Age-related variations in acylcarnitine and free carnitine concentrations measured by tandem mass spectrometry

BACKGROUND: The acylcarnitine profiles obtained from dried blood spots on "Guthrie cards" have been widely used for the diagnosis and follow-up of children suspected of carrying an inherited error of metabolism, but little attention has been paid to potential age-related variations in the reference values. In this study, we evaluated the variations in free carnitine and acylcarnitine concentrations with age, as measured by tandem mass spectrometry. METHODS: Filter-paper blood spots were collected from 433 healthy individuals over a period of 17 months. Eight age groups were defined: cord blood, 3-6 days (control group), 15-55 days, 2-18 months, 19-59 months, 5-10 years, 11-17 years, and 18-54 years. Free carnitine and acylcarnitines were measured for each individual. Mean values were calculated for each age group and compared with those for the control group. RESULTS: Free carnitine was significantly higher in older children than in newborns (P <0.05), but the concentrations of several acylcarnitines tended to be significantly lower in cord blood and in groups of older children than in the control group. Only minor sex-related differences were observed. CONCLUSION: Although the risk of underdiagnosis of fatty acid oxidation disorders with the use of newborn values as reference can be considered as small, in some circumstances the use of age-related reference values may have a potential impact on the diagnosis and management of inherited errors of metabolism.     

Circulating 3,3', 5'-triiodothyronine (reverse T3) in the human newborn.

Serum concentrations of 3,3',5'-triiodothyronine (reverse T3 rT3), 3,3',5-triiodothyronine (T), and thyroxine (T4) were measured in cord blood and invenous blood samples obtained between 2 h and 30 days of postnatal life from healthy full-term newborn infants. The mean serum rT3 concentration of (mean plus or minus SE) 151 plus or minus 12 ng per 100 ml in 18 cord blood samples was significantly higher than the level (41 plus or minus 2 ng per 100 ml) in 27 normal adult sera; the corresponding mean serum T4 of 12.7 plus or minus 0.8 mug per 100 ml in cord blood also was significantly higher than that (8.6 plus or minus 1.9 mug per 100 ml) in 108 normal adults. By contrast, the mean serum T3 concentration in 15 cord blood samples, 24 plus or minus 3 mg per 100 ml, was significantly lower than the value of 126 plus or minus 3.2 ng per 100 ml measured in 108 normal adults. At 4 h of age the mean serum rT3 concentration (165 plus or minus 13 ng per 100 ml) in six newborns was 4ot significantly different from that in paired cord blood samples (194 plus or minus 25 ng per 100 ml); on the other hand, whenever, studied, the mean serum T3 and T4 levels were significantly higher at 4 h than at birth. The failure of serum rT3 concentrations to rise after delivery in response to the early neonatal thyrotropin (TSH) surge and at a time when serum T3 and T4 levels increase significantly prompted a study of the rT3 response to 10 IU of intramuscular TSH in three healthy adult subjects. Just as in the newborns, serum rT3 failed to rise appreciably in these subjects, even though serum T3 and T4 showed the expected increments. Serum rT3 concentrations in 1-4 day-old newborn infants did not differ significantly from values in the cord blood but were significantly lower in older neonates. The mean serum rT3 level in 5-7-day-old infants was higher than that in normal adults, but in 9-11 day and 20-30-day-old infants, mean rT3 values were statistically similar to the adult value. The mean serum T3 concentrations in neonates between 1-30 days old were either higher than or comparable to the values of normal adults. The mean serum T4 concentrations in neonates between birth and 30 days of age were significantly higher than the mean adult level. The mean serum rT3 to T4 ratios (rT3/T4) were elevated in 1-4-day-old neonates; the values in older neonates were similar to those in adults. These results suggest that (a) factors other than TSH are important modulators of serum rT3 in man; (b) high serum rT3 concentration in the newborn becomes comparable to that in the normal adult by 9-11 days of neonatal life.     

Technical evaluation of a new immunoradiometric and a new immunoluminometric assay for thyroglobulin

BACKGROUND: After removal of differentiated thyroid carcinoma (DTC), serum thyroglobulin (Tg) can indicate persistent or recurrent disease. We describe two novel two-step assays designed to measure low Tg concentrations. METHODS: We evaluated prototypes of the new IRMA, DYNOtest Tg-pluS, and the new immunoluminometric assay (ILMA), LUMItest) Tg-pluS. In the first step, a high-salt incubation buffer leads to dissociation of Tg-Tg antibody complexes in serum and is intended to reduce nonspecific interference and interference of potential Tg autoantibodies in the system. We studied recovery of human Tg (from thyroid glands) added to horse serum. We also studied 58 patients with DTC in whom Tg values under thyroid-stimulating hormone (TSH) suppression and TSH stimulation (without thyroxine) were available. RESULTS: The detection limits were 0.04 microg/L Tg for the IRMA and 0.02 microg/L for the ILMA. Intraassay imprecision (CV) was <10% over the range of the calibration curve in both assays. The day-to-day CV was <20% at 0.2 microg/L for the IRMA and at 0.06 microg/L for the ILMA. No high-dose hook effect was seen with up to 200 000 microg/L added Tg or in dilutions of 12 patient sera with Tg values of 307-38 880 microg/L. Mean recovery of 50 microg Tg/L was 96% in those patients. Among 77 samples with Tg antibody values of 65.2-8150 kilounits/L, recovery by the IRMA was disturbed in 7 cases (9%) and by the ILMA in 9 cases (12%). Tg increased as measured in both assays in 50 of 58 patients after thyroxine withdrawal. CONCLUSIONS: The new assays have improved precision for Tg <1 microg/L, and even low measured Tg concentrations respond physiologically to thyroxine withdrawal. The assays are free of a high-dose hook effect up to a Tg concentration of at least 38 000 microg/L and may further reduce Tg antibody interference.     

Reference intervals from birth to adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4, thyroxine binding globulin (TBG) and thyrotropin (TSH).

Disorders in thyroid function can impair normal development in children. Therefore it was our aim to establish reference intervals for serum triiodothyronine (T3), free T3 (fT3), thyroxine (T4), free T4 (fT4), thyroxine binding globulin (TBG) and thyrotropin (TSH) which are applicable from birth to adulthood by using the non-isotopic automated chemiluminescence immunoassay system, Immulite (DPC Los Angeles, USA). Serum samples from 762 euthyroid newborns, children and adolescents (369 female, 393 male; age 1 day to 19 years) were examined; of these, 381 were classified as pubertal. Due to non-normal distribution, the 2.5th, 50th and 97.5th percentiles (the central 95% interval) were calculated for each group. The median concentrations of T4, fT4 and TSH were up to 3.2-fold higher during the first 2 weeks, while T4 increased during the first month of life. The concentrations in all age groups showed no sex differences. From 1 year onwards, the concentration of all parameters tended to decrease until adult age, with the exception of TBG which increased by >60% (p<0.02) and reached a maximum at approximately 5 years of age. The findings underscore the fact that thyroid hormones are not associated with sexual development, except for TBG, which decreased slightly (p<0.04) between Tanner stages 1 and 5. However, the reference intervals established here demonstrate that marked changes occur in concentrations of thyroid hormones after the neonatal period. Our findings complement these of earlier studies. The developed reference intervals can be used to assess the thyroid status of patients, particularly if the measurements are done on the Immulite/Immulite 2000 system.     

Continuous age-dependent reference ranges for thyroid hormones in neonates, infants, children and adolescents established using the ADVIA Centaur Analyzer.

In neonates, infants, children and adolescents serum concentrations of the thyroid hormones show a clear age dependency. Currently, age-dependent thyroid hormone reference ranges for the new ADVIA Centaur immunoanalyzer are not available. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), total thyroxine (T4), free triiodothyronine (FT3) and total triiodothyronine (T3) were determined in the sera of 460 healthy children aged 0 daysto 18 years from an inland (n=308) and a seaside city (n=152) using the Bayer ADVIA Centaur analyzer. Square root functions defining the upper and lower limit of the continuous age-dependent reference range and the median line for each thyroid hormone were estimated applying a parametric regression technique. Continuous age-dependent reference ranges show a better fit to the obtained data than discontinuous reference ranges. The median TSH and FT4 concentrations decrease within the first year of life and are nearly constant until 18 years of age. The median T4 decreases within the entire age interval, whereas the median FF3 is constant. The median T3 increases within the first year of life and decreases afterwards. The calculated continuous reference ranges for T4, T3 and partly FT4 are consistent with published reference ranges. However, the reference ranges obtained for FT3 and partly TSH differed considerably, compared to published reference ranges. No significant residence- or sex-specific effects on age-adjusted hormone concentrations were found except for a slight residence-specific effect on age-adjusted FT4, which was probably due to assay imprecision. Due to the lack of international standardization, the assay-specific evaluation of reference ranges is very important. Continuous age-dependent reference ranges comply better with the biological reality and are more reliable than discontinuous reference ranges.     

Hypothalamic-pituitary-thyroid axis status of humans during development of ageing process.

We have investigated hypothalamic-pituitary-thyroid function in four groups of healthy elderly male humans. Group A (n=18, age range 20-45 years) served as healthy younger controls, group B (n=10, age range 50-60 years), group C (n=15, age range 60-70 years) and group D (n=16, age range 70-85 years) are the subjects of this study. Groups C and D showed significantly lower T3 and thyroid-stimulating hormone (TSH), and higher T4 levels with respect to controls. Evidence for TSH circadian modulation was found in group A (control) and group B subjects. The TRH-stimulated TSH peak was reduced among all elderly subjects with respect to controls and appeared to be pronounced with the ageing process. The maximal prolactin response was also inhibited with increasing age. Our study suggest that a resetting of the pituitary threshold for the TSH feed-back suppression along with complex alterations in peripheral thyroid hormone concentrations may, in turn, develop in older people and that appeared to manifest prominently among the oldest population. Additionally, the TSH nocturnal response appeared to be impaired with increasing age indicating an alteration of hypothalamic function.     

Age influences TSH serum levels after withdrawal of l-thyroxine or rhTSH stimulation in patients affected by differentiated thyroid cancer.

Recombinant human TSH (rhTSH) has been recently suggested for radioiodine ablation in patients with differentiated thyroid cancer (DTC). To date, studies are still not available about the effectiveness of rhTSH stimulation depending on the age, since serum TSH clearance may be different in younger and in older patients. The aim of this study was to investigate the influence of age to serum TSH levels after rhTSH stimulation and thyroid hormone withdrawal (THW). We retrospectively evaluated two groups of consecutive DTC patients: group 1 (311 patients, age 49.0+/-13.6 years, ranging 15-86) underwent rhTSH stimulation 6-12 months after thyroid ablation (rhTSH-group); group 2 (84 patients, age 46.9+/-13.5 years, ranging 20-77) was followed by THW (THW-group). The influence of age, gender, body mass index and body surface area to serum TSH levels were evaluated in both groups. RhTSH-group: on day 5 (d5), TSH levels were 32.7+/-21.4 microU/ml (range 0.8-136.6). By univariate analysis, d5-TSH was positively related to age (r=0.27, p=0.0001) and no correlations were found with the other parameters. At multivariate analysis, both age and gender (female) were independently associated with d5-TSH levels. THW-group: after thyroid hormone withdrawal, TSH levels were 71.1+/-36.4 microU/ml (range 8.5-200). At univariate analysis, only age was significantly and negatively related to serum TSH levels (r=-0.31, p=0.004). Our data indicate that age and gender seem to positively influence serum TSH levels after rhTSH stimulation. An opposite effect of age on serum TSH levels has been observed after THW. Therapeutic implications ((131)I-treatment) of these findings have to be better investigated in prospective studies.     

A radioimmunoassay for human thyroglobulin: methodology and clinical applications

A specific double-antibody radioimmunoassay with a sensitivity of 2.5 ng/ml has been developed for measuring thyroglobulin (Tg) in human serum. As endogenous anti-Tg antibodies in serum interfere in the assay, only sera with a negative tanned red cell (TRC) test are suitable for analysis. Tg was detectable in 84.7% of the euthyroid subjects, with a mean value of 6.1 (values ranging from nondetectable to 43.0 ng/ml). Values were significantly higher in women than in men. Tg release by the thyroid appears to be under pituitary control, as suggested by TSH stimulation and T3 suppression tests. Elevated Tg levels were found in hyperthyroidism, simple goitre, and differentiated thyroid carcinoma. The significance of circulating Tg and the possible application of the Tg RIA are discussed.     

Thyroid function and prevalence of anti-thyroperoxidase antibodies in a population with borderline sufficient iodine intake: influences of age and sex

BACKGROUND: We present a large European population-based study of thyroid function, performed in a population with longstanding borderline sufficient iodine intake. METHODS: The Nijmegen Biomedical Study is a population-based survey conducted in the eastern part of The Netherlands. Randomly selected inhabitants received a postal questionnaire on lifestyle and medical history, which was filled out by 9371 individuals (41.7%). We measured serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), and anti-thyroperoxidase antibodies (TPOAbs) in 6434 responders. A reference population of 5167 individuals was selected by excluding those at risk for thyroid disease. RESULTS: Overt thyrotoxicosis was found in 0.4% of the total population and subclinical thyrotoxicosis in 0.8%. Overt hypothyroidism was found in 0.4% and subclinical hypothyroidism in 4.0%. In individuals older than 60 years, mean FT4 concentrations increased with age. Mean TSH decreased with age, from 1.46 mIU/L at 18-24 years to 1.07 mIU/L after 85 years. The mean TSH in the total population did not differ from the mean TSH in the reference population; the exclusion of those at risk for thyroid disease, however, lowered the upper limit of the TSH reference interval considerably. In the total population, 8.6% of males and 18.5% of females had positive TPOAbs. The presence of TPOAbs was associated with abnormally high and low TSH concentrations. CONCLUSION: In inhabitants of the eastern part of The Netherlands, serum TSH gradually decreases with age, whereas after age 60, serum FT4 increases, possibly because of the development of thyroid autonomy after longstanding borderline sufficient iodine intake.     

Lipid Pentad Index: A novel bioindex for evaluation of lipid risk factors for atherosclerosis in young adolescents and children of premature coronary artery disease patients in India

OBJECTIVE: To evaluate the role of non-conventional lipid risk factors like Lipoprotein(a) [Lp(a)], Apolipoprotein A-I (Apo A-I) and Apolipoprotein B-100 (Apo B-100) and other conventional lipid profile parameters in children and adolescents of premature coronary artery disease (CAD) patients in India; and thereby explain the highest occurrence of premature CAD in this population. METHODS: Forty-five children and adolescents of premature CAD patients (cases, mean age 12.08+/-3.71 years) and forty-five age and sex matched children and adolescents of healthy parents without any history or clinical evidence suggestive of CAD were studied (controls, mean age 12.14+/-3.91 years). RESULTS: We found a significant increase in mean levels of Lp(a), Apo B-100, Total cholesterol (TC), Low Density Lipoprotein-Cholesterol (LDL-C) and Triglyceride (TG) in cases than controls. In contrast, Apo A-I and High Density Lipoprotein-Cholesterol (HDL-C) values decreased. Lipid Tetrad Index (LTI) and Atherogenic Index in Indian children and adolescents were also calculated. Kolmogorov D statistic and cumulative probability plot suggest that the new Lipid Pentad Index (LPI) defined by us is able to discriminate case and control populations more precisely than the existing LTI and Atherogenic Index. CONCLUSIONS: The new proposed LPI appears to be a better indicator of lipid risk factors in children and adolescents of premature CAD patients from India, than the prior LTI and Atherogenic Index.     

Population-specific reference values for thyroid hormones on the Abbott ARCHITECT i2000 analyzer.

Reliable reference ranges are important in the interpretation of laboratory data, and it is incumbent on each laboratory to verify that the ranges they use are appropriate for the patient population they serve. The objective of this study was to determine population-specific reference ranges for thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and total triiodothyronine (TT3) on the Abbott ARCHITECT 12000 analyzer. For this study, we used human serum samples collected from a population in Castilla y León, Spain. Serum samples were collected from 304 individuals (male, n = 151; female, n = 153; age 12-94 years) representing outpatients (n=100), hospitalized patients (n = 104) and apparently healthy subjects (n = 100). Individuals taking any medications, with a history of thyroid disorder, or severe non-thyroidal illness were excluded from the study. For healthy subjects, the following reference intervals were determined: TSH, 0.51-5.95 mlU/l; fT4, 0.84-1.42 ng/dl (10.77- 18.21 pmol/l); fT3, 1.48-3.37 pg/ml (2.27-5.18 pmol/l); and TT3, 0.65-1.46 ng/ml (1.00-2.24 nmol/l). In this group, TSH and fT4 showed significant differences between men and women, but fT3 and TT3 did not. Conversely, fT3 and TT3 showed significant age-related differences, but TSH and fT4 did not. Within the outpatient group, no significant differences were seen between men and women for any of the hormones, but age-related differences were significant for fT3 and TT3. Within the hospitalized patient group, significant differences between men and women were found for TSH only, and age-related differences were significant for TSH, fT3 and TT3. Our findings are basically in accordance with previously published results for fT3, TT3 and TSH, but for fT4 our results differ from other data in the literature. This highlights the need for laboratories to confirm that the reference ranges they use are appropriate for the population they serve.     

A novel method of transport for thyroxine (T4), cortisol, thyroid stimulating hormone (TSH), parathormone (PTH), and insulin

A simple and convenient method of transport of serum in the form of protein disc on water resistant medium is described. The method was used to study the stability of thyroxine (T4), cortisol, thyroid stimulating hormone (TSH), parathormone (PTH) and insulin. The mean recoveries of these hormones were between 98 and 100%. The standard deviations of duplicates of assays for protein disc samples were comparable to that of serum samples except in assays using enzyme immunoassay techniques. The correlation coefficients of the results between the serum and protein disc samples were satisfactory ranging from 0.86-0.99. The proposed method could be used for interlaboratory referral of serum.     

Sonographic measurement of calcaneal volume for determination of skeletal age in children

PURPOSE: The purposes of this study were first to prospectively evaluate the feasibility of using sonographic measurements of volume of the ossified part of the calcaneus to determine skeletal age in healthy children and second, to provide normal ranges of this volume by sex and age up to 6 years. METHODS: Four hundred normal girls and boys ranging in age from 1 day to 6 years were examined sonographically to determine the volume of the calcaneal ossification center. The children were randomly divided into 2 groups. The first group (300 children) was used to determine normal values for the mean calcaneal volume by age and sex. The second group (100 children) was used to validate those normal values. RESULTS: The sonographically determined volume of the calcaneal ossification center correlated well with the chronologic age of the children. The calcaneal ossification centers of boys were larger than those of girls within the same age groups from ages 2 to 10 months, but from 11 months to 6 years old, they were larger in the girls. The differences, however, were not statistically significant. The volume of the calcaneal ossification center increased the most between the first and second years of life, reaching 183% and 140% in girls and boys, respectively. Using the normal values obtained from the first group, we correctly predicted the chronologic age in 91% of children in the validation group. Among the remaining 9%, the error in prediction of chronologic age never exceeded 1 age interval. CONCLUSIONS: The use of sonography provides a quantitative means of measuring calcaneal volume, and its use is feasible for determining skeletal age in children. The normal values we obtained may be used as a baseline for sonographic assessment of skeletal maturation and diagnosis of growth retardation.     

Thyroid function tests, serum lipids and gender interrelations in a middle-aged population.

OBJECTIVE: To study the value of screening for thyroid function in a screening program for hyperlipidaemia. DESIGN: A screening study in primary health care. SETTING: All individuals in a defined rural area, S?der?kra, Sweden, aged 40-59 years were invited to a screening programme at the local primary health care centre. PARTICIPANTS: 782 individuals were invited for screening. Blood samples were obtained from 88% of the invited males and from 92% of the females. MAIN OUTCOME MEASURES: Thyroid function tests (thyroid stimulating hormone (TSH) and free T4), serum lipids (total-cholesterol, HDL-cholesterol, LDL-cholesterol and s-triglycerides), b-glucose and body anthropometry (body mass index and waist to hip circumference) were measured. RESULTS: 0.57% of males and 1.13% of females showed evidence of hypothyroidism as defined by a TSH value greater than 3.75 mU/l of those with s-cholesterol concentration above 7 mmol/l. In addition, higher TSH values in females were associated with higher s-cholesterol, s-LDL-cholesterol and s-triglycerides. CONCLUSION: It seems appropriate to screen for hypothyroidism in females with s-cholesterol above 7.0 mmol/l.     

Triiodothyronine, Thyroxine, and Iodine in Purified Thyroglobulin from Patients with Graves'' Disease

Previous studies have suggested that there is an overproduction of triiodothyronine (T(3)) relative to thyroxine (T(4)) in patients with thyrotoxicosis associated with Graves' disease. To evaluate whether or not an increased ratio of T(3) to T(4) in thyroidal secretion could be contributing to this relative T(3) hyperproduction, T(3), T(4), and iodine were measured in thyroglobulin (Tg) from controls and patients with Graves' disease who had been treated either with propranolol only or with antithyroid drugs plus iodide before surgery. To avoid possible artifacts associated with pulse labeling and chromatography, T(3) and T(4) were determined by radioimmunoassay of Pronase hydrolysates of purified Tg. Results of analyses of Tg from six control patients and seven with Graves' disease, not receiving thiourea drugs or iodide, showed that the iodine content of Graves' disease Tg was not different from normal. Both contained 3.4 residues of T(4)/molecule Tg, but there was 0.39+/-0.08 (mean+/-SD) residue of T(3)/molecule Tg in Graves' Tg as opposed to 0.23+/-0.07 residue T(3) molecule Tg in controls matched for iodine content (P < 0.01). This difference resulted in a significantly lower T(4)/T(3) molar ratio (9+/-2) in Graves' Tg as opposed to control (15+/-2, P < 0.001). In Tg from patients with treated Graves' disease, iodine, T(3), and T(4) were reduced, but the reduction in the latter was more substantial, resulting in a T(4)/T(3) molar ratio of 3.4+/-1. Fractionation of Tg from all groups by RbCl density gradient ultracentrifugation indicated that at physiological levels of Tg iodination, the molar ratio of T(3)/Tg was consistently higher in Graves' disease. The specific mechanism for this difference is not known, but it is not due to iodine deficiency. If T(3) and T(4) are secreted in this altered ratio in patients with Graves' disease, the magnitude of the difference could explain the relative T(3) hyperproduction which is characteristic of this state.     

Total and free triiodothyronine and thyroid-binding globulin concentration in elderly human persons.

Total thyroxine (TT4) and triiodothyronine (TT3) were found to be low in healthy elderly subjects with a preferential decrease of triiodothyronine. In order to determine the importance of these findings 22 healthy elderly subjects were examined. Free triiodothyronine (FT3), thyroid binding globulin (TBG) concentration and basal thyroid stimulating hormone (TSH) were measured by radioimmunoassay. Liver enzymes, cholesterol and total protein concentration were also assayed. TBG was significantly increased compared to a middle-aged group and did not correlate with TT4, TT3 and TSH. Basal TSH values were in the normal range and could be detected in all the elderly subjects in contrast to undetectable values in 40% of the younger subjects. FT3 determined directly did not correlate with the values calculated according to the law of mass action. According to the FT3 values the elderly subjects could be subdivided into three groups independent of their TT4, TT3, TBG and TSH values. FT3 was undetectable in one group, in the low normal to normal range in another and elevated in the third group. Our results suggest that 1) there is no correlation between TT4, TT3, elevated TBG and FT3 determined directly or by calculation, 2) basal TSH values seem to indicate possible hypothyroidism in elderly persons which is correlated with elevated cholesterol levels and 3) FT3 measured directly subdivides this metabolic state into three groups possibly depending on the intracellular concentration of T4.     

Thyroid autoimmunity in children and adolescents with type 1 diabetes: a multicenter survey

OBJECTIVE: To investigate thyroid autoimmunity in a very large nationwide cohort of children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Data were analyzed from 17,749 patients with type 1 diabetes aged 0.1-20 years who were treated in 118 pediatric diabetes centers in Germany and Austria. Antibodies to thyroglobulin (anti-TG) and thyroperoxidase (anti-TPO) were measured and documented at least once in 7,097 patients. A total of 49.5% of these patients were boys, the mean age was 12.4 years (range 0.3-20.0 years), and the mean duration of diabetes was 4.5 years (range 0.0-19.5 years). A titer exceeding 100 units/ml or 1:100 was considered significantly elevated. RESULTS: In 1,530 patients, thyroid antibody levels were elevated on at least one occasion, whereas 5,567 were antibody-negative during the observation period. Patients with thyroid antibodies were significantly older (P < 0.001), had a longer duration of diabetes (P < 0.001), and developed diabetes later in life (P < 0.001) than those without antibodies. A total of 63% of patients with positive antibodies were girls, compared with 45% of patients without antibodies (P < 0.001). The prevalence of significant thyroid antibody titers increased with increasing age; the highest prevalence was in the 15- to 20-year age group (anti-TPO: 16.9%, P < 0.001; anti-TG: 12.8%, P < 0.001). Thyroid-stimulating hormone (TSH) levels were higher in patients with thyroid autoimmunity (3.34 microU/ml, range 0.0-615.0 microU/ml) than in control subjects (1.84 microU/ml, range 0.0-149.0 microU/ml) (P < 0.001). Even higher TSH levels were observed in patients with both anti-TPO and anti-TG (4.55 microU/ml, range 0.0-197.0 microU/ml). CONCLUSIONS: Thyroid autoimmunity seems to be particularly common in girls with diabetes during the second decade of life and may be associated with elevated TSH levels, indicating subclinical hypothyroidism.     

妊娠期甲状腺减退患者妊娠期间左旋甲状腺素钠替代剂量探讨

目的 探讨妊娠甲状腺功能减退症(甲减)妊娠期间左旋甲状腺素钠替代剂量。方法 2014年3月至 2015年3月入选在我院分娩的274例妊娠合并甲减孕妇,其中亚临床型甲减组(SHT)207例,临床型甲减组(HT)67 例,以妊娠早期促甲状腺激素(TSH)<2.5mU/L,妊娠中晚期TSH<3.0mU/L为治疗目标,根据TSH 及孕周变化 予调整左旋甲状腺素钠治疗剂量。并根据TSH 水平分为TSH1 组,TSH3~5mU/L,TSH2 组,TSH5~8mU/L, TSH3 组,TSH8~10mU/L,TSH4 组,TSH10~15mU/L,TSH5 组,TSH15~20 mU/L 和TSH6 组,TSH>20 mU/L。结果 各组达治疗目标后,SHT 组T1、T2 和T3 期,左旋甲状腺素钠剂量分别为:(52.26±19.43)μg、 (56.69±20.58)μg和(56.76±19.99)μg;HT组在T1、T2 和T3 期,左旋甲状腺素钠剂量分别为:(64.58±50.26) μg、(66.67±47.64)μg和(65.91±34.06)μg;TSH1 组-TSH6 组左旋甲状腺素钠剂量分别为(45.65±16.08)μg、 (72.32±14.85)μg、(75.00±13.06)μg、(112.5±53.03)μg、(137.5±23.18)μg和(150.00±23.13)μg;T1、T2 和 T3 妊娠期TSH2、TSH3、TSH4 和TSH5 组左旋甲状腺素钠剂量高于TSH1 组(P <0.05);TSH4、TSH5 和TSH6 组 左旋甲状腺素钠片剂量高于TSH2 组(P <0.05);TSH4、TSH5 和TSH6 组高于TSH3 组(P <0.05);TSH5 和 TSH6 组高于TSH4 组(P <0.05);TSH6 组高于TSH5 组(P <0.05)。结论 妊娠期临床型甲减左旋甲状腺素钠 剂量在T1、T2 和T3 妊娠期均高于亚临床型甲减(P <0.05)。随着TSH 水平增高,所需左旋甲状腺素钠明显增加 (P <0.05)。     

Reference intervals for thyroid hormones on the architect analyser.

The objective of this study was to establish reference intervals for thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyronine (TT4) and total triiodothyronine (TT3) on the Architect i2000 analyser (Abbott). Serum samples were obtained from apparently healthy adults (n=217, age 18-90 years) excluding individuals taking oral contraceptives or under hormone replacement therapy. The second group were ambulatory euthyroid patients (n=323) excluding those with a history of thyroid disorders. We also investigated thyroid hormones in sera from euthyroid hospitalised patients (n=490) excluding those with severe non-thyroidal illness. The reference intervals for the healthy adults were for TSH 0.17-4.23 mIU/l, for FT4 11.24-26.86 pmol/l, for FT3 2.56-6.36 pmol/l, for TT4 55.8-155.1 nmol/l and for TT3 0.90-2.54 nmol/l. TSH and TT3 concentrations were similar in males and females. However, FT4, FT3 and TT4 levels exhibited significant differences between females and males. No significant differences were observed between the concentrations of TSH, FT3, TT3, FT4 and TT4 in healthy subjects and in euthyroid ambulatory patients aged 18-90 years. TSH levels in healthy subjects were the same in younger and older individuals. In contrast, in outpatients and in hospitalised patients TSH concentrations were significantly lower (20%) in subjects older than 50 years compared to those younger than 50 years. For FT3 and TT3 we consistently observed in all three study groups 6-7% and 8-12% higher concentrations in the younger (< 50 years) compared to the older (> 50 years) subjects. For FT4 and TT4 no consistent pattern of correlation with age was detectable when the three study groups were analysed independently. The reference intervals for thyroid hormones determined in this study differ considerably from values found in other European and non-European countries. This underlines the need for population-specific reference ranges.     

Observations on the maturation of thyroid function in early fetal life

Serum samples were obtained from 21 normal human fetuses after therapeutic abortion for psychiatric indications. Fetal crown-rump length ranged from 5.2 to 22.5 cm, corresponding to the gestational age of 65-168 days.Serum thyroxine, assayed by a modification of the Murphy-Pattee method, was identified in the second smallest fetus examined at 78 days gestation. Thereafter it increased rapidly, maintaining a significant linear correlation with crown-rump length until term (r = 0.800, P < 0.001). Free thyroxine (FT4) also increased in a linear relation to gestational age (r = 0.908, P < 0.001), but reached term levels by 18-20 wk. Radioimmunoassayable thyroid-stimulating hormone (TSH) was detected at 78 days gestation. Levels increased rapidly with advancing gestation, so that by 16 wk almost all were within the range of term infants. After 16 wk gestation, levels were usually greater than 4.0 muU/cc, higher than that seen in normal children.No correlation was demonstrated between the serum TSH levels and total thyroxine. TSH and FT4, however, increased in a parallel manner with a significant positive correlation. This suggested that fetal TSH secretion was responsive to FT4 levels from very early in gestation, possibly as early as 11 wk.Thyroxine-binding globulin (TBG) was detected in a fetus of 78 days gestation (1.4 mug/100 ml). Levels increased rapidly, paralleling the rise in serum thyroxine and maintaining a linear correlation with crownrump length (r = 0.864, P < 0.001). Thyroxine-binding prealbumin binding capacity (TBPA) in fetuses 14-24 wk gestation was comparable with that seen at term.When examining the distribution of tracer amounts of thyroxine-(131)I (T4-(131)I) between the thyroxine-binding proteins, it was found that a major fraction was bound to TBPA and albumin during the early part of gestation. This decreased linearly with maturation of the fetus as the fraction bound to TBG increased. By 20 wk gestation fetal TBG was able to bind 78% of tracer despite a TBG capacity of only 7.7 mug/100 ml. This appeared to be the result of relatively low concentrations of TBPA and albumin during this period of gestation. The theoretical association constant calculated for fetal and newborn TBG was found to be similar to that estimated for normal adult males and females.