Serum Free T4 Concentrations Research Articles

Lower Thyroid Compensatory Reserve of Rat Pups after Maternal Hypothyroidism: Correlation of Thyroid, Hepatic, and Cerebrocortical Biomarkers with Hippocampal Neurophysiology

The developing central nervous system of the fetus and neonate is recognized as very sensitive to maternal or gestational hypothyroidism. Despite this recognition, there is still a lack of data concerning the relationship between thyroid-related biomarkers and neurological outcomes. We used propylthiouracil administered at 0, 3, or 10 ppm in drinking water from gestational d 2 until weaning to create hypothyroid conditions to study the relationship between hypothalamic-pituitary-thyroid axis compensation and impaired neurodevelopment. In addition to serum T(3), T(4), free T(4), and TSH concentrations, cerebrocortical T(3) concentration (cT(3)), hepatic type I and cerebrocortical type II (D2) 5'-deiodinase activity, and thyroidal mRNA for thyroglobulin and sodium iodide symporter were measured. Extracellular recordings from the CA1 region in hippocampal slices were obtained from both postnatal d 21-32 (pups) and postnatal d 90-110 (adults) rats to assess neurophysiological effects. Thyroidal mRNA for thyroglobulin and sodium iodide symporter were increased in pups but not in dams. Both propylthiouracil doses increased cerebrocortical D2 activity approximately 5-fold in pups but only 10 ppm increased D2 activity in dams. In dams, cT(3) concentrations were maintained at 3 ppm but fell 75% at 10 ppm. cT(3) concentration in pups fell 50% at 3 ppm and more than 90% at 10 ppm. In both 3 and 10 ppm pups, hippocampal baseline synaptic activity correlated negatively with cerebrocortical D2 activity. In 3 ppm adults, impaired long-term potentiation was evident. In summary, during depletion of serum T(4), D2 activity served as a sensitive marker of tissue thyroid status, an indicator of the brain's compensatory response to maintain cT(3), and correlated with a neurophysiological outcome.

Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort

Thyroid hormone action influences many metabolic and synthetic processes, but the degree of regulation attributed to genes and environmental factors affecting normal variation remains controversial. We investigated the magnitude of the genetic and environmental determination of serum concentrations of free (f) T3, fT4, TSH and the fT4 x TSH product and their variation, in a large cohort of twin pairs. Female dizygous and monozygous twins (849 and 213 pairs, respectively) from the TwinsUK registry (mean age 45.5, range 18-80 years) were studied. Comparison of thyroid parameters within various groups showed no differences between smoking categories, and higher serum TSH and lower fT3 in subjects with positive thyroid antibodies. Using structural equation modelling, we estimated the heritable contribution to serum thyroid parameters (with 95% confidence intervals) to be 65% (58%-71%) for TSH, 65% (58%-71%) for the fT4 x TSH product, 39% (20%-55%) for fT4 and 23% (3%-41%) for fT3. We conclude that genetic regulation is a particularly important determinant of TSH and the fT4 x TSH product, and is a less important determinant of fT4 and fT3 concentrations in Caucasian women. These data from a large well-characterized cohort suggest that while there is a strong heritable contribution to serum TSH, variation in fT4 and fT3 concentrations may be less explained by genetic factors and more driven by environmental effects than previously thought.

Endocrine predictors of mortality in canine babesiosis caused by Babesia canis rossi

This prospective, cross-sectional, observational study was designed to determine the association between the hormones of the pituitary-adrenal and pituitary-thyroid axes and outcome in dogs with naturally occurring Babesia canis rossi babesiosis. Ninety-five dogs with canine babesiosis were studied and blood samples were obtained from the jugular vein in each dog prior to treatment at admission to hospital. Serum cortisol, adrenocorticotrophic hormone (ACTH), thyroxine, free thyroxine and thyrotropin (TSH) concentrations were measured. Diagnosis was confirmed by polymerase chain reaction and reverse line blot and dogs infected with Babesia canis vogeli or Ehrlichia canis were excluded. Three outcomes were defined: hospitalization with subsequent death ( n = 7); hospitalization followed by recovery ( n = 56); and treatment as an outpatient ( n = 32). Serum cortisol and ACTH concentrations were significantly higher in the dogs that died, compared to hospitalized dogs that survived and compared to dogs treated as outpatients. Serum T4 and free T4 concentrations were significantly lower in the dogs that died, compared to the hospitalized dogs that survived and compared to dogs treated as outpatients. Serum TSH concentrations were not significantly different between any of the groups. Mortality was significantly associated with high cortisol and high ACTH concentrations and with low T4 and fT4 concentrations in dogs suffering from B. canis rossi babesiosis.

Hyperthyroidism in molar pregnancy: Rapid preoperative preparation by plasmapheresis and complete improvement after evacuation

Human chorionic gonadotropin bears structural homology to pituitary thyrotropin. The extremely elevated levels of human chorionic gonadotropin in patients with molar pregnancy or other trophoblastic diseases can lead to hyperthyroidism. We describe a patient with molar pregnancy who had secondary hyperthyroidism prepared rapidly by plasmapheresis for surgery. The clinical picture improved dramatically after the first plasmapheresis. Three subsequent plasmapheresis provided a 75.1% decrease in serum free T3 concentrations and 63.9% free T4 concentrations and recovery after evacuation. This is the first use of plasmapheresis in rapid preparation of a patient who had secondary hyperthyroidism due to molar pregnancy.

Thyroglobulin Gene Mutations Producing Defective Intracellular Transport of Thyroglobulin Are Associated with Increased Thyroidal Type 2 Iodothyronine Deiodinase Activity

Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T3 (FT3) concentrations with disproportionately low free T4 (FT4) resulting in a high FT3/FT4 ratio. The mechanism of this change in FT3/FT4 ratio remains unknown. We hypothesize that increased type 2 iodothyronine deiodinase (D2) activity in the thyroid gland may explain the higher FT3/FT4 ratio that is frequently observed in patients with abnormal Tg synthesis. We recently identified a compound heterozygous patient (patient A) with a Tg G2356R mutation and one previously described (C1245R) that is known to cause a defect in intracellular transport of Tg. In the current study, after determining the abnormality caused by G2356R, we measured D2 activity as well as its mRNA level in the thyroid gland. We also measured the thyroidal D2 activity in three patients with Tg transport defect and in normal thyroid tissue. Morphological and biochemical analysis of the thyroid gland from patient A, complemented by a pulse-chase experiment, revealed that G2356R produces a defect in intracellular Tg transport. D2 activity but not type 1 deiodinase in thyroid glands of patients with abnormal Tg transport was significantly higher than in normal thyroid glands, whereas D2 mRNA level in patient A was comparable with that in normal thyroid glands. Furthermore, there was a positive correlation between D2 activity and FT3/FT4 ratios. Increased thyroidal D2 activity in the thyroid gland is responsible for the higher FT3/FT4 ratios in patients with defective intracellular Tg transport.

A Case of Down's Syndrome with Thyrotoxic Crisis

Patients with Down's syndrome have an increased prevalence of autoimmune disorders that affect both the endocrine and non-endocrine organs. The most common thyroid abnormality in Down's syndrome is subclinical hypothyroidism (12.5~32.5%). The occurrence of Down's syndrome in conjunction with hyperthyroidism is rare (0.6~2.5%). A 35-year old female was transferred to our hospital because of hypotension and mental change. She had suffered from a poor oral intake and general weakness for the previous 1 week. She had been admitted local hospital and was diagnosed as hyperthyroidism. On the third day after admission, she lost consciousness and was then transferred to University Hospital. Physical examination revealed hypotension (76/39 mmHg), sinus tachycardia (111/min) and tachypnea (28/min). The upward-outward slant of the palpebral fissures, epicanthal folds, low-set ears, short stature and clinodactyly were all identified. The thyroid gland was not enlarged and there was no evidence of ophthalmopathy. The serum free T4 concentration was 3.32 ng/dL, the T3 level was 212 ng/dL and the TSH level was 0.01 uIU/mL. She was positive for TBII. Abdominal computed tomography showed ascites and pneumoperitoneum. Primary closure was done on the duodenal ulcer perforation site. She was treated with transrectal propylthiouracil and intravenous esmolol. Chromosomal analysis revealed 47XX and 21 trisomy. She was finally diagnosed as Down's syndrome, Graves' disease and duodenal ulcer perforation. Her hyperthyroidism was controlled with PTU 100 mg after discharge.

Glucocorticoid Response in Amiodarone-Induced Thyrotoxicosis Resulting from Destructive Thyroiditis Is Predicted by Thyroid Volume and Serum Free Thyroid Hormone Concentrations

Amiodarone-induced thyrotoxicosis (AIT) resulting from destructive thyroiditis (type 2) is commonly treated with glucocorticoids, but time needed to restore euthyroidism may be unacceptable for patients with underlying cardiac disorders. The objective of this prospective study was to identify factors affecting the response to glucocorticoids in a large cohort of patients with type 2 AIT followed prospectively. This study was conducted at university centers. Sixty-six untreated patients with type 2 AIT were enrolled in the study. All patients were treated with prednisone (initial dose, 0.5 mg/kg.d) as long as needed to restore euthyroidism, defined as cure of AIT. The main outcome measure was cure time. The median cure time was 30 d (95% confidence interval, 23-37 d). Serum free T4 concentration (picograms per milliliter) and thyroid volume (milliliters per square meter) (and, to a lesser extent, serum free T3 concentration) at diagnosis were the main determinants of response to glucocorticoids, with a cure hazard ratio of 0.97 (95% confidence interval, 0.95-0.99; P = 0.005) and 0.84 (95% confidence interval, 0.77-0.91; P = 0.000) for unit of increment, respectively. AIT was cured in all patients with a complete follow-up; euthyroidism was reached in 30 d or less in 60% of patients but in more than 90 d in 16%. A prompt control of thyrotoxicosis (<or=30 d of treatment) was more frequent (77%) in patients with serum basal free T4 concentration no greater than 50 pg/ml and thyroid volume (normalized for body surface area) no greater than 12 ml/m2. The cure probability and the mean cure time in an individual patient can be obtained using a formula generated by multiple regression models. Baseline serum thyroid hormone concentrations and thyroid volume help identify patients with type 2 AIT at risk of a delayed response to glucocorticoids.

Long-term outcome of thyroid function after amiodarone-induced thyrotoxicosis, as compared to subacute thyroiditis

Two main forms of amiodarone- induced thyrotoxicosis (AIT) exist: type 1 AIT is a condition of true hyperthyroidism developing in patients with pre-existing thyroid disorders, and usually requires thyroid ablative treatment. On the other hand, type 2 AIT is a form of destructive thyroiditis occurring in normal thyroids, the management of which usually consists in glucocorticoid treatment. To assess the long-term outcome of thyroid function in a prospective study of type 2 AIT patients, as compared to patients with De Quervain's subacute thyroiditis (SAT). Sixty consecutive patients with type 2 AIT were evaluated during oral glucocorticoid treatment (oral prednisone 30 mg/day, gradually tapered and withdrawn over a 3-month period) and followed for 38+/-4 months (range 6-72) thereafter. Sixty consecutive patients with SAT, referred to our Institutes during the same period and treated with the same therapeutic schedule, served as controls. Type 2 AIT patients were older (p<0.0001) and showed a larger male preponderance (M:F 3.6:1 vs 0.5:1, p<0.0001) than SAT patients. Mean serum free T4 (FT4) and free T3 (FT3) concentrations at diagnosis were increased in both conditions, but higher in type 2 AIT than in SAT (FT4 47.6+/-18.8 and 29.6+/-8.3 pmol/l, respectively, p<0.0001; FT3 15.4+/-7.0 and 11.2+/-3.0 pmol/l, respectively, p<0.001). Correction of thyrotoxicosis was obtained in all patients in both groups, but restoration of euthyroidism occurred earlier in SAT than in type 2 AIT (p=0.006). Ten type 2 AIT patients (17%) and 3 SAT patients (5%, p<0.03) became permanently hypothyroid after glucocorticoid withdrawal and required levothyroxine replacement. A relevant proportion of type 2 AIT patients develop permanent hypothyroidism after correction of thyrotoxicosis. Thus, periodic surveillance of thyroid status is required after type 2 AIT.

Resting and exercise energy use in Antarctica: effect of 50% restriction in temperate climate energy requirements

To determine the impact of energy restriction (ER) upon the previously reported increased resting and exercise-related oxygen utilization, reduced body temperature, increased serum TSH, and reduced serum free T3 concentrations found during Antarctic residence (AR). Prospective, intervention with both paired controls and a similar reference control group (RG). Seven subjects were assessed before and after a 50% ER period of 60 h. This ER was carried out within 30 days of arriving in Antarctica in October (OCT) and again after 10 months AR in August (AUG). During the periods of ER, mean energy consumption was 5662 +/- 1344 kJ/day in OCT and 5529 +/- 967 kJ/day in AUG. Resting metabolic rate (RMR), a calculated resting metabolic rate (RMR(reg)) using a submaximal work regression, serum TSH, FT3 and tympanic temperature (Tty) were measured. These values were compared with a similar RG of 12 subjects reported previously who were studied in California, USA before and then again during AR. Weight declined by 1.1 +/- 0.1 kg/day (OCT) and 0.92 +/- 0.2 kg/day (AUG) with ER, resulting in a reduction of body weight by 3.1 +/- 0.4% in OCT (P = 0.0001) and 2.5 +/- 0.4% in AUG (P = 0.0015) during AR. The RMR before ER did not change with AR and it was not significantly different from the RG studied in California. With ER the RMR tended to decline in both OCT (132 +/- 5 to 122 +/- 4 mlO2/min/m2) and AUG (134 +/- 5 to 126 +/- 5 mlO2/min/m2), but these were not significant. By contrast, RMR(reg) obtained before ER was increased with AR by 22.5 +/- 7.8% (P = 0.01) in OCT and by 28.1 +/- 7.0% (P = 0.0008) in AUG over the RG values obtained in California. RMR(reg) did not decrease with ER in either OCT or AUG. The total energy expenditure derived from these measures of weight loss suggests that 24-h energy requirements are 74.4%[95% confidence interval (CI) 2.6-146.3; P < 0.05] more than those expected in temperate climates. Tty declined by 0.6 +/- 0.2 degrees C (P < 0.01) with AR compared with the RG measured in California, but was not affected by either period of ER. ER had no effect on FT3 but tended to decrease serum TSH in AUG (P = 0.06). Exercise-related energy requirements are increased with AR. Moderate ER may reduce resting but not exercise-related energy expenditure and it is associated with a weight loss exceeding expectations for 50% restriction of temperate climate energy predictions.

Effect of Long-Term Calorie Restriction with Adequate Protein and Micronutrients on Thyroid Hormones

Caloric restriction (CR) retards aging in mammals. It has been hypothesized that a reduction in T(3) hormone may increase life span by conserving energy and reducing free-radical production. The objective of the study was to assess the relationship between long-term CR with adequate protein and micronutrient intake on thyroid function in healthy lean weight-stable adult men and women. In this study, serum thyroid hormones were evaluated in 28 men and women (mean age, 52 +/- 12 yr) consuming a CR diet for 3-15 yr (6 +/- 3 yr), 28 age- and sex-matched sedentary (WD), and 28 body fat-matched exercising (EX) subjects who were eating Western diets. Serum total and free T(4), total and free T(3), reverse T(3), and TSH concentrations were the main outcome measures. Energy intake was lower in the CR group (1779 +/- 355 kcal/d) than the WD (2433 +/- 502 kcal/d) and EX (2811 +/- 711 kcal/d) groups (P < 0.001). Serum T(3) concentration was lower in the CR group than the WD and EX groups (73.6 +/- 22 vs. 91.0 +/- 13 vs. 94.3 +/- 17 ng/dl, respectively) (P < or = 0.001), whereas serum total and free T(4), reverse T(3), and TSH concentrations were similar among groups. Long-term CR with adequate protein and micronutrient intake in lean and weight-stable healthy humans is associated with a sustained reduction in serum T(3) concentration, similar to that found in CR rodents and monkeys. This effect is likely due to CR itself, rather than to a decrease in body fat mass, and could be involved in slowing the rate of aging.

A bioluminescence assay for thyrotropin receptor antibodies predicts serum thyroid hormone levels in patients with de novo Graves’ disease

TSH receptor antibodies (TBII) in Graves' disease (GD) may be TSH receptor stimulating (TSAb) and blocking (TBAb) antibodies. In commercially available assays however, only total TBII titres can be measured, without discriminating between TSAb and TBAb. To design a TBII bioassay to detect of TSAb and to correlate TSAb activity with severity of hyperthyroidism in de novo GD patients. Thirty-five patients with de novo GD and 27 controls. The JP-26-26 cell line, which constitutively expresses the TSH receptor (TSHR), was stably transfected with a cyclic adenosine monophosphate responsive element--luciferase construct. The clone B1 exhibited a near linear increase in luminescence from 0.2 mU/l to 50 mU/l bovine TSH and was used as a TBII bioassay. TBII, free T4 and TSH were measured in the sera of all patients and controls. In the sera of 35 GD patients, TBII titres did not correlate with serum free T4 concentrations. In contrast, a strong and highly significant correlation was found between TSHR stimulating activity (luminescence) as measured with the TBII bioassay and serum free T4 levels (R = 0.80, P < 0.001). Interestingly, the luminescence/TBII ratio had a wide range at low TBII titres, whereas high TBII titres were associated with a low degree of TSHR activation. The TBII bioassay also detected TBAb in GD patients who spontaneously developed hypothyroidism. The B1-TBII-bioassay as developed in our laboratory has a high sensitivity for the detection of TSAb in GD and predicts the severity of hyperthyroidism in untreated GD patients. In addition, we found that high TBII titres are associated with weak TSHR activation.

Lack of association between serum TSH or free T4 and body mass index in euthyroid subjects

There is ongoing debate regarding the influence of minor changes in thyroid status within the normal range and body mass index (BMI). Overt thyroid dysfunction is well recognized to affect weight, but the influence of minor perturbations of thyroid function remains unclear. To examine in euthyroid subjects the association of serum concentrations of TSH and free T4 within the normal range and BMI. To compare serum TSH and free T4 concentrations in nonobese and obese subjects. A cohort of 401 euthyroid subjects with normal serum TSH (361 females, 40 males, mean age 48.2 years) who had been referred to a Thyroid Clinic due to the presence of a thyroid nodule or goitre. Measurements of serum TSH and free T4 were recorded, together with BMI (calculated from weight and height). Associations between measures of TSH, free T4 and BMI were investigated. There was no association between either serum TSH or free T4 concentration when considered as a continuous variable and BMI, and no difference in BMI when subjects were categorized according to serum TSH or free T4. There was also no difference in serum TSH or free T4 between lean and obese euthyroid subjects. Evidence of thyroid autoimmunity indicated by the presence of antibodies to thyroid peroxidase was likewise not associated with a difference in BMI. This study provides no evidence for an association between thyroid status within the normal range and BMI.

Dysprealbuminemic Hyperthyroxinemia in a Patient with Hyperthyroid Graves Disease

Rare mutant forms of circulating albumin and prealbumin [transthyretin (TTR)] have increased binding affinity for thyroxine (T4). Patients with these variant plasma proteins, as a result of inherited mutations or as a paraneoplastic phenomenon, typically present with increased serum total T4 and, by some assay methodologies, an increased free T4 as well. Although these individuals are, in fact, euthyroid, nonspecific symptoms may lead to inappropriate treatment for hyperthyroidism. We present a 34-year-old woman in whom a mutant form of TTR with increased T4 binding affinity and coexisting Graves disease was present. Subsequent 131I therapy led to development of postablative hypothyroidism, which was obscured by her higher serum free T4 concentration. Circulating thyroid-binding globulin (TBG), albumin, and TTR concentrations were all within their respective reference limits. A T4-binding protein panel confirmed that TTR-bound T4 was significantly increased, whereas TBG- and albumin-bound T4 was normal, indicating that this patient had euthyroid dysprealbuminemic hyperthyroxinemia, which had been masked by the initial presentation of hyperthyroidism. These findings indicate that hypothyroidism can be masked by coexisting euthyroid dysprealbuminemic hyperthyroxinemia.

Atrial fibrillation in elderly patients after cardiac surgery: Postoperative hemodynamics and low postoperative serum triiodothyronine

The purpose of this study was to evaluate serum triiodothyronine levels as a trigger of postoperative atrial fibrillation (AF) in elderly patients undergoing cardiac surgery and to study the possible association of serum triiodothyronine levels with preoperative and postoperative hemodynamics. Prospective study. University hospital. Forty-six consecutive nonemergency patients 65 years or older undergoing cardiac surgery during 1999 to 2000 in Tampere University Hospital, Tampere, Finland. Free serum T3 concentration was used as a measure of serum triiodothyronine levels. Samples were taken preoperatively, on the fourth postoperative day, and at the 3-month follow-up. The hemodynamic state of the patients was estimated by whole-body impedance cardiography preoperatively, during the intensive care unit period, daily until the fourth postoperative day, and at the 3-month follow-up. AF occurred in 43% of the patients. The patients in the AF group had significantly more grafts (3.9 v 3.1, p = 0.02), and there was a small difference in age between the AF and non-AF groups (73 years v 69 years, p = 0.06). The free T3 concentration on the fourth postoperative day was significantly lower in the AF group (3.5 nmol/L v 4.6 nmol/L, p = 0.04). In logistic regression analysis, the independent predictors of AF were age, number of grafts, and serum free T3 concentration on the fourth postoperative day. In the group with low T3 concentration, the cardiac index was lower (1.4 v 1.8, p = 0.05) and the systemic vascular resistance index was higher (4,064 v 2,969, p = 0.04) but only immediately after the operation. Although the AF mostly appeared during the second to fourth postoperative days, there were no longer any differences in the hemodynamic state at that time. In a group of elderly patients undergoing cardiac surgery, there was a strong association between a postoperative decrease of serum triiodothyronine levels and atrial fibrillation. The decrease of serum triiodothyronine levels was related to the changes of hemodynamic parameters only in the immediate postoperative period.

Pediatric reference intervals for FSH, LH, estradiol, T3, free T3, cortisol, and growth hormone on the DPC IMMULITE 1000

Background We studied serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), triiodothyronine (T3), free T3 (FT3), cortisol and growth hormone (GH) concentrations in a population of pediatric patients. The reference intervals were determined separately for females and males stratified by age groups to assess age- and sex-related differences. Our objective was to obtain reference intervals for the 7 serum analytes for our pediatric population using the IMMULITE 1000 system. Methods Serum samples of 800 in- and out-patients, newborn to 19 years old were analyzed using the DPC IMMULITE 1000 chemiluminescent immunoassay system. Results and conclusions We report pediatric reference intervals for FSH, LH, E2, T3, FT3, cortisol, and GH. These reference intervals provide the basis for clinical interpretation of laboratory results using the IMMULITE 1000 system and the assessment of child development.

Endocrine Disruptive Effects of Polychlorinated Biphenyls on the Thyroid Gland in Female Rats

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants. Aroclor 1221 (A1221) and Aroclor 1254 (A1254) are commercial PCB mixtures with low and high number of chlorination, respectively. We have comparatively investigated effects of A1221 and A1254 on serum levels of thyroid hormones and thyroid gland histology in adult female Wistar rats. Animals were subcutaneously injected with A1221 (10 mg/kg) or A1254 (10 mg/kg) for six weeks. One group of animals served as control. At the end, all animals were decapitated and trunk blood collected. Serum levels of triiodothyronine (T3) and thyroxine (T4) were measured by the electrochemiluminescence immunoassay method. Thyroid glands were removed for histopathological examination under light microscopy. Serum total T4 levels were significantly increased in A1221- and A1254-treated rats (p < 0.05). Serum free T4 levels were significantly increased in the A1254-treated rats (p < 0.01), but not in the A1221-treated rats. In contrast, the treatment with A1221 caused a significant increase in serum free T3 concentrations (p < 0.05) but not with A1254. Notably, either A1221 or A1254 caused distinct histopathological changes, such as formation of many microfollicles in the thyroid gland, which mimic the changes seen in thyrotoxicosis. In conclusion, both PCB mixtures induce toxic effects in the thyroid gland regardless of their degree of chlorination. We suggest that these environmental contaminants may disrupt thyroid hormone homeostasis in exposed individuals and thus pose a threat to human health.

Influence of Low Protein Diet on Nonthyroidal Illness Syndrome in Chronic Renal Failure

Renal failure causes alterations in thyroid hormone metabolism known as nonthyroidal illness syndrome. In the present study we have examined the effect of a low protein diet (LPD) on circulating levels of hormones of the pituitary-thyroid axis, and tumor necrosis factor alpha (TNF-alpha) in patients with chronic renal failure. Seventeen subjects with conservatively treated chronic renal failure (estimated creatinine clearance 39.5+/-11.1 mL/min) were studied before and after 8 wk of dietary intervention (0.6 g/kg of ideal body mass protein, 30% of calories derived from fat, 62% of calories derived from carbohydrates, and 10 mg/kg of phosphorus). Body fat and fat-free mass remained unchanged. Urea and TNF-alpha serum concentrations significantly decreased, whereas T3 and total and free T4 serum concentrations increased significantly. Triiodothyronine level after treatment correlated negatively with baseline urea level. Changes in T3, T4, and fT4 serum concentrations as well as calculated peripheral deiodinase activity correlated negatively with their baseline values. Alterations in TNF-alpha correlated positively with protein intake, whereas changes in T4 and T4/TSH were inversely related to vegetal protein intake. In conclusion, low protein, low phosphorus diet, which is often prescribed to patients with moderate impairment of renal function, exerts a beneficial effect on low T3 syndrome coexisting with renal failure. The effect of low protein diet on the pituitary-thyroid axis is dependent on the degree of renal functional impairment and LPD-induced decrease in TNF-alpha may also contribute to the observed effects of dietary treatment.

Administration of a single dose of recombinant human thyrotrophin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres

Patients with very large multinodular goitres, frequently found among elderly people, often suffering from cardiovascular or other disabling disorders, may be considered as unsuitable for surgery. We have evaluated the feasibility of relatively high-dose 131I therapy in such patients. As subclinical or clinical hyperthyroidism is commonly found in these patients, associated with a low radioiodine (RAI) uptake at 24 h, we pretreated a group of patients with a single intramuscular injection of recombinant human TSH (rhTSH 0.45 mg) in order to increase the uptake of the therapeutic dose of RAI. Forty-one patients with large, long-standing multinodular goitres, were recruited for this study. After a careful and detailed clinical and laboratory evaluation, 34 patients (28 women, six men) were included and randomly assigned to group 1 (control, n = 17, 15 women, two men, age 63.1 +/- 11.2 years) receiving only RAI. Patients in group 2 (n = 17, 13 women, four men, age 63.6 +/- 12.3 years) received the therapeutic dose of RAI, having been pretreated (24 h) with 0.45 mg of rhTSH. Both groups of patients were submitted to a low iodine diet, 4-6 months before RAI treatment, while seven thyrotoxic patients also received methimazole (40 mg/day) until they reached euthyroidism. Ultrasonographic studies were performed for all patients and fine-needle aspiration biopsy (FNAB) were performed on one or two nodules before RAI treatment. RAI was given as a single oral dose to the hospitalized isolated patients. Blood samples for thyroid function tests and serum thyroglobulin (Tg) were collected daily during the first week following RAI treatment, and at 1, 3, 6, 9 and 12 months thereafter. Goitre volume was estimated by computed tomography scan. Thyroid function tests (total T3, free T4, TSH and serum Tg) were assayed with commercial kits. Urinary excretion of iodine was assayed by the Sandell-Kolthoff method. After the RAI therapeutic dose, serum thyroid function tests were carried out daily for the first week and then on a monthly basis (1, 3, 6, 9 and 12 months). Serum TSH levels rose to a peak level of 45.9 +/- 19.1 mU/l (24 h) in group 2 returning to normal at 72 h. Free T4 serum concentrations rose significantly to 59.35 +/- 21.61 pmol/l at 48 h (in group 2) returning to normal at 7 days. Similarly, serum TT3 also peaked above normal levels only in group 2 (6.12 +/- 1.89 nmol/l) at 24 h. Serum Tg increased in both groups (significantly higher in group 2) and remained elevated during the following 12 months. Both groups had a significant reduction in goitre volume at 12 months (group 2: 57.8%vs. group 1: 39.7%, P < 0.05). Hypothyroidism was detected after RAI treatment, respectively, in 21.4% (group 1) and 64.7% (group 2), of the patients at 12 months. Our results indicate that the use of hTSH increased the efficacy of the RAI therapeutic dose. This was basically due to an increased uptake of the radionuclide (as a consequence of the higher serum TSH levels) and a more extensive distribution of 131I within the nodules of the multinodular goitre. A more intense radiation effect was reflected in there being a higher output of serum Tg and thyroid hormones (group 2). As a consequence this group had a significantly higher reduction of the goitre volume. Also incidence of hypothyroidism post-RAI was significantly higher in group 2. We concluded that pretreatment with rhTSH in elderly patients with large multinodular goitres increases the uptake of the RAI therapeutic dose, thereby significantly reducing the multinodular goitre volume and relieving the compressive symptoms with relatively few side-effects.

Serum concentrations of adipocytokines in patients with hyperthyroidism and hypothyroidism before and after control of thyroid function

Adipose tissue is a hormonally active system that produces and releases different bioactive substances. Leptin, adiponectin and resistin are some of the recently discovered adipocytokines that participate in the regulation of intermediate metabolism. The aim of this study was to evaluate the circulating levels of leptin, adiponectin and resistin in patients with thyroid dysfunction before and after normalization of thyroid function with appropriate therapy. We studied 20 patients with hyperthyroidism (16 women and 4 men; mean age 47.2 +/- 3.9 years) and 20 patients with hypothyroidism (17 women and 3 men; 51.5 +/- 4.1 years). A group of 20 euthyroid subjects served as control group. Patients were evaluated at the time of diagnosis and again after normalization of thyroid function with appropriate therapy. Serum concentrations of free T4 (FT4), total T3, TSH, insulin, leptin, adiponectin and resistin were measured in all subjects. Hyperthyroid patients showed significantly decreased leptin levels in comparison with controls (11.0 +/- 1.1 vs. 30.4 +/- 5.0 microg/l, P < 0.001). No significant differences in adiponectin levels between hyperthyroid and control groups were found (27.8 +/- 4.0 vs. 46.0 +/- 12.0 mg/l, NS). Patients with hyperthyroidism exhibited reduced resistin levels in comparison with euthyroid subjects (6.4 +/- 0.8 vs. 8.4 +/- 0.7 microg/l, P < 0.05). Normalization of circulating thyroid hormone was accompanied by a nonsignificant increase in leptin levels (12.9 +/- 1.7 microg/l, P < 0.01 vs. control) and no significant modification both in adiponectin (32.0 +/- 7.1 mg/l, NS) and resistin (5.4 +/- 0.7 microg/l, NS) levels. Adjustment of adipocytokine concentrations for body mass index (BMI) showed that treatment of hyperthyroidism induced a significant reduction in adjusted resistin concentrations (0.21 +/- 0.03 vs. 0.28 +/- 0.03 microg/l/BMI units, P < 0.05), with no changes in adjusted leptin and adiponectin. Hypothyroid patients showed significantly lower leptin levels compared with the controls (16.0 +/- 3.5 vs. 30.4 +/- 5.0 microg/l, P < 0.05). Adiponectin levels in patients with hypothyroidism (71.8 +/- 16.0 mg/l) were similar to those in the control group and were not modified with therapy. Resistin levels were significantly reduced among hypothyroid patients (5.8 +/- 1.0 microg/l, P < 0.05), and were not increased after levothyroxine therapy. A significant rise in BMI-corrected leptin levels was observed after replacement therapy, with no changes in adiponectin- and resistin-corrected values. The results suggest that (1) low serum leptin levels are present in both hyperthyroid and hypothyroid patients but are only increased after therapy in the latter; (2) resistin might be implicated in the insulin resistance state that accompanies thyrotoxicosis; and (3) inadequate secretion of adiponectin seems to have no role in metabolic changes associated with thyroid dysfunction.

Follow-up of newborns with elevated screening T4 concentrations

ObjectiveTo determine the type and incidence of hyperthyroxinemic disorders detected by follow-up of infants with elevated screening total T4 (TT4) values. Study designInfants born in Oregon with a screening TT4 measurement >3 SD above the mean were offered enrollment. Serum TT4, free T4, total T3, free T3, and thyroid-stimulating hormone concentrations were measured in study infants and their mothers. ResultsOver a 20-month period, 101 infants (51 boys) and their mothers enrolled in the study (of 241 eligible infants), from a total screening population of 80,884; 17 infants were identified with persistent hyperthyroxinemia (TT4 >16 μg/dL). Ten had thyroxine-binding globulin excess (1:8088), 5 had evidence for increased T4 binding but not thyroxine-binding globulin excess (1:16,177), and 2 had findings compatible with thyroid hormone resistance (1:40,442); the other 84 infants had transient hyperthyroxinemia. Sequence analysis revealed a point mutation in the thyroid hormone receptor-β gene in one infant with thyroid hormone resistance; no mutation was identified in the other infant. ConclusionsAlthough neonatal Graves' disease occurs in approximately 1 in 25,000 newborn infants, we did not detect any case among 80,884 infants, most likely because their mothers were receiving antithyroid drugs. Although the other hyperthyroxinemic disorders in the aggregate occur frequently (1:4758) and may benefit from detection, in general they do not require treatment.