick euthyroid syndrome, we tried to establish an animal model of non-thyroidal illness in mice by the administration of a sub-lethal dose of bacterial endotoxin (lipopolysaccharide; LPS) which induces a variety of cytokines, including tumour necrosis factor (TNFα), interleukin-1 (IL-1α), interleukin-6 (IL-6) and interferon-γ (IFNγ). When compared with pair-fed controls, a single dose of LPS resulted in (a) systemic illness, (b) induction of TNFα and IL-6 and (c) a decrease of liver 5′-deiodinase mRNA from 4 h onwards followed by a decrease of serum tri-iodothyronine (T 3 ) and thyroxine (T 4 ) at 8 h and of serum free T 3 (fT 3 ) and free T 4 (fT 4 ) at 24 h; serum TSH remained unchanged.
We then studied whether a single dose or a combination of IL-1α, TNFα, IL-6 or IFNγ could induce the sick euthyroid syndrome in mice, again using pair-fed controls. None of the cytokines except IL-1α caused systemic illness, and IL-1α was the only cytokine that decreased liver 5′-deiodinase mRNA transiently. IL-1α, TNFα or IL-6 did not decrease serum T 3 , T 4 and TSH, but administration of IFNγ decreased serum T 4 , T 3 and fT 3 in a dose-dependent manner without changes in serum TSH. Administration of all four cytokines together had no synergistic effects; observed changes were of a smaller magnitude than after LPS.
The following conclusions were reached. (1) Administration of LPS in mice is a suitable experimental model for the acute induction of the sick euthyroid syndrome. (2) Acute administration of IL-1α, TNFα or IL-6 in mice does not induce changes in thyroid hormones but IFNγ results in a dose-dependent decrease of serum T 4 , T 3 and fT 3 and IL-1α decreases liver 5′-deiodinase mRNA transiently. (3) Combined administration of IL-1α, TNFα, IL-6 and IFNγ had no synergistic effects; observed changes were of a smaller magnitude than after LPS. (4) The LPS-induced sick euthyroid syndrome is currently best explained by a direct thyroidal inhibition due to IFNγ and an extrathyroidal inhibition of liver 5′-deiodinase due to IL-1α, but other still unidentified factors seem to be involved as well.
Journal of Endocrinology (1995) 146, 475–483
Interleukin-1 (IL-1) has been implicated as a mediator of the euthyroid sick syndrome. The effects of IL-1 can be blocked by the naturally occurring IL-1 receptor antagonist (IL-1ra). In the present study, iv administration of endotoxin was used as a human model of the euthyroid sick syndrome. To assess the role of endogenous IL-1 in endotoxin-induced changes in plasma thyroid hormone and TSH concentrations, 18 healthy postabsorptive humans were studied on a control study day, followed 3 days later by a study day on which they were randomly assigned to one of three treatments: a 6-h infusion of recombinant human IL-1ra alone (133 mg/h), endotoxin alone (lot EC-5; 20 U/kg), or both endotoxin and IL-1ra. Administration of IL-1ra alone did not affect the plasma concentrations of thyroid hormones or TSH compared with those on the control day. Endotoxin injection was associated with decreases in T4 (P = 0.06 vs. the control day), free T4 (P = 0.02), T3 (P < 0.001), and TSH (P < 0.0001) and a rise in rT3 (P < 0.001), reproducing the major features of the euthyroid sick syndrome. Coinfusion of IL-1ra did not influence these endotoxin-induced changes. Our results suggest that endogenous IL-1 does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.
In the present study, we describe for the first time the distribution of thyrotropin‐releasing hormone (TRH)‐containing cells and fibers in the human hypothalamus using brain material obtained with a short postmortem delay. Following fixation in paraformaldehyde, glutaraldehyde and picric acid, excellent staining was obtained with two different TRH antisera. Many TRH‐containing neurons were present in the paraventricular nucleus (PVN), especially in the dorsocaudal part of this nucleus. They were mostly parvicellular, but a few magnocellular TRH‐positive neurons were observed as well. The PVN also contained a dense network of TRH fibers. The supraoptic nucleus (SON) did not show any TRH immunoreactivity, excluding the possibility of cross‐reactivity of the antiserum with neurohypophysial hormones or their precursors. In addition, TRH cells were found in the suprachiasmatic nucleus (SCN), which is the circadian clock of the brain, in the sexually dimorphic nucleus (SDN) and dorsomedially of the SON. We observed small numbers of TRH cells throughout the hypothalamic gray in all subjects studied.
A high density of TRH‐containing fibers was seen not only in the median eminence but also in other hypothalamic areas, e.g., in the ventromedial nucleus (VM) and in the perifornical area. The results generally agree with earlier data in the rat, with the exception of the absence of TRH cells in the SON. The large number of sites of TRH‐containing fiber terminations on neurons suggests important physiological functions of this neuropeptide as a neurotransmitter or neuromodulator in the human brain in addition to its role as a neurohormone in pituitary secretion of thyroid‐stimulating hormone (TSH).
To determine the ability of various endocrine parameters, measured at the time of intensive care unit (ICU) admission, to predict patient outcome.
Prospective, cohort study of patients requiring intensive care.
The medical/surgical ICU at South Cleveland Hospital, UK and a medical/surgical ICU in a UK district hospital.
A total of 260 consecutive patients requiring intensive care over a 2-yr period.
Patients were investigated within 1 hr of ICU admission by measuring plasma cortisol, serum thyroxine, triiodothyronine, and thyrotropin concentrations and by obtaining the Acute Physiology and Chronic Health Evaluation (APACHE II) score. Individual variables were compared between survivors and nonsurvivors.
There were significant differences for each endocrine parameter between survivors and nonsurvivors (all p < .01). A multiple logistic regression analysis showed that only thyroxine, thyrotropin, and cortisol concentrations were independent predictors of outcome. An equation using these variables predicted outcome with 82% accuracy at the 0.5 cutoff point of the receiver operating curve. APACHE II scores predicted outcome with 72% accuracy at the same point on the receiver operating curve. Correct prediction of death was more frequent with the Endocrine Index than with APACHE II scores. Overall predictive power of the Endocrine Index, as measured by the area under the receiver operating curve, was 0.94 (95% confidence interval 0.91 to 0.96) vs. 0.85 (95% confidence interval 0.81 to 0.89) for APACHE II scores. Combining APACHE II scores and the endocrine parameters in a single index did not improve prediction (area under receiver operating curve = 0.94).
An endocrine prognostic index based on ICU admission measurements of thyroxine, thyrotropin, and cortisol concentrations is a superior discriminator of patient outcome than the APACHE II score.
Nonthyroidal illness is characterized by low thyroid hormone levels and inappropriately normal or decreased TSH levels. To determine whether the hypothalamus contributes to these responses, TRH gene expression in hypophysiotropic neurons of the paraventricular nucleus (PVN) was investigated using semiquantitative in situ hybridization histochemistry in an animal model of nonthyroidal illness. Following the systemic administration of bacterial lipopolysaccharide (LPS; 250 micrograms/100 g BW), plasma T4, T3 and TSH were reduced but this was not associated with an increase in the content of proTRH mRNA in the PVN as occurs when plasma T4 and T3 concentrations fall during primary hypothyroidism. Constant infusion of human interleukin-1 beta (IL-1 beta) into the cerebrospinal fluid also reduced plasma T4 concentration. This persisted for the duration of the infusion but TSH was only suppressed after 7 days of infusion when body weight had declined. By 24 h, the content of proTRH mRNA in the PVN in IL-1 beta infused animals was significantly reduced from control values. These studies indicate that the peripheral administration of endotoxin or central administration of IL-1 beta in the rat is associated with a proTRH mRNA content in the PVN that may be inappropriately normal or reduced for the level of circulating thyroid hormone. We propose that the inability of hypophysiotropic neurons to induce TRH gene expression in nonthyroidal illness, when circulating thyroid hormone levels are low, is one of several factors that contributes to the inability of the anterior pituitary to increase its secretion of TSH.
Thyroid hormone uptake into cultured human hepatocytes was studied using measurement of cell-associated radioactivity of radioiodinated thyroid hormones after 10-min incubation in culture medium with 0.5% BSA. Furthermore, 20-h incubations were performed to study transport and further intracellular metabolism. The results indicate the presence of saturable active uptake systems for T4, T3, and rT3, as addition of the unlabeled hormone (1, 5, and 2 mumol/L, respectively) to the medium resulted in a decrease in cell-associated radioactivity of 20-30%. Inhibition was also achieved after 30-min preincubation with fructose (10 mmol/L), which induces a decrease in intracellular ATP or ouabain (0.5 mmol/L), indicating energy dependence and the necessity for a sodium gradient for at least part of the transport process, respectively. After 20-h incubation, iodide production was inhibited in the presence of ouabain (0.5 mmol/L), propylthiouracil (100 mumol/L), or a monoclonal antibody (81-1A1-10; ascites dilution, 1:200) directed against thyroid hormone transport systems in rat hepatocytes. These data indicate that there is a high degree of similarity between the properties of the uptake process and subsequent conversion of thyroid hormones in human and rat hepatocytes, although the rates of uptake and conversion are lower in human hepatocytes. Furthermore, regulation of thyroid hormone uptake at the level of the plasma membrane may also be operative in human hepatocytes.
Patients with severe nonthyroidal illnesses (NTIs) frequently have decreased serum concentrations of triiodothyronine (T3) and less often of thyroxine (T4) without clear evidence of hypothyroidism. To determine whether T3 and T4 levels are also reduced in the tissues, we analyzed autopsy samples from 12 patients dying of NTI and 10 previously healthy individuals dying suddenly from trauma. Mean serum T3, T4, and free T4 index values were lower by 79%, 71%, and 49%, respectively, in the NTI group than in controls, but serum thyrotropin (TSH) values did not differ significantly. Mean T3 concentrations in cerebral cortex, hypothalamus, pituitary, liver, kidney, and lung were lower in the NTI group than in controls by 43% to 76%, but mean values in heart and skeletal muscle did not differ significantly between the groups. The mean liver T4 concentration was 66% lower in the NTI group, but mean T4 concentrations in the cerebral cortex were similar in the two groups. These results indicate that many tissues may be deficient in thyroid hormones in patients with fatal NTI, although the severity of the reduction in thyroid hormone concentrations may vary from one organ to another.
Type 2 deiodinase (D2) is a low K(m) iodothyronine deiodinase that catalyzes the removal of a single iodine from the phenolic ring of T4 or rT3. We sequenced and subcloned the open reading frame from a partial complementary DNA (cDNA) clone (2.1 kilobases) prepared by Genethon (Z44085) from a human infant brain cDNA library. The open reading frame encodes a putative 273-amino acid protein of 31 kDa with greater than 70% similarity to the Rana catesbeiana D2 protein. Transient expression of the cDNA produces a low K(m) (5 nM for T4; 8 nM for rT3) propylthiouracil- and gold thioglucose-resistant 5'-deiodinase in 293-HEK cells. Human D2, like human type 1 (D1) and type 3 (D3) deiodinases, is a selenoenzyme, as evidenced by 1) the presence of two in-frame UGA codons (positions 133 and 266), 2) the synthesis of a 31-kDa 75Selabeled protein in D2 cDNA-transfected cells, and 3) the requirement for a 3'-selenocysteine incorporation sequence element for its translation. Unlike D1 and D3, we were not able to covalently label overexpressed D2 with N-bromoacetyl [125I]T3 or -T4. We found that the human D2 messenger RNA is 7-8 kilobases and is expressed in brain, placenta, and, surprisingly, cardiac and skeletal muscle. Type 2 deiodinase activity was also present in human skeletal muscle. These results indicate that there are unique features of D2 that distinguish it from the two other selenodeiodinases. The expression of D2 in muscle suggests that it could play a role in peripheral, as well as intracellular, T3 production.
Nonthyroidal illness (NTI) and fasting in man are characterized by a low serum concentration of T3 and an increased serum concentration of rT3. Since the serum level of T3 is one of the most important factors that determine the metabolic rate, the low serum T3 during NTI or fasting results in reduction of the energy consumption of the body. This can be regarded as an adaptive mechanism to save energy, and thus to conserve protein and to protect organ function. The low serum T3 concentration should preferentially be maintained until recovery from illness or adequate calorie supply. This implies that the low serum T3 should not result in a rise in serum TSH. We postulate that different regulation of thyroid hormone transport into the relevant tissues, i.e., liver and pituitary, may play a role in maintenance of the low T3 production during NTI and fasting. This hypothesis is further elaborated in this paper by comparing (i) the properties of the thyroid hormone uptake mechanism in rat and human hepatocytes, perfused rat liver, and rat anterior pituitary cells, and (ii) the effects of fasting and conditions that mimic NTI on thyroid hormone transport in the same preparations. In addition, the consequences of changes in thyroid hormone transport and peripheral thyroid hormone metabolism during fasting and NTI for the serum level of rT3 and for TSH secretion are discussed. The data are compatible with the existence of different transport systems for thyroid hormone in liver and pituitary. We suggest that these different thyroid hormone carriers allow tissue-specific regulation of the intracellular availability of T3.
We studied the distribution of mRNA coding for thyrotropin-releasing hormone (TRH) in the human hypothalamus by means of in situ hybridization. In 10% formalin-fixed paraffin-embedded tissue sections of five hypothalami, TRH mRNA-containing cells were found in several nuclei and areas. Numerous TRH mRNA-containing cells were detected in the medial region of the caudal part of the paraventricular nucleus. These neurons were heavily labeled and mainly small to medium-sized. Few, lightly- and medium-labeled, small cells were detected in the suprachiasmatic nucleus. In addition, heavily labeled single cells were found in the perifornical area and the anterior- and lateral hypothalamic regions. In the latter region, occasional heavily labeled cells were found just dorsal to the supraoptic nucleus. Neither in the supraoptic nucleus nor in the sexually dimorphic nucleus of the preoptic area were TRH mRNA-containing cells found. This is the first description of TRH mRNA containing cells in the human hypothalamus.
The sick euthyroid syndrome is a state of altered thyroid hormone metabolism which occurs during illness. The pathogenesis is incompletely understood but recent studies indicate a role of cytokines. It is unknown if cytokines released during illness are directly responsible for the changes in thyroid hormone metabolism. Therefore we studied if previous immunoneutralization of cytokines can prevent endotoxin (lipopolysaccharide LPS), induced sick euthyroid syndrome.
LPS administration resulted in systemic illness, an increase in serum tumor necrosis factor (TNFα) and interleukin (IL)-6 and a decrease in serum triiodothyronine (T 3 ) and thyroxine (T 4 ). Immunoneutralization of the effects of cytokines was accomplished by administration of monoclonal antibodies against mouse IL-1 type-1 receptor (IL-1R), TNFα, IL-6 or interferon (IFNα) prior to LPS. The LPS-induced release of cytokines was affected by previous immunoneutralization as compared with control experiments with normal immunoglobulin (IgG): anti-IL-1R did not affect serum TNFα but decreased serum IL-6, anti-TNFα decreased serum TNFα but not IL-6, anti-IL-6 did not affect serum TNFα but hugely increased IL-6 and anti-IFNγ decreased both serum TNFα and IL-6. Specific immunoneutralization of IL-1, TNFα or IFNγ did not prevent the LPS-induced decrease in serum T 3 , T 4 and liver 5′-deiodinase mRNA. However, immunoneutralization of IL-6, although not preventing the fall in serum T 3 and T 4 , did mitigate the LPS-induced decrease in liver 5′-deiodinase mRNA.
In view of possible non-specific effects of the huge dose of immunoglobulins (1 mg), used only in the immunoneutralization of IL-6, we repeated the experiment with F(ab′) 2 fragments of anti-IL-6 antibodies. Compared with F(ab′) 2 fragments of control IgG, anti-IL-6 F(ab′) 2 did not affect the LPS-induced rise in serum TNFα or the decrease in serum T 3 and T 4 and liver 5′-deiodinase mRNA. Serum IL-6 levels induced by LPS were, however, cleared more rapidly from the circulation when anti-IL-6 F(ab′) 2 fragments rather than intact anti-IL-6 were administered. In conclusion, immunoneutralization of IL-1, TNFα or IFNγ did not prevent the LPS-induced sick euthyroid syndrome in mice; immunoneutralization of IL-6, however, transiently inhibits the LPS-induced decrease of liver 5′-deiodinase mRNA.
Journal of Endocrinology (1997) 153, 115–122
Changes in hypothalamus-pituitary-thyroid function occur in patients with a variety of illnesses and are referred to as the euthyroid sick syndrome or nonthyroidal illness (NTI). In NTI, serum concentrations of T3 decrease to low, or even undetectable, levels without giving rise to elevated concentrations of TSH. We hypothesized that decreased activity of TRH-producing cells in the paraventricular nucleus (PVN) contributes to the persistence of low TSH levels. To test this hypothesis, we collected a series of formalin-fixed, paraffin-embedded hypothalami of patients whose plasma concentrations of T3, T4, and TSH had been measured in a blood sample taken less than 24 h before death. Quantitative TRH messenger RNA in situ hybridization (intraassay coefficient of variation: 13%) was performed in the PVN. Total TRH messenger RNA in the PVN showed a positive correlation with serum T3 (r = 0.66; P < 0.05) and with logTSH (r = 0.64; P < 0.05), but not with T4 (r = -0.02; P = 0.95). This is the first study to correlate premortem serum concentrations of thyroid hormones with postmortem gene expression of identified neurons in the human hypothalamus. The results suggest an important role for TRH cells in the pathogenesis of NTI.
Infusion of GH secretagogues appears to be a novel endocrine approach to reverse the catabolic state of critical illness, through amplification of the endogenously blunted GH secretion associated with a substantial IGF-I rise. Here we report the dynamic characteristics of spontaneous nightly TSH and PRL secretion during prolonged critical illness, together with the concomitant effects exerted by the administration of GH-secretagogues, GH-releasing hormone (GHRH) and GH-releasing peptide-2 (GHRP-2) in particular, on night-time TSH and PRL secretion.
Twenty-six critically ill adults (mean +/- SEM age: 63 +/- 2 years) were studied during two consecutive nights (2100-0600 h). According to a weighed randomization, they received 1 of 4 combinations of infusions, within a randomized, cross-over design for each combination: placebo (one night) and GHRH (the next night) (n = 4); placebo and GHRP-2 (n = 10); GHRH and GHRP-2 (n = 6); GHRP-2 and GHRH + GHRP-2 (n = 6). Peptide infusions (duration 21 hours) were started after a bolus of 1 microgram/kg at 0900 h and infused (1 microgram/kg/h) until 0600 h.
Serum concentrations of TSH and PRL were determined by IRMA every 20 minutes and T4, T3 and rT3 by RIA at 2100 h and 0600 h in each study night. Hormone secretion was quantified using deconvolution analysis.
During prolonged critical illness, mean night-time serum concentrations of TSH (1.25 +/- 0.42 mlU/l) and PRL (9.4 +/- 0.9 micrograms/l) were low-normal. However, the proportion of TSH and PRL that was released in a pulsatile fashion was low (32 +/- 6% and 16 +/- 2.6%) and no nocturnal TSH or PRL surges were observed. The serum levels of T3 (0.64 +/- 0.06 nmol/l) were low and were positively related to the number of TSH bursts (R2 = 0.32; P = 0.03) and to the log of pulsatile TSH production (R2 = 0.34; P = 0.03). GHRP-2 infusion further reduced the proportion of TSH released in a pulsatile fashion to half that during placebo infusion (P = 0.02), without altering mean TSH levels. GHRH infusion increased mean TSH levels and pulsatile TSH production, 2-fold compared to placebo (P = 0.03) and 3-fold compared to GHRP-2 (P = 0.008). The addition of GHRP-2 to GHRH infusion abolished the stimulatory effect of GHRH on pulsatile TSH secretion. GHRP-2 infusion induced a small increase in mean PRL levels (21%; P = 0.02) and basal PRL secretion rate (49%; P = 0.02) compared to placebo, as did GHRH and GHRH + GHRP-2.
The characterization of the specific pattern of anterior pituitary function during prolonged critical illness is herewith extended to the dynamics of TSH and PRL secretion: mean serum levels are low-normal, no noctumal surge is observed and the pulsatile fractions of TSH and PRL release are reduced, as was shown previously for GH. Low circulating thyroid hormone levels appear positively correlated with the reduced pulsatile TSH secretion, suggesting that they have, at least in part, a neuroendocrine origin. Finally, the opposite effects of different GH-secretagogues on TSH secretion further delineate particular linkages between the somatotrophic and thyrotrophic axes during critical illness.
Acute and prolonged critical illness are different metabolic and neuroendocrine paradigms and should perhaps be approached with different therapeutic strategies. The initial endocrine response consists primarily of an activated release of anterior pituitary hormones and peripheral inactivation of anabolic pathways, thought to provide substrates for survival while anabolism is postponed and to activate the immune cascade while the host is being protected against deleterious effects of the latter. There is still no solid basis for hormonal intervention in the acute phase of illness. The development of modern intensive care now enables survival of previously lethal conditions and unmasked previously unknown disorders such as the "wasting syndrome" of chronic intensive care-dependency. In the chronic phase of critical illness, we documented a uniformly impaired pulsatile secretion of anterior pituitary hormones, at least in part of hypothalamic origin, to correlate positively with reduced activity of target tissues. An acute event complicating the chronic phase of illness may evoke mixed acute/prolonged endocrine patterns, which are difficult to interpret and account for some of the apparent paradoxes in the literature. It is unlikely that the reduced neuroendocrine stimulation, distinctively present in the chronic phase of illness, has been selected by evolution and should accordingly be considered as time-honoured and appropriate. The hypothesis of inappropriate neuroendocrine dysfunction can be validated by studying the effects either of combined peripheral hormonal substitution or of hypophysiotropic releasing peptide administration. We demonstrated that selected pituitary-dependent axes can be reactivated in the chronic phase of critical illness, with preserved peripheral responsiveness. Intervening at the hypothalamic-pituitary level appears to be a safer strategy compared to administration of peripheral hormones, as presence of active feed-back inhibition prevents overtreatment on an individual basis at a time when it is difficult--if not impossible--to determine what is a "normal" or "optimal" level of circulating peripheral hormones. Whether this novel endocrine strategy will result in beneficial metabolic effects and, ultimately, will stimulate the recovery process in those patients who need it most, remains to be elucidated.
Although triiodothyronine deficiency has been described after cardiopulmonary bypass, data supporting its use have been conflicting. A double-blind, randomized, placebo-controlled study was undertaken to further define the effect of triiodothyronine on hemodynamics and outcome after coronary artery bypass grafting.
A total of 170 patients undergoing elective coronary artery bypass grafting were enrolled and completed the study from November 1996 through March 1998. On removal of the aortic crossclamp, patients were randomized to receive either intravenous triiodothyronine (0.4 microgram/kg bolus plus 0.1 microgram/kg infusion administered over a 6-hour period, n = 81) or placebo (n = 89). Outcome variables included hemodynamic profile and inotropic drug/pressor requirements at several time points (mean +/- standard error of the mean), perioperative morbidity (arrhythmia/ischemia/infarction), and mortality.
Despite similar baseline characteristics, patients randomized to triiodothyronine had a higher cardiac index and lower inotropic requirements after the operation. Subjects receiving triiodothyronine demonstrated a significantly lower incidence of postoperative myocardial ischemia (4% vs 18%, P =.007) and pacemaker dependence (14% vs 25%, P =.013). Seven patients in the placebo group required postoperative mechanical assistance (intra-aortic balloon pump, n = 4; left ventricular assist device, n = 3), compared with none in the triiodothyronine group (P =.01). There were 2 deaths in the placebo group and no deaths in the triiodothyronine group.
Parenteral triiodothyronine given after crossclamp removal during elective coronary artery bypass grafting significantly improved postoperative ventricular function, reduced the need for treatment with inotropic agents and mechanical devices, and decreased the incidence of myocardial ischemia. The incidence of atrial fibrillation was slightly decreased, and the need for postoperative pacemaker support was reduced.
Fasting and refeeding have considerable effects on thyroid hormone metabolism. In the present study, 8-day-old meat-type cockerels were subjected to a 2-day starvation period followed by 3 days' refeeding. Blood and tissue samples were collected at the start of the experiment, at 4, 24, and 48 h of starvation, and at 4, 8, 24, 48, and 72 h of refeeding. This study demonstrates that in chicken, fasting decreased plasma T(3) and TSH levels and increased plasma T(4) concentrations. This was accompanied by increased hepatic type III deiodinase (D3) and decreased renal D3 activity. There were no changes in hepatic or renal type I deiodinase (D1). Refeeding restored normal plasma T(3), T(4), and TSH levels, while hepatic D3 and renal D3 activities returned to prefasting levels. Again hepatic D1 was not affected, but renal D1 was lower than the ad libitum values during the entire refeeding period. These results confirm that liver D3 is involved in the regulation of plasma T(3) during fasting and refeeding in the chicken. Northern blot analysis demonstrated increased hepatic D3 mRNA levels during the first day of starvation that disappeared by the end of the second day; refeeding had no additional effects. These results suggest that in fasted chickens the rapid upregulation of hepatic D3 occurs predominantly at a pretranslational level, whereas the drop in hepatic D3 activity after refeeding is probably regulated at a posttranslational level. In addition, renal D3 may play a role in the regulation of local T(3) availability.
A trial of thyroxine in acute renal failure.
Acute renal failure (ARF) remains a serious medical problem with a high mortality rate. Efforts to shorten the course of ARF might reduce this mortality. Since thyroxine has been shown in experimental models to shorten the course of ARF, we designed a trial to determine if a defined course of thyroxine would alter the course or change the mortality of clinical ARF.
A prospective, randomized, placebo-controlled, double-blind trial of thyroxine was carried out in patients with ARF. End points were the percentage requiring dialysis, the percentage recovering renal function, time to recovery, and mortality.
Fifty-nine patients were randomized to receive either thyroxine or placebo. The groups were well matched in terms of basal and entry creatinines, age, sex, APACHE II scores at entry, and percentage oliguric. Baseline thyroid functions, including T3, T4, rT3, and thyroid stimulating hormone (TSH) levels, were equal between the two groups and typical of patients with euthyroid sick syndrome. Thyroxine resulted in a progressive and sustained suppression of TSH levels in the treated group, but had no effect on any measure of ARF severity. Mortality was higher in the thyroxine group than the control group (43 vs. 13%) and correlated with suppression of TSH.
In contrast to the beneficial effects seen in experimental ARF, thyroxine has no effect on the course of clinical ARF and could have a negative effect on outcome through prolonged suppression of TSH. Critically ill euthyroid sick patients should not be replaced with thyroid hormone.
The discovery of leptin has enhanced understanding of the interrelationship between adipose energy stores and neuronal circuits in the brain involved in energy balance and regulation of the neuroendocrine axis. Leptin levels are dependent on the status of fat stores as well as changes in energy balance as a result of fasting and overfeeding. Although leptin was initially thought to serve mainly as an anti-satiety hormone, recent studies have shown that it mediates the adaptation to fasting. Furthermore, leptin has been implicated in the regulation of the reproductive, thyroid, growth hormone, and adrenal axes, independent of its role in energy balance. Although it is widely known that leptin acts on hypothalamic neuronal targets to regulate energy balance and neuroendocrine function, the specific neuronal populations mediating leptin action on feeding behavior and autonomic and neuroendocrine function are not well understood. In this review, we have discussed how leptin engages arcuate hypothalamic neurons expressing putative orexigenic peptides, e.g., neuropeptide Y and agouti-regulated peptide, and anorexigenic peptides, e.g., pro-opiomelanocortin (precursor of alpha-melanocyte-stimulating hormone) and cocaine- and amphetamine-regulated transcript. We show that leptin's effects on energy balance and the neuroendocrine axis are mediated by projections to other hypothalamic nuclei, e.g., paraventricular, lateral, and perifornical areas, as well as other sites in the brainstem, spinal cord, and cortical and subcortical regions.
Serum thyroid hormone concentrations decline transiently during critical illness and after surgical procedures. We investigated prospectively the endocrine and haemodynamic effects of tri-iodothyronine treatment after cardiopulmonary bypass operations in children with congenital cardiac malformations.
We did a randomised, double-blind, placebo-controlled trial, in which 40 children (median age 0.6 years; range 2 days to 10.4 years) were randomly assigned placebo (saline) or one daily infusion of tri-iodothyronine (2 microg/kg bodyweight on day 1 after surgery and 1 microg/kg bodyweight on subsequent postoperative days up to 12 days after surgery. Before and 2 h, 24 h, and 72 h after the first infusion, plasma concentrations of thyroid hormones were measured by RIA, and systolic cardiac function was evaluated by echocardiography. During the postoperative course intensive-care measures were assessed by use of the therapeutic intervention scoring system.
In all patients, postoperative plasma concentrations of thyrotropin, thyroxine, free thyroxine, tri-iodothyronine were abnormally low and plasma concentrations of reverse tri-iodothyronine were raised. After start of treatment, tri-iodothyronine was significantly higher in patients given tri-iodothyronine than in those receiving placebo, whereas thyrotropin, thyroxine, free thyroxine, and reverse tri-iodothyronine remained similar in the two groups. At discharge, thyroid hormones of all patients were within the normal range, but thyrotropin secretion increased to plasma concentrations higher than those seen before treatment. The mean change of cardiac index was significantly higher in children given tri-iodothyronine (20.4% [SD 19.6] vs 10.0% [15.2]; p=0.004). Systolic cardiac function improved most in patients given tri-iodothyronine after longer cardiopulmonary bypass operations. Overall, patients given tri-iodothyronine had significantly lower mean treatment scores.
Treatment of children with tri-iodothyronine after cardiopulmonary bypass operations raises tri-iodothyronine plasma concentrations and improves myocardial function especially in patients with low postoperative cardiac output without adverse events, and without delaying postoperative recovery of thyroid function. Furthermore, tri-iodothyronine reduces the need for postoperative intensive care.