help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Michalaki, M.
Right arrow Articles by Kyriazopoulou, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Michalaki, M.
Right arrow Articles by Kyriazopoulou, V.
The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 9 4198-4205
Copyright © 2001 by The Endocrine Society

Other Original Articles

Dissociation of the Early Decline in Serum T3 Concentration and Serum IL-6 Rise and TNF{alpha} in Nonthyroidal Illness Syndrome Induced by Abdominal Surgery

Marina Michalaki, Apostolos G. Vagenakis, Maria Makri, Fotios Kalfarentzos and Venetsana Kyriazopoulou

Departments of Medicine (M.Mi., A.G.V., M.Ma., V.K.) and Surgery (F.K.), Division of Endocrinology, University of Patras Medical School, University Hospital, Patras 26500, Greece

Address all correspondence and requests for reprints to: Dr. Apostolos G. Vagenakis, University Hospital, P. O. Box 1045, Patras 26500, Greece. E-mail: vag.inmd{at}med.upatras.gr

Abstract

The etiology of the prompt decline in serum T3 in patients with nonthyroidal illness syndrome has not been adequately explained. It has been attributed to various parameters, including test artifacts, inhibitors of T4 and T3 binding to proteins, decreased 5'-deiodinase activity, and circulating cytokines. Currently, much attention is centered on the role of IL-6 and TNF{alpha} in developing the nonthyroidal illness syndrome through an effect on the hypothalamus, pituitary, and possibly 5'-deiodinase activity.

We therefore studied the relation of the endogenous serum IL-6 and TNF{alpha} rise early in the course of nonthyroidal illness syndrome to the early decline in serum T3 in 19 apparently healthy individuals, aged 43 ± 16 yr, who underwent elective abdominal surgery for cholelithiasis or gastroplasty. Serum T3, free T3, T4, free T4, rT3, TSH, IL-6, and TNF{alpha} were measured before and at various time intervals up to 42 h after skin incision. We observed a prompt decline in serum T3 30 min before skin incision, which continued to decline throughout the observational period. The magnitude of the decline reached 20% from the baseline value at 2 h. The early decline of T3 was attenuated and lasted from the 2–8 h, probably due to the sharp increase in serum TSH that started immediately after the entrance to the operating room and lasted for 2 h. In contrast, serum T4 and free T4 concentrations were increased soon after skin incision and remained elevated during the first postoperative day. Serum rT3 increased approximately 6 h after the initiation of surgery and remained elevated thereafter. Serum IL-6 remained essentially undetectable for 2 h after skin incision, whereas serum T3 was low. Two hours after skin incision, serum IL-6 increased sharply and remained elevated throughout the observational period. Serum TNF{alpha} remained essentially undetectable throughout the postoperative period. Serum cortisol increased rapidly upon entrance to the operating room and remained elevated throughout the postoperative period.

We conclude that the decline in serum T3 early in the course of nonthyroidal illness syndrome is not due to increased serum IL-6 or TNF{alpha} levels. The brisk TSH secretion soon after the onset of the syndrome attenuates the decline in serum T3 due to T3 secretion from the thyroid. The early and brisk cortisol response to surgery may at least in part explain the early decrease in serum T3 in nonthyroidal illness syndrome.

IT IS WELL known that during the course of various nonthyroidal diseases and fasting, profound alterations occur in the serum concentration and metabolism of thyroid hormones (reviewed in Refs. 1, 2, 3, 4, 5, 6, 7, 8). The term euthyroid sick syndrome or, more recently, nonthyroidal illness syndrome (NTIS) has been coined (4). The observed abnormalities are usually reversible and have been attributed to disturbances in peripheral metabolism, tissue uptake, binding, and receptor occupancy of thyroid hormones, whereas a low activity state of the hypothalamic-pituitary-thyroid axis has been observed in more severe and prolonged nonthyroidal illnesses (1, 2, 3, 4, 5, 6, 7, 8).

Despite the description of the syndrome some 38 yr ago (9, 10), its pathogenesis remains elusive. Recently, the role of cytokines, especially IL-6, IL-1, and TNF{alpha}, have been implicated in the pathogenesis of NTIS (reviewed in Refs. 5, 6, 7, 8). IL-6 is a proinflammatory and pleiotropic cytokine that has been reported to influence several parameters of thyroid hormone metabolism in vitro and in vivo (8, 11, 12). In healthy subjects, serum IL-6 is undetectable, whereas it was elevated in many patients with nonthyroidal illnesses. The serum IL-6 concentration inversely correlates with serum T3 in a number of NTIS states (12, 13, 14). Administration of recombinant human IL-6 (rhIL-6) to experimental animals results in alterations in thyroid function (15, 16). Acute administration of rhIL-6 (sc or 4-h iv infusion) in humans resulted in decreased serum T3 after 3 h in cancerous patients (17) and after 24 h in healthy volunteers (18). Chronic administration (6 wk) of rhIL-6 in human volunteers did not produce significant alterations in serum thyroid hormone levels (17). The administration of rhIL-6 is followed by symptoms reminiscent of systemic illness, and it is unclear whether the observed alterations in thyroid hormone metabolism and TSH secretion are the result of illness induced by cytokines or an effect of cytokines per se. Furthermore, the association of serum thyroid hormone changes with circulating cytokine levels in systemic disease has been observed long after the initiation of the illness, and it is not known whether the decrease in serum T3 preceded, accompanied, or followed the increase in serum IL-6 or TNF{alpha} concentrations.

Alterations of thyroid hormone metabolism have been observed after various surgical procedures (19, 20, 21, 22, 23), an experimental form of NTIS in humans. It has been reported that the IL-6 concentration in the portal vein and peripheral vein blood increases rapidly after abdominal surgery (24, 25, 26). We therefore undertook a detailed study in humans to examine the acute effects of a form of NTIS, such as elective surgery, on the hypothalamic-pituitary-thyroid axis and whether the endogenous production of the cytokines, IL-6 and TNF{alpha}, induced by elective abdominal surgery precedes, accompanies, or follows the early alterations in serum thyroid hormone concentration observed in NTIS.

Materials and Methods

Nineteen healthy subjects (5 males and 14 females), aged 46 ± 13 yr, were programmed for elective abdominal operation. None of the subjects was receiving any medication and/or had any evidence of acute, chronic, or endocrine disease. All patients were maintained on a free diet before admission to the hospital. Ten underwent open cholocystectomy for cholelithiasis without acute inflammation (eight women and two men; body mass index, 27.5 ± 1) and nine (six women and three men; body mass index, 49 ± 10) underwent abdominal surgery for morbid obesity (vertical banded gastroplasty or gastric bypass Roux-en-Y). Patients received general anesthesia, and the same protocol was applied to all. The induction of anesthesia was obtained by iv administration of 3 mg midazolame, 1–3 µg/kg fentanyl, 0.08–0.1 mg/kg vecuronium, and 1.5–2.5 mg/kg propofol. Core temperature was obtained by a Folley catheter with temperature sensor (Thermistor L100 series, YSI, Inc., Yellow Springs, OH). Normal volume was maintained by administering ringer solution iv. The anesthesia was maintained with inhaled O2/N2O (1:2), isoflurane (0.5–1.5%), and iv fentanyl (1–2 µg/kg·h) and vecuronium (0.02–0.03 mg/kg). Epidural analgesia was given to patients who underwent abdominal surgery for morbid obesity. All subjects were admitted to the hospital the day before surgery, and food was withheld after 2000 h. The operation commenced at 0800 h the next morning. Serum samples were collected by an iv catheter as follows: upon admission to the hospital (-24 h), upon entrance to the operating room (-1 h), at the induction of anesthesia (-0.5 h), at the time of skin incision (0 h), and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 30, 36, and 42 h thereafter. To prevent the effects of food deprivation on serum T3, total parenteral nutrition of 2000 kCal/d was administered (1 g/kg BW protein and the rest of calories equally divided between carbohydrates and fat) during the experimental period beginning immediately after surgery. During the operation a 5% dextrose solution was administered in a volume of 500 ml. We measured total T3, free T3 (FT3), total T4, free T4 (FT4), rT3, cortisol, IL-6, and TNF{alpha}. In seven healthy volunteers matched to the cholocystectomy group (three men and four women, aged 40 ± 5 yr) after an overnight fast, 50 ml normal saline were injected at 0800 h, blood was drown at -15, 0, 30, 60, 90, and 120 min thereafter, and serum T3 was measured. The protocol was approved by the ethics committee of the hospital. Informed consent was obtained from all patients.

Hormone assays

Blood samples were collected, and serum was stored in aliquots at -20 C, until assayed. T3, T4, and TSH were measured within one run for each subject by semiautomatic analyzer IMX (Abbott, Chicago, IL). Serum rT3, FT3, FT4, cortisol, IL-6, and TNF{alpha} were measured in duplicate within one assay for each subject using commercial available RIAs or ELISAs. Serum FT3 was measured with the Clinical Assays GammaCoat RIA kit (INCSTAR Corp., Stillwater, MN) (27). Serum FT4 was measured by the Clinical Assays GammaCoat (two-step) RIA kit, manufactured by INCSTAR Corp. (28). Serum rT3 was measured by an RIA kit from Biodata S.p.A. (Rome, Italy). Serum cortisol was measured by a Clinical Assays GammaCoat RIA kit (INCSTAR Corp., Stillwater, MN). Serum IL-6 and TNF{alpha} were measured with a Quantikine ELISA kit from R & D Systems, Inc. (Minneapolis, MN). The lowest detectable values for IL-6 and TNF{alpha} were 3.1 and 0.5 pg/ml, respectively. Intra- and interassay coefficients of variation were less than 10% for all assays.

Statistics

All values are expressed as the mean ± SD. The data were analyzed by ANOVA for repeated measures, followed by post-hoc analysis for pairwise comparisons, and were corrected by Tukey test or paired t test when indicated. Regression analysis was performed to obtain T3 curve estimation. To compare percentages of increase or decrease at specific points in time between groups, we used t test for the proportion of the mean difference. Significance was accepted at P < 0.05. Analyses were performed with SPSS software version 9.0 (SPSS, Inc., Chicago, IL).

Results

Serum T3

Serum T3 hormone changes are shown in Fig. 1Go, expressed as percent changes from baseline, and in Table 1Go, where the absolute values are given for the first 6 h after surgery. The alterations in serum T3 during the observational period were significant (df = 18; F = 345.8; P < 0.04). The serum T3 concentration decreased rapidly 30 min before skin incision from a baseline value of 1.56 ± 0.3 to 1.33 ± 0.2 nmol/liter (P < 0.05), reaching a value of 1.16 ± 0.2 nmol/liter within 2 h after skin incision (P < 0.001, by ANOVA). Inspecting the linearity of the T3 curve for the first 24 h, we observed three distinctive parts. An early part from -1 to 0.5 h after surgery [slope = -0.118 ± 0.017 (±SE); r2 = 0.95; P < 0.03], a second part from 1–8 h after surgery with essentially no slope (slope = -0.006 ± 0.003; r2 =0.63; P > 0.05), and a late part from 10–24 h (slope = -0.01± 0.002; r2 = 0.79; P < 0.03).



View larger version (12K):
[in this window]
[in a new window]
  		Figure 1. Serum T3 and IL-6 concentrations in the study subjects. Values are percent changes from the baseline. Left, T3; right, IL-6.

 

View this table:
[in this window]
[in a new window]
  		Table 1. Serum concentrations of total and free thyroid hormone, TSH, and cortisol

 
The early changes in serum T3 in the study group reflect true changes, as normal controls injected with 50 ml saline solution and sampled every 30 min from 0800–1000 h displayed a decline in T3 from 5–7%. In particular, the magnitude of the changes in serum T3 samples taken from -15 to 120 min every 30 min was lower in the study group than in the control group at each time point (P < 0.05). Serum FT3 followed a similar pattern as T3 (Table 1Go).

When the group subjected to cholecystectomy was compared with the group subjected to gastroplasty, the decline in T3 was more pronounced in the latter, probably due to more severe surgical stress in these patients (Fig. 4Go).



View larger version (22K):
[in this window]
[in a new window]
  		Figure 4. Serum T3, TSH, T4, rT3, and cortisol in normal weight subjects subjected to cholecystectomy (NWS) and obese patients subjected to gastroplasty (MOS). Values are percent changes from the baseline.

 
Serum T4

The serum T4 concentration increased by 10% 1 h after skin incision from a baseline value of 106 ± 19 to 117 ± 19 nmol/liter (P < 0.001), remained high for the next 3 h, and returned to baseline 6 h after the skin incision (Table 1Go). A second increase was noted 12 h after the skin incision, which lasted until the end of the observational period. (Fig. 4Go). Serum FT4 increased 1 h after the skin incision from a baseline value of 20 ± 3.3 to 25 ± 4.6 pmol/liter (P < 0.001) and remained high thereafter (Table 1Go).

When patients subjected to cholecystectomy were compared with patients subjected to gastroplasty, the rise in serum T4 was more pronounced in the latter, but did not reach statistical significance (Fig. 4Go).

Serum rT3

Serum rT3 increased 6 h after the initiation of the surgery from a baseline value of 0.43 ± 0.8 to 0.49 ± 0.1 nmol/liter (P < 0.02; Table 1Go) and remained elevated throughout the study period (Fig. 4Go). As shown in Table 1Go and Fig. 4Go, the increase in serum rT3 was delayed 6 h after skin incision in all patients and did not follow the early decrease in serum T3.

Serum TSH

Serum TSH increased upon admission to the operating room from a baseline value of 1.21 ± 0.65 to 1.47 ± 0.76 mU/liter (P < 0.001). A more pronounced and prolonged increase was observed 0.5 h after skin incision and lasted approximately 2 h (Table 1Go and Figs. 2Go and 4Go). The rise in serum TSH was similar in patients subjected to cholecystectomy and those with gastroplasty. This increase preceded the observed attenuation of the fall in serum T3, seen from approximately 2–8 h after surgery. We also observed loss of the normal nocturnal peak of TSH the day of the operation, which was restored the first postoperative day (Fig. 2Go). The mean core temperature decreased to 35.5 ± 0.1 C in all patients.



View larger version (12K):
[in this window]
[in a new window]
  		Figure 2. Serum TSH and serum T3 values in the study subjects. Values are percent changes from the baseline value.

 
Serum cortisol

Serum cortisol increased 63% above the baseline upon admission to the operating room from a baseline of 350 ± 168 to 571 ± 190 nmol/liter (P < 0.001) and remained high throughout the observation period (Table 1Go and Fig. 3Go). The epidural analgesia administered to obese subjects did not prevent the brisk response of cortisol to surgical stress, but was less pronounced compared with that in lean patients (Fig. 4Go).



View larger version (13K):
[in this window]
[in a new window]
  		Figure 3. Serum T3 and serum cortisol values in the study subjects. Values are percent changes from the baseline. Left, Serum T3; right, serum cortisol.

 
Serum IL-6 and TNF{alpha}

Baseline serum IL-6 was measured in 11 patients. It was in the range of detectability (3.1 pg/ml) in four and was undetectable in seven (Table 2Go). An increase in serum IL-6 to 20.1 ± 17.7 pg/ml was observed 2 h after the skin incision (P < 0.001). IL-6 continued to increase until 6 h, reaching a level of 10–253 pg/ml and then decreased to 10–72 pg/ml by 18 h postskin incision and remained at that level for the remainder of the observation period (Fig. 1Go).


View this table:
[in this window]
[in a new window]
  		Table 2. Serum concentration of IL-6 (picograms per ml)

 
Serum TNF{alpha} was measured in 11 patients. It was barely detectable in 5 obese patients and was undetectable (<0.5 pg/ml) in 6. Serum TNF{alpha} remained at the same level for each subject before and after surgery.

Discussion

To our knowledge, this is the first detailed study in humans in which we examined the relation of the serum IL-6 rise and the early fall in serum T3 in patients subjected to elective surgery when assessed in a disease state that appears to be a suitable model of the acute form of NTIS. Our findings clearly demonstrate that the acute increase in serum IL-6 was not related to the fall in serum T3, at least in the early hours. The decrease in serum T3, was observed 30 min before the skin incision and continued gradually to decrease until 2 h after skin incision, whereas IL-6 remained essentially undetectable and appeared in the systemic circulation approximately 2 h after surgery.

The cause of the observed early fall in serum T3 is not readily apparent. This is not due to circadian variation, as in seven healthy volunteers examined at the same time period (0800–1000 h), the magnitude of the fall in serum T3 was smaller (5–7%) than that in the study group (20%). The former is consonant with the findings of Torpy et al. (18), who reported similar changes after saline administration to normal subjects. The expansion of blood volume or fasting does not explain the decrease in serum T3, because the patients received no blood transfusion during the operation, and the volume was replaced according to measured minimal losses. Moreover, T4 and FT4 did not decrease, but, rather, increased. This may be due to anesthesia and to an increase in serum TSH (29, 30). Food deprivation for 14 h, as expected, had no effect on serum T3 or FT3 (31), and therefore, in our patients had no effect on serum T3, as the caloric deprivation lasted 10 h, from 2000–0800 h. Total parenteral nutrition started after surgery had no effect on the decline in serum FT3 in patients subjected to cholecystectomy (32).

Previous studies have examined the effects of increased serum IL-6 concentration on the hypothalamic-pituitary- thyroid axis in various states of NTIS. It was invariably found that in these states, serum T3 levels were inversely related to serum IL-6 concentration (12, 13, 14). However, these studies were cross-sectional, and the serum samples were taken long after the initiation of systemic illness, when both serum T3 and IL-6 concentrations had already been affected by the illness. In an attempt to correlate the serum IL-6 concentration with the fall in serum T3 in humans, Murai et al. (23) reported that surgical procedures resulted in an increase in IL-6 and a fall in T3 12 h after skin incision. Welby et al. (22) studied in detail the relation of serum T3 to IL-6 in the early hours after surgery. They concluded that the early changes in thyroid hormones do not appear to be caused by changes in IL-6 concentrations. This conclusion is consonant with our findings. Inspecting their data, it is apparent that they did not measure serum IL-6 levels and serum T3 the first 4 h after the induction of anesthesia. This was evaluated in our study, which demonstrated that the fall in T3 precedes the increase in the appearance of IL-6 in serum.

Inspecting the course of the fall of serum T3 at various time intervals after admission to the operating room, we noticed that after the early fall in serum T3, the decline was attenuated and followed by a prolonged second decline. The most suitable explanation for the attenuation of the decrease in serum T3 was the marked early increase in TSH secretion, probably induced by TRH release resulting from a drop in core temperature, probably induced by the anesthesia. An early TSH surge was also reported during surgery by Welby et al. (22). It is known that the TSH surge after TRH administration increases serum concentrations of thyroid hormones 3–8 h thereafter (33). The simultaneous increase in serum IL-6 could not be responsible for the attenuation of the decrease in serum T3. It has been reported (18) that sc administration of rhIL-6 in normal individuals affects the serum T3 concentration for at least 24 h thereafter and has an accelerating, rather than attenuating, effect on the decline in serum T3 concentration.

The late fall in serum T3 displayed a similar pattern to the early fall. This is judged from the almost identical slopes of the T3 decrease in the early and late first 24-h period. As IL-6 was not detectable in serum in the early phase, obviously IL-6 had no effect on the early decline in T3, as has been previously discussed. The dramatic increase in serum IL-6, which peaked 6 h postsurgery, could have an effect by accelerating the late fall of T3. However, this was not observed, as indicated by the almost identical slopes of the early and late parts of the serum T3 curve, suggesting that IL-6 had a minimal, if any, role in the decline in serum T3 for the first 24 h. These conclusions are in agreement with the data reported by Torpy et al. (18) and Boelen et al. (34). Torpy et al. reported that the sc administration of rhIL-6 in healthy humans resulted in a decrease in serum T3 24 h thereafter. Unfortunately, serum T3 values from 6–24 h were not reported in their study, and serum levels of the injected IL-6 were elevated. Boelen et al. (34) reported that IL-6 knockout mice displayed a decrease in serum T3 despite the complete lack of IL-6 in these animals.

It has been reported that TNF{alpha} may be responsible for the low serum T3 in NTIS (2, 3, 4, 5, 6). In animals, the administration of recombinant TNF{alpha} resulted in a decrease in serum T3 and T4, unchanged rT3, decreased or unchanged TSH secretion, and conflicting findings for 5'-deiodinase activity (11). In humans with various NTIS, serum TNF{alpha} was either increased (35, 36) or normal (37). Administration of recombinant TNF{alpha} to normal individuals mimicked the alterations in serum thyroid hormones observed in patients with NTIS (38). In our study the serum TNF{alpha} concentration was barely detectable in five patients and was undetectable in six, and it did not change during the 42 h of observation. Similar findings have been reported by others (24, 25). Therefore, TNF{alpha} could not be incriminated in the low T3 syndrome, at least in surgical patients, although rapid clearance from the circulation cannot be excluded (7).

Glucocorticoids can affect thyroid function in many ways, and it is known that glucocorticoid levels are increased in surgical and other stresses. They inhibit type 5'-deiodinase activity and have been associated with decreased serum T3, elevated serum rT3, and suppressed serum TSH levels (1). In our study the inhibitory effects of cortisol on TSH secretion were not exerted due to stress and anesthesia. In some reports the fall in serum T3 in surgical stress was not associated with the increased cortisol levels, as epidural analgesia blocked the cortisol secretion, but did not prevent the decrease in serum T3 (39, 40). These findings were not confirmed by others (41). In the obese patients the response of cortisol to surgical stress was less pronounced, probably due to epidural analgesia. It should be noted, however, that the fall in serum T3 was more pronounced in obese patients, suggesting that factors in addition to cortisol operate in surgical patients.

Our findings suggest that the increased cortisol levels induced by psychological and surgical stress may explain at least in part the decline in serum T3. In our patients serum cortisol was increased long before the appearance of IL-6 in the circulation, almost simultaneously with the beginning of the decline in serum T3. This suggests that cortisol might have an effect on serum T3 independent of IL-6, and that the effects of IL-6 on serum T3, if any, are late and might be additive via its action on cortisol secretion.

In conclusion, the fall in serum T3 in surgical patients early in the course of the disease is not due to IL-6 or TNF{alpha} production or to TSH suppression. On the contrary, a sharp increase in TSH secretion occurs, leading to T3 and T4 secretion from the thyroid and therefore attenuating the fall in serum T3 and increasing serum T4. Whether this pattern is seen in other acute states of NTIS remains to be seen. The effects of glucocorticoids on peripheral thyroid hormone metabolism may at least in part explain the observed fall in serum T3 in NTIS, although the exact mechanism still remains elusive.

Acknowledgments

Footnotes

This work was supported by the K. Karatheodoris Grant from the research committee, University of Patras.

Abbreviations: FT3, Free T3; FT4, free T4; NTIS, nonthyroidal illness syndrome; rhIL-6, recombinant human IL-6.

Received January 9, 2001.

Accepted May 15, 2001.

References

  1. Wartofsky L, Burman KD 1982 Alterations in thyroid function in patients with systemic illness: the "euthyroid sick syndrome." Endocr Rev 3:164–217[Abstract/Free Full Text]
  2. Docter R, Krenning EP, de Jong M, Hennemann G 1993 The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 39:499–518[Medline]
  3. Vagenakis AG 1997 Alterations of thyroid function in non thyroidal illness: the euthyroid sick syndrome. In: Grossman A, ed. Clinical endocrinology, 2nd Ed. London: Blackwell; 383–391
  4. Chopra IJ 1997 Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab 82:329–334[Free Full Text]
  5. De Groot LJ 1999 Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 84:151–164[Free Full Text]
  6. Van den Berghe G 1998 Novel insights into the neuroendocrinology of critical illness. Eur J Endocrinol 143:1–13
  7. Wiersinga WM, Boelen A 1996 Thyroid hormone metabolism in nonthyroidal illness. Curr Opin Endocrinol Diabetes 3:422–427
  8. Bartalena L, Brogioni S, Grasso L, Martino E 1995 Interleukin-6 and the thyroid. Eur J Endocrinol 132:386–393[Abstract/Free Full Text]
  9. Oppenheimer JH, Squef R, Surks MI, Hauer H 1963 Bindings of thyroxine by serum proteins evaluated by equilibrium dialysis and electrophoretic techniques: alterations in non thyroidal disease. J Clin Invest 42:1769–1782
  10. Chopra IJ, Chopra U, Smith SR, Reza M, Solomon DH 1975 Reciprocal changes in serum concentrations of 3, 3', 5' triidothyronine (reverse T3) and 3,3',5-triidothyronine (T3) in systemic illnesses. J Clin Endocrinol Metab 41:1043–1049[Abstract/Free Full Text]
  11. Bartalena L, Bogazzi F, Brogioni S, Grasso L, Martino E 1998 Role of cytokines in the pathogenesis of the euthyroid sick syndrome. Eur J Endocrinol 138:603–614[CrossRef][Medline]
  12. Boelen A, Platvoet-Ter Schiphorst MC, Wiersinga WM 1993 Association between serum interleukin-6 and serum 3,5,3'-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab 77:1695–1699[Abstract]
  13. Bartalena L, Brogioni S, Grasso L, Velluzi F, Martino E 1994 Relationship of the increased serum interleukin-6 concentration to changes of thyroid function in nonthyroidal illness. J Endocrinol Invest 17:269–274[Medline]
  14. Davies PH, Black EG, Sheppard MC, Franklyn JA 1996 Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital in-patients with nonthyroidal illness. Clin Endocrinol (Oxf) 44:199–205[CrossRef][Medline]
  15. Bartalena L, Grasso L, Brogioni S, Martino E 1994 Interleukin-6 effects on the pituitary-thyroid axis in the rat. Eur J Endocrinol 131:302–306[Abstract/Free Full Text]
  16. Van Haasteren GA, Van der Meer MJ, Hermus AR, et al. 1994 Different effects of continuous infusion of interleukin-1 and interleukin-6 on the hypothalamic-hypophysial-thyroidal axis. Endocrinology 135:1336–1345[Abstract]
  17. Stouthard JML, Van der Poll T, Endert E, et al. 1994 Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab 79:1342–1346[Abstract]
  18. Torpy DJ, Tsigos C, Lotsikas AJ, Defensor R, Chrousos GP, Papanikolaou DA 1998 Acute and delayed effects of single-dose injection of interleukin-6 on thyroid function in healthy humans. Metabolism 47:1289–1293[CrossRef][Medline]
  19. Cherem JH, Hummel HN, Barabejski FG, Martinez BAC, Guinzberg AL 1992 Thyroid function and abdominal surgery. A longitudinal study. Arch Med Res 23:143–147
  20. Legakis IN, Golematis BC, Dourakis N, Lymberopoulou I, Mountokalakis T, Leandros EA 1998 Low T3 syndrome with asynchronous changes of TT3 and rT3 values in laparoscopic cholocystectomy. Endocr Res 24:205–213[Medline]
  21. Reinhardt W, Mocker V, Jockenhuvel F, et al. 1997 Influence of coronary artery bypass surgery on thyroid hormone parameters. Horm Res 47:1–8[Medline]
  22. Welby ML, Kennedy JA, Barrean PB, Roediger WEW 1994 Endocrine and cytokine changes during elective surgery. J Clin Pathol 47:1049–1051[Abstract/Free Full Text]
  23. Murai H, Murakami S, Ishida K, Sugawara M 1996 Elevated serum interleukin-6 and decreased thyroid hormone levels in postoperative patients and effects of IL-6 on thyroid cell function in vitro. Thyroid 6:601–606[Medline]
  24. Wortel CH, Van Deventer SJH, Aarden LA, et al. 1993 Interleukin-6 mediates host defense responses induced by abdominal surgery. Surgery 114:564–570[Medline]
  25. Baigrie RJ, Lamont PM, Kwiatkowski D, Dallman MJ, Morris PJ 1992 Systemic cytokine response after major surgery. Br J Surg 79:757–760[Medline]
  26. Ohzato H, Yoshizaki K, Nishimoto N, et al. 1992 Interleukin-6 as new indicator of inflammatory status: detection of serum levels of interleukin-6 and C-reactive protein after surgery. Surgery 111:201–209[Medline]
  27. Vermaak WJH, Kalk WJ, Kuyl JM, Smit AM 1986 Fatty acid induced changes in circulating total and free thyroid hormones: in vivo effects and methodological artefacts. J Endocrinol Invest 9:121–126[Medline]
  28. Kaptein EM, Macintyre SS, Weiner JM, Spencer CA, Nicoloff JT 1981 Free thyroxine estimates in non-thyroidal illness: comparison of eight methods. J Clin Endocrinol Metab 52:1073–1077[Abstract/Free Full Text]
  29. Redondo M, Rubio V, de la Pena A, Morell M 1997 The effects of the degree of surgical trauma and glucose load concentration on thyrotropin, growth hormone and prolactin under enflurane anesthesia. Horm Metab Res 29:66–69[Medline]
  30. Chikenji T, Mizutani M, Kitsukawa Y 1990 Anaesthesia, not surgical stress, induces increases in serum concentrations of reverse triiodothyronine and thyroxine during surgery. Exp Clin Endocrinol 95:217–223[Medline]
  31. Spencer CA, Lum SM, Wilber JF, Kaptein EM, Nicoloff JT 1983 Dynamics of serum thyrotropin and thyroid hormone changes in fasting. J Clin Endocrinol Metab 56:883–888[Abstract/Free Full Text]
  32. Eliman A, Tjader I, Norgen S, et al. 2001 Total parenteral nutrition after surgery rapidly increases serum leptin levels. Eur J Endocrinol 144:123–128[Abstract]
  33. Scanlon MF 1991 Neuroendocrine control of thyrotropin secretion. In: Braverman L, Utiger R, eds. The thyroid. Philadelphia: Lippincott Williams and Wilkins; 230–256
  34. Boelen A, Maas MA, Lowik CW, Platvoet MC, Wiersinga WM 1996 Induced illness in interleukin-6 (IL-6) knock-out mice: a causal role in the development of the low 3,5,3'-triiodothyronine syndrome. Endocrinology 137:5250–5254[Abstract]
  35. Mooradian AG, Reed RL, Osterweil D, Schiffman R, Scuderi P 1990 Decreased serum triiodothyronine is associated with increased concentrations of tumor necrosis factor. J Clin Endocrinol Metab 71:1239–1242[Abstract/Free Full Text]
  36. Reincke M, Allolio B, Petzke F, et al. 1993 Thyroid dysfunction in african trypanosomiasis: a possible role for inflammatory cytokines. Clin Endocrinol (Oxf) 39:455–461[Medline]
  37. Chopra IJ, Sakane S, Chua Teco GN 1991 A study of the serum concetration of tumor necrosis factor-a in thyroidal and nonthyroidal illnesses. J Clin Endocrinol Metab 72:1113–1116[Abstract/Free Full Text]
  38. Van der Poll, Romijn JA, Wiersinga WM, Sauerwein HP 1990 Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab 71:1567–1572[Abstract/Free Full Text]
  39. Brandt MR, Kehlet H, Skovsted L, Hansen JM 1976 Rapid decrease in plasma-triiodothyronine during surgery and epidural analgesia independent of afferent neurogenic stimuli and cortisol. Lancet 2:1333–1336[Medline]
  40. Rutberg H, Anderberg B, Hekanson E, Jorfeldt L, Kegedal B, Tegler L 1985 Influence of extradural blockade on serum thyroid hormone concentrations after surgery. Acta Chir Scand 151:97–103[Medline]
  41. Rao MV, Chari P, Malhotra SK, Dash RJ 1990 Role of epidural analgesia on endocrine and metabolic responses to surgery. Indian J Med Res 92:13–16[Medline]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
L. Mebis, L. Langouche, T. J. Visser, and G. Van den Berghe
The Type II Iodothyronine Deiodinase Is Up-Regulated in Skeletal Muscle during Prolonged Critical Illness
J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3330 - 3333.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Michalaki, M.
Right arrow Articles by Kyriazopoulou, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Michalaki, M.
Right arrow Articles by Kyriazopoulou, V.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals