Association between serum interleukin-6 and serum 3,5,3'-triiodothyronine in nonthyroidal illness

Increased serum concentrations of FFA, bilirubin, and carboxyl-methyl-propyl-furanpropionic acid, accumulating in chronic renal failure in direct relationship with serum creatinine, have all been implicated in the pathogenesis of the low T3 syndrome during illness. Cytokines may also be involved in the sick euthyroid syndrome. In contrast to interleukin-1 (IL-1) and tumor necrosis factor-alpha, IL-6 is usually detectable in serum during illness and acts as a systemic hormone. We studied the association between serum T3 and IL-6 in consecutive hospital admissions with a wide variety of medical conditions. Patients were divided into group A (T3, > or = 1.30 nmol/L; T4, > or = 75 nmol/L; n = 41), group B (T3, or = 75 nmol/L; n = 46), and group C (T3, <1.30 nmol/L; T4, <75 nmol/L; n = 13). Serum IL-6 levels in groups C and B were higher than those in group A (median values 59, 39, and 9 U/mL, respectively; P <0.01). Serum creatinine and bilirubin/albumin ratios were similar in the three groups, but the FFA/albumin ratio in group C was higher than in group A (P <0.05). When all patients were analyzed together, serum T3 was negatively correlated to serum IL-6 (r = -0.56; P <0.001), bilirubin/albumin ratio (r = -0.29; P = 0.004), and FFA/albumin ratio (r = -0.21; P = 0.03), but not with creatinine (r = -0.16; P = 0.11). Stepwise multiple regression resulted in the following equation: serum T3 = 2.13-0.18ln(IL-6)-0.15ln(creatinine)-0.094ln(bilirubin /albumin) (r = 0.61). The variability in serum T3 was accounted for 28% by ln(IL-6), 5% by ln(creatinine), and 4% by ln(bilirubin/albumin). FFA/albumin did not contribute in this respect. We conclude that the low T3 syndrome in nonthyroidial illness is associated with high serum IL-6 levels. However, even when IL-6 is assumed to play a causative role, the variation of serum T3 in NTI-patients remains largely unexplaine

The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice

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 (TNF alpha), interleukin-1 (IL-1 alpha), interleukin-6 (IL-6) and interferon-gamma (IFN gamma). When compared with pair-fed controls, a single dose of LPS resulted in (a) systemic illness, (b) induction of TNF alpha and IL-6 and (c) a decrease of liver 5'-deiodinase mRNA from 4 h onwards followed by a decrease of serum tri-iodothyronine (T3) and thyroxine (T4) at 8 h and of serum free T3 (fT3) and free T4 (fT4) at 24 h; serum TSH remained unchanged. We then studied whether a single dose or a combination of IL-1 alpha, TNF alpha, IL-6 or IFN gamma could induce the sick euthyroid syndrome in mice, again using pair-fed controls. None of the cytokines except IL-1 alpha caused systemic illness, and IL-1 alpha was the only cytokine that decreased liver 5'-deiodinase mRNA transiently. IL-1 alpha, TNF alpha or IL-6 did not decrease serum T3, T4 and TSH, but administration of IFN gamma decreased serum T4, T3 and fT3 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.(ABSTRACT TRUNCATED AT 250 WORDS

A survey of iodine intake and thyroid volume in Dutch schoolchildren: reference values in an iodine-sufficient area and the effect of puberty

Iodine deficiency and endemic goiter have been reported in the past in The Netherlands, especially in the southeast. To evaluate iodine intake and thyroid size in Dutch schoolchildren, contrasting those living in a formerly iodine-deficient region in the east (Doetinchem) with those living in an iodine-sufficient region in the west (Amsterdam area). Cross-sectional survey of 937 Dutch schoolchildren aged 6--18 years, of whom 390 lived in the eastern and 547 in the western part of the country. Thyroid size was assessed by inspection and palpation as well as by ultrasound. Iodine intake was evaluated by questionnaires on dietary habits and by measurement of urinary iodine concentration. Eastern and western regions were similar with respect to median urinary iodine concentration (15.7 and 15.3 microg/dl, NS, Mann-Whitney U test), goiter prevalence by inspection and palpation (0.8 and 2.6%, P=0.08, chi-squared test), and thyroid volumes. The P97.5 values of thyroid volumes per age and body surface area group were all lower than the corresponding sex-specific normative WHO reference values. Iodized salt was not used by 45.7% of households. Daily bread consumption was five slices by boys and four slices by girls. Weekly milk consumption was 3 liters by boys and 2 liters by girls. Seafish was consumed once monthly. From these figures we calculated a mean daily iodine intake of 171 microg in boys and 143 microg in girls, in good agreement with the measured median urinary concentration of 16.7 microg/dl in boys and 14.5 microg/dl in girls. The sex difference in iodine excretion is fully accounted for by an extra daily consumption of one slice of bread (20 microg I) and one-seventh of a liter of milk (8.3 microg I) by boys. Thyroid volume increases with age, but a steep increase by 41% was observed in girls between 11 and 12 years, and by 55% in boys between 13 and 14 years, coinciding with peak height velocity. Girls have a larger thyroid volume at the ages of 12 and 13 years, but thyroid volume is larger in boys as of the age of 14 years. (1) Iodine deficiency disorders no longer exist in The Netherlands. (2) Bread consumption remains the main source of dietary iodine in The Netherlands; the contribution of iodized table salt and seafish is limited. (3) The earlier onset of puberty in girls renders their thyroid volume larger than in boys at the age of 12--13 years, but boys have a larger thyroid volume as of the age of 14 year

Skeletal muscle deiodinase type 2 regulation during illness in mice

We have previously shown that skeletal muscle deiodinase type 2 (D2) mRNA (listed as Dio2 in MGI Database) is up-regulated in an animal model of acute illness. However, human Studies on the expression Of muscle D2 during illness report conflicting data. Therefore, we evaluated the expression of skeletal Muscle D2 and D2-regulating factors in two mouse models OF illness that differ in timing and severity of illness: 1) turpentine-iuduced inflammation, and 2) Streptococcus pneumoniae infection. During tupentine-induced inflammation, D2 mRNA and activity increased compared to pair-fed controls, most prominently at day I and 2, whereas after S. pneumoniae infection D2 mRNA decreased. We evaluated the association of D2 expression with scrum thyroid hormones, (de-)ubiquitinating enzymes ubiquitin-specific peptidase 33 and WD repeat and SOCS box-containing 1 (Wsb1) cytokine expression and activation of inflammatory pathways and cAMP pathways During chronic inflammation the increased muscle D2 expression is associated with the activation of the cAMP pathway. The normalization of D2 5 days after turpentine injection coincides with increased Wsb1 and tumor necrosis factor a expression. Muscle iuterleukiu-1 beta (II1b) expression correlated with decreased D2 mRNA expression after S. pneumoniae infection. In conclusion, Muscle 02 expression is differentially regulated during illness, probably related to differences in the inflammatory response and type of pathology. D2 mRNA and activity increases in skeletal muscle during the acute phase Of chronic inflammation compared to pair-fed controls probably due to activation of the cAMP pathway. In contrast, muscle D2 mRNA decreases 48h after 1 severe bacterial infection, which is associated with local II1b mRNA expression and might also be due to diminished food-intake. Journal of Endocrinology (2009) 203, 263-27

TR(beta)1 protein is preferentially expressed in the pericentral zone of rat liver and exhibits marked diurnal variation

We investigated the distribution and diurnal variation of TR(beta)1 protein expression in liver with specific antibodies against TR(beta)1. Immunohistochemistry showed a zonal distribution of TR(beta)1 with maximum expression in the pericentral zone matching some known T(3)-responsive enzyme activities in the liver, such as glutamine synthetase, cholesterol 7alpha- hydroxylase, and spot 14. Combining immunohistochemistry and image analysis we found and quantified the same zonal distribution for 5'-deiodinase type 1 as for TR(beta)1. Western blot analysis revealed a profound diurnal variation for TR(beta)1 protein expression, with highest levels at the beginning of the dark period. TR(beta)1 diurnal variation partly overlaps with the T(3)-responsive genes, cholesterol 7alpha-hydroxylase and spot 14. Furthermore, TR(beta)1 distribution along the porto-central axis does not change during the day, indicating that the zonal expression of TR(beta)1 is stable. This is the first time that zonal distribution in liver has been demonstrated for a member of the nuclear receptor family. This finding together with the observed diurnal rhythm has major implications for interpreting and timing experiments concerning the TR and its downstream actions in live